The hippocampus and TNF: Common links between chronic pain and depression.

Neuroscience and Biobehavioral Reviews 53 (2015) 139–159

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

The hippocampus and TNF: Common links between chronic pain and depression Victoria Fasick a , Robert N. Spengler b , Shabnam Samankan a , Nader D. Nader a,c , Tracey A. Ignatowski a,b,d,∗ a Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States b NanoAxis, LLC, Clarence, NY 14031, United States c Department of Anesthesiology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States d Program for Neuroscience, School of Medicine and Biomedical Science, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States

a r t i c l e

i n f o

Article history: Received 21 March 2014 Received in revised form 2 February 2015 Accepted 28 March 2015 Available online 7 April 2015 Keywords: Comorbid Chronic pain Depression Brain Hippocampus Tumor necrosis factor-␣

a b s t r a c t Major depression and chronic pain are significant health problems that seriously impact the quality of life of affected individuals. These diseases that individually are difficult to treat often co-exist, thereby compounding the patient’s disability and impairment as well as the challenge of successful treatment. The development of efficacious treatments for these comorbid disorders requires a more comprehensive understanding of their linked associations through common neuromodulators, such as tumor necrosis factor-␣ (TNF␣), and various neurotransmitters, as well as common neuroanatomical pathways and structures, including the hippocampal brain region. This review discusses the interaction between depression and chronic pain, emphasizing the fundamental role of the hippocampus in the development and maintenance of both disorders. The focus of this review addresses the hypothesis that hippocampal expressed TNF␣ serves as a therapeutic target for management of chronic pain and major depressive disorder (MDD). © 2015 Elsevier Ltd. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The hippocampus and pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Pain pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Stress and pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Stress-induced analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Chronic stress and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Hippocampus and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; AR, adrenergic receptor; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; CREB, cAMP response element-binding protein; cAMP, cyclic adenosine monophosphate; ERK, extracellular signal-regulated kinase; FDA, Food and Drug Administration; GR, glucocorticoid receptor; HPA, hypothalamic–pituitary–adrenal; IDO1, indoleamine 2,3-dioxygenase 1; IL, interleukin; MAOI, monoamine oxidase inhibitor; mGlu1R, metabotropic glutamate 1 receptor; MDD, major depressive disorders; MR, mineralocorticoid receptor; mTOR, mammalian target of rapamycin; NE, norepinephrine; NK-1R, neurokinin-1 receptor; NMDA, N-methyl-d-aspartate; SP, substance P; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; trkB, tyrosine protein kinase B; TNF␣, tumor necrosis factor-␣. ∗ Corresponding author at: Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 206 Farber Hall, 3435 Main Street, Buffalo, NY 14214, United States. Tel.: +1 716 829 3102; fax: +1 716 829 2911. E-mail address: [email protected] (T.A. Ignatowski). http://dx.doi.org/10.1016/j.neubiorev.2015.03.014 0149-7634/© 2015 Elsevier Ltd. All rights reserved.

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V. Fasick et al. / Neuroscience and Biobehavioral Reviews 53 (2015) 139–159

Comorbidity of chronic pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Comorbidity theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Hippocampus in pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Cognitive dysfunction in comorbid pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. HPA axis and comorbid pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Glucocorticoids and glucocorticoid receptors in pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. Stress-induced excitatory amino acids common to pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Animal models of comorbid pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immune-neural interactions common to chronic pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Proinflammatory cytokine TNF␣ in pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Monoamines common to pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Agmatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. NE and serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Reciprocal interactions between TNF␣ and the ␣2 -AR in pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Trophic factors and transcription factors common to pain and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatments and medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Antidepressants and mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Anti-TNF drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Enhancing neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Increasing BDNF levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Modulation of the HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Other mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.1. Other enzyme and receptor targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.2. Ketamine and NMDA antagonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.3. Non-pharmacologic alternative therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction It is well known in the primary care setting that both depression and chronic pain result in decreased quality of life, inability to interact with others, and an overall patient disability, even to the point of not being able to function in everyday life (Bair et al., 2003). Often patients who have injuries which result in pain lasting longer than six months (chronic) will go on to develop depressive symptoms. On the other hand, patients with a long history of depressive episodes will often have vague, unclassified pain syndromes (Bair et al., 2003). These two disorders when seen together often exacerbate each other, leading to a vicious cycle that is difficult to treat medically. Antidepressant medications are commonly used to manage both chronic pain and depression, but unfortunately many cases of depression and/or chronic pain are refractory to medical management. Interestingly, the hippocampus is a therapeutic target for many antidepressants (Sairanen et al., 2005; Santarelli et al., 2003), possibly explaining their effectiveness for management of both disorders in some patients. Although it is well recognized that chronic pain and depression co-exist, it is not well-studied as to why, or how, they do so. Having a better understanding of how they are connected may lead to a more effective way to treat one and hopefully both of the disorders and especially as comorbid events. One possible link between the two pathologies is the hippocampus, a region common to neurological pathways and neurotransmitters that regulate both chronic pain and depression. For example, the hippocampus is a key region for development of memory and learning, both of which are integral in the development of chronic pain and depression. Elevations in pro-inflammatory cytokines have been reported in patients suffering from depression and chronic pain (Backonja et al., 2008; Hannestad et al., 2011; Kraychete et al., 2010; Martinez et al., 2012). These cytokines are known to play a role in the turnover of monoamine neurotransmitters within the hippocampus. For example, the cytokine tumor necrosis factor-␣ (TNF␣) inhibits the release of the neurotransmitter norepinephrine (NE) (Elenkov et al., 1992a; Ignatowski and Spengler, 1994; Ignatowski

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et al., 2005; Nickola et al., 2001; Reynolds et al., 2004b), contributing to the overall insufficiency of hippocampal NE that is commonly observed in depressive illness and chronic neuropathic pain. Despite many years of investigation into the mechanisms of antidepressant drug action for both chronic pain and depression, a definitive mechanism for either disorder remains elusive. The administration of antidepressants, such as tricyclic antidepressants and selective norepinephrine or serotonin reuptake inhibitors, increases the availability of monoamines (Blier and Abbott, 2001; Maletic et al., 2007), regulates the production of cytokines, such as TNF␣ (Ignatowski et al., 1997; Nickola et al., 2000; Reynolds et al., 2005a), and mediates an increase in hippocampal neurogenesis (Santarelli et al., 2003; Warner-Schmidt and Duman, 2006), all of which exemplifies that a mechanism does exist in this brain region that explains their analgesic and antidepressant effects. We herein provide a review of the literature that supports the interrelationship of chronic pain and depression with special focus on the hippocampus as a major common denominator between these two disorders. We will also discuss targeting cytokines within the hippocampus, namely TNF␣, as a more efficacious treatment option. A review of other factors, such as other brain regions, neurotrophic factors, and immune/inflammatory mediators common to chronic pain and depression is beyond the scope of the present review, but detailed information on these topics may be found elsewhere (Robinson et al., 2009; Walker et al., 2014). 2. Pain Pain is a subjective experience and there is not any specific test to measure its severity. Classification is based on the patient’s pain history and personal perception, ranging from mild to severe or constant (NIH MedlinePlus, 2011). In general, pain is an unpleasant sensation and an important defense mechanism. However, prolonged pain can result in processes that can damage tissues. Pain stimuli, referred to as “noxious”, are detected by specific sensory receptors (pain receptors) called “nociceptors” (Sherington, 1906). When a noxious stimulus produces an enhanced pain response,


this is referred to as “hyperalgesia”. Even innocuous stimuli that are normally below the pain threshold can produce pain, a condition referred to as “allodynia” (Vanderah, 2007). It is important to note that pain does not only consist of a sensory component, but also encompasses perception, cognition, and higher brain center processing making it a dynamic, multidimensional experience. The increasing incidence of pain-related illnesses and their psychological impact and economic burden has resulted in increased interest in both the neurobiological mechanisms underlying chronic pain development, and the effects of pain on a range of processes, including neural processes. 2.1. Chronic pain More than 76 million people in the United States live with chronic pain, but according to surveys, almost half of them receive no treatment (NIH MedlinePlus, 2011). Chronic pain is an ongoing, abnormal condition with sufficient intensity to negatively affect a person’s level of functioning and quality of life. Unlike acute pain that is a transient, protective response and usually treatable, chronic pain persists even after the injury ends and is often resistant to treatment. Chronic pain is defined as any pain lasting more than 12 weeks and as an aberrant somatosensory processing in the peripheral or central nervous system (CNS) that is sustained beyond the normally expected time course relative to the stimulus (Greene, 2010; NIH MedlinePlus, 2011). Chronic pain is generally classified by physiological changes that are associated with the injury or illness as nociceptive (due to persistent tissue injury), neuropathic (due to damage to the brain, spinal cord, or peripheral nerves), visceral (due to nociceptor activation in the thoracic, pelvic, or abdominal organs), or undetermined causes. Whereas these chronic pain classifications are frequently associated with depression, the comorbid profile for each may differ. A study of comorbidities with these various chronic pain classifications would be useful in determining whether depression is a recurrent, common condition. Neuropathic pain, defined as “pain caused by a lesion or disease of the somatosensory nervous system” (Jensen et al., 2011), is a specific type of chronic pain that results from disease of the neurons in or injury to the peripheral or CNS, and does not primarily signal noxious tissue stimulation. It often presents as persistent burning or short bursts of electrical shock sensation as reported in trigeminal neuralgia, and the duration of this type of pain persists long after resolution of the initial injury (Janig and Baron, 2003). Neuroplasticity refers to changes in neuronal synapses and pathways, including degeneration and remodeling of synapses and neural ganglia, which is fundamental to the development of chronic pain (Covey et al., 2000; Woolf and Salter, 2000). An afferent barrage, whereby nerve fibers continually send noxious signals to the spinal cord and brain, results in neuroplastic changes within the CNS also known as central sensitization (Covey et al., 2000; Khanna and Sinclair, 1989). The prolonged activation of sensory pain pathways and altered neural function modifies production of neurotransmitters and decreases normal inhibition of pain signals being transmitted to the CNS (Stanfa et al., 1994). 2.2. The hippocampus and pain Whereas several supra-spinal regions, including the locus coeruleus (LC) (adrenergic neuron cell bodies), hippocampus (contains adrenergic nerve terminals extending from the LC), periaqueductal gray (PAG), and rostral ventromedial medulla (RVM) play a key role in modulating pain signals, brain regions such as the prefrontal cortex, anterior cingulate cortex, thalamus, and hippocampus are activated during pain processing (Apkarian et al., 2005). The hippocampus participates in both the processing and modification of nociceptive stimuli (Covey et al., 2000; Jones and

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Gebhart, 1986). Several experimental studies have found that direct manipulation of the hippocampus alters nociceptive behavior. Injection of a local anesthetic with sodium channel-blocking effect (lidocaine), directly into the dentate gyrus produces analgesia (McEwen, 2001; McKenna and Melzack, 1992). Stimulation of the dorsal hippocampus affects nociception without being aversive, supporting the hippocampal contribution to pain awareness (Lathe, 2001). Furthermore, a lesion in the hippocampus can alter the perception of noxious stimuli and partially alleviate pain (Al Amin et al., 2004; Maletic et al., 2007). The hippocampus can also be altered by peripheral manipulation. In an animal model of chronic inflammatory pain, a unilateral, hindpaw injection of complete Freund’s adjuvant caused bilateral neurodegeneration in the hippocampus (Duric and McCarson, 2005, 2006b). Cingulotomy, the surgical resection of the anterior cingulum, which connects the posterior frontal cortex to the rest of the limbic system, eliminates the affective component of chronic pain (Foltz and White, 1962; Khanna and Sinclair, 1989). Neurons within the CA1 region of the hippocampus and dentate gyrus respond to painful stimuli and are involved in neural processing related to persistent pain (Soleimannejad et al., 2006). These observations support that the hippocampus is involved in the development and reoccurring effects of chronic pain. Adult neurogenesis is a mechanism by which neurons are generated from neural stem and neural progenitor cells in the mammalian brain (Eriksson et al., 1998; Kee et al., 2002). This process occurs in two regions of the adult brain: the subventricular zone and the hippocampus. Chronic pain interferes with hippocampal mossy fiber-CA3 synaptic plasticity and dentate gyrus neurogenesis, which is still being explored. The changes of these hippocampal properties may relate to the hippocampal volume loss seen in chronic pain patients (Erickson et al., 2011; Mutso et al., 2012). Chronic pain in both human and animal studies have shown hippocampal volume loss and pathophysiological changes in the hippocampus, which can predict behavioral manifestations of anxiety and increased susceptibility to stress (Al Amin et al., 2004; Lyons et al., 2001; McEwen, 2001; Zimmerman et al., 2009). Recently, studies exploring the hippocampus in terms of segregation along the septo-temporal (dorsal-ventral) axis have shown functional distinctions, such that the ventral portion (in rats; analogous to the anterior hippocampus in humans) plays a role in stress and anxiety and the dorsal portion (corresponds to posterior hippocampus in humans) is involved in cognition, memory, and learning (Strange et al., 2014). Whether pain modulation and perception is preferentially regulated along this axis has yet to be determined. However, the finding that stimulation of the dorsal hippocampus affects nociception (Lathe, 2001), and that the functional connection between the hippocampus and the cortex changes with transition from sub-acute to chronic pain (Mutso et al., 2014) suggests that specific domains of the hippocampus may subserve specific pain functions. 2.3. Pain pathways The hippocampus plays a role in pain processing via indirect and direct nociceptive inputs. The indirect nociceptive inputs from the periphery innervate the hippocampus through the spinothalamic and parabrachial ascending pathways (Duric and McCarson, 2006b), while septo-hippocampal neurons receive direct input from the spinal cord and respond to intense peripheral thermal stimulation (Cliffer et al., 1991; Khanna and Sinclair, 1989). Through indirect sensory information input from many structures in the brain, the hippocampus plays an important role in integrating sensory, autonomic and affective information. The hippocampus is connected to the parabrachial or thalamic regions by way of complex neuronal networks that modulate spinal nociceptive

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processing via activation of descending monoaminergic pathways running through the brain stem (Duric and McCarson, 2007; Suzuki et al., 2002). Thus, through these extensive connections, the hippocampus is well-positioned within the brain to participate in the pain experience: it receives nociceptive inputs by way of ascending pathways to allow pain processing, and it modulates subsequent nociceptive processing as a result of activation of descending pain pathways (Duric and McCarson, 2006a, 2006b, 2007; Khanna and Sinclair, 1989; Suzuki et al., 2002). 2.4. Stress and pain Stress (acute) is a normal physiologic, protective response to events that are perceived as threatening or upsetting. The brain responds to stress by activating the hypothalamic–pituitary– adrenal (HPA) axis initiating the “fight-or-flight” response, whereby the nervous system releases neurotransmitters and stress hormones, including norepinephrine, epinephrine and cortisol (glucocorticoid). Through concerted efforts, these stress hormones and neurotransmitters restore internal homeostasis and turn-off the stress response by negative feedback inhibition. Patients with chronic pain often display impairment in the HPA axis physiology (Galli et al., 2009; Niddam et al., 2011), a major adaptation imposed by the pain state (McEwen and Kalia, 2010). These proposed interactions between stresses, chronic pain and novel functions of the hippocampus may explain chronic pain persistence and individual variations in the intensity of the pain. Potential consequences of allostatic load (i.e., a kind of modification in metabolism to adapt to chronic stresses) are an over-activation of the HPA axis and the subsequent structural and functional changes in the hippocampal formation, which are associated with sensitivity to the deleterious effect of sustained high levels of glucocorticoids (de Kloet et al., 2005; Mirescu and Gould, 2006; Sapolsky et al., 1990). Prolonged stress exerts an inhibitory effect on the formation of the new granular neurons in the hippocampal dentate gyrus of various mammalian species (Gould et al., 1999; Tanapat et al., 1998). Further, pathophysiological changes of the hippocampus in an animal model of chronic pain are associated with decreased aversive conditioning, which is representative of the behavioral manifestation of anxiety (Mutso et al., 2012). We conclude that hippocampus-mediated behavior, synaptic plasticity and neurogenesis, which are abnormal in neuropathic pain, may underlie learning and emotional deficits commonly observed in such patients (Mutso et al., 2012). 2.5. Stress-induced analgesia As a protective mechanism, the body generates suppression to pain in response to stressful stimuli or mental anguish; this is referred to as “stress-induced analgesia” (Butler and Finn, 2009). This response is mediated by activation of the descending inhibitory pain pathway, and similar brain regions activated during pain processing, such as the somatosensory cortex and anterior cingulate cortex, are activated during stress-induced analgesia as determined by functional magnetic resonance imaging (Yilmaz et al., 2010). In fact, stress-induced analgesia involves not only sensory, but also affective and cognitive modulatory circuits, thereby further linking pain perception and mood. However, stress does not always suppress pain, and in fact, may aggravate it. This is referred to as “stress-induced hyperalgesia”. Whereas the neural biological factors underlying this effect are not fully understood, activation of pain-facilitating neurons/pathways has been implicated as playing a role (Martenson et al., 2009). The awareness that stress itself can regulate pain (alleviating or enhancing pain) provides evidence for a strong association between pain and affective circuitry, offering another link underlying pain and depression comorbidity.

3. Depression Depression is one of the most common psychiatric disorders seen in the clinical setting and is also one of the leading causes of disability worldwide, as measured by the number of years enduring a disabling condition (Herpfer and Lieb, 2005; Maletic et al., 2007; Murray et al., 1996). Depression is a term used to describe a group of illnesses that have some fundamental symptoms in common (Blackburn-Munro and Blackburn-Munro, 2001). Diagnosis of major depressive disorder (MDD) requires that the patient experience depressed mood or loss of interest along with at least four of the following symptoms for a duration of no less than two weeks: appetite/weight disturbance, sleep disturbance, psychomotor change, loss of energy, worthlessness/guilt, concentration difficulties/indecisiveness, and/or thoughts of death or suicide (American Psychiatric Association, 2013; Maletic et al., 2007). Patients need to meet the criteria as listed above to be specifically diagnosed as MDD (Bair et al., 2003). Patients with depressive illnesses often suffer from repeated episodes of depression, which seem to be partially due to neurobiological instability (Maletic et al., 2007). The “biogenic amine theory” or “monoamine theory” of depression was based on the discovery that there was a lack of bioavailable neurotransmitters (i.e. NE or serotonin) in the brain during depressive disorder (Andrews and Pinder, 2000; Blackburn-Munro and Blackburn-Munro, 2001; Maletic et al., 2007). Supporting this theory, imaging studies of patients with untreated depression have shown a high global density of monoamine oxidase-A, an enzyme that nonspecifically catabolizes monoamines (e.g. serotonin and NE) (Maletic et al., 2007). It is implausible if not impossible that depression is caused by a defect in a single neurotransmitter pathway; depression is mediated by a combination of genetic, biochemical, socio-economic, psychological, environmental, and life-experience factors, with the biggest risk factor being chronic stress (Blackburn-Munro and Blackburn-Munro, 2001). 3.1. Chronic stress and depression A major risk factor predisposing an individual to development of depression is chronic stress, or “an excess of negative events in the six months prior to the onset of depression” (BlackburnMunro and Blackburn-Munro, 2001; Pancner and Jylland, 1996). Physiological and psychological stresses trigger a variety of signals that affect behavior and the systemic and metabolic processes that are responsible for coping with these changes. Alteration of these signaling systems, as those seen in persistent chronic painful stimuli, may lead to the development of depressive disorders (Henn and Vollmayr, 2005; Van Kolen et al., 2008). Stress-related neuropsychiatric disorders are associated with dysregulation of the HPA axis, activation of the immune system and heightened sympathetic nervous system tone (Magarinos et al., 1999; Raison and Miller, 2003). Chronic stress disturbs the negative feedback mechanisms involving the hippocampus and leads to maladaptive responses of the HPA axis and an elevation in glucocorticoid concentration (Blackburn-Munro and BlackburnMunro, 2001). Patients with depressive illnesses share common depression-related abnormalities of the HPA axis, which may include increased glucocorticoid production from the adrenal gland and/or increased corticotrophin releasing hormone production from the hypothalamus (Colla et al., 2007; Holsboer, 2000; Maletic et al., 2007). Advances in brain imaging technology have allowed researchers to identify the brain regions (such as the limbic structures) and neural pathways that regulate mood and memory functions in clinical states of depression. The hippocampus is the part of the limbic


system that plays a central role in memory formation and emotionbased disorders, such as depression (Maletic et al., 2007). 3.2. Hippocampus and depression Several studies show a significant association between depressive illness and loss of hippocampal volume in the form of atrophy (Colla et al., 2007; MacQueen et al., 2003). The stress-induced morphological changes of the hippocampus include atrophy of CA3 pyramidal neurons (Duman and Charney, 1999; Sapolsky, 1996; Watanabe et al., 1992), down-regulation of serotonin transporters within the CA3 sub region (Magarinos et al., 1999; McKittrick et al., 2000), and diminished BDNF levels (Duman and Charney, 1999), all of which contribute to the development and long-term pathophysiology of depression (Duric and McCarson, 2006b). Atrophy of hippocampal dendrites and loss of hippocampal neurons have been observed with magnetic resonance imaging in animal stress models, and also in patients who suffer from recurrent depressive illness as per postmortem analysis (Duric and McCarson, 2005; Magarinos et al., 1999; Maletic et al., 2007; McEwen, 2001; Sheline et al., 1996; Stockmeier et al., 2004). The extent of hippocampal atrophy is directly related to the duration and number of depressive episodes that a patient has suffered (Colla et al., 2007; Sheline et al., 2003), and this size remains reduced even after an episode has resolved (Neumeister et al., 2005), indicating an irreversible change in the hippocampal neurons (Maletic et al., 2007). Untreated depression leads to hippocampal volume loss, which may result in increased stress sensitivity (Hasler et al., 2007) and consequently increased risk of recurrence of depressive episodes (Frodl et al., 2008). There is also a correlation between hippocampal volume reduction and the therapeutic lag of depressive episodes (Colla et al., 2007; Sheline et al., 2003). Correlation between number of episodes and hippocampal volume suggests that the reduction is a morphological reaction that escalates throughout the duration of disease. Additionally, cognitive abnormalities seen with depression are thought to be related to a decrease in neurogenesis of the hippocampus (Duric and McCarson, 2006b). The mechanism of neuronal loss in depression is not well understood, but overall, studies suggest that either increased neurotoxicity due to glucocorticoids and/or glutamate or decreased neurotrophic factors, such as BDNF, attenuates neurogenesis at the level of hippocampus (Martinowich et al., 2007). In fact, attenuation of hippocampal neurogenesis has been suggested as the potential etiology for depression (Santarelli et al., 2003). Thus, the observed volume loss within the hippocampus in depression is either due to the shrinking size of the neurons and/or because of decreasing number of cells (hypoplasia). Interestingly, whereas antidepressant-mediated neurogenesis in either the ventral or dorsal sub-regions of the hippocampus (in rodents) can be effective, neurogenesis may be preferentially impacted in the ventral hippocampus as opposed to in the dorsal hippocampus (O’Leary and Cryan, 2014; Tanti and Belzung, 2013). This finding is important since the ventral hippocampal connections to regions such as the hypothalamus and amygdala that are involved in behavioral responses to stress are often dysfunctional in depression. 4. Comorbidity of chronic pain and depression Depression and chronic pain symptoms commonly occur together. According to the Institute of Medicine, approximately 100 million Americans suffer from chronic pain and about 50% of these patients have a type of depressive disorder (Asmundson and Katz, 2009; IOM, 2011). Patients with depression may have complicated overlapping emotional and physical symptoms such

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as unexplained pain (Bair et al., 2003). Clinicians often label the comorbidity between chronic pain and depressive illness as the depression-pain syndrome or the depression-pain dyad, implying that these disease states often co-exist and respond to similar treatments (Bair et al., 2003; Blier and Abbott, 2001). 4.1. Comorbidity theory Tricyclic antidepressants are often used for treatment of neuropathic pain with underlying depression. This supports the assertion that pain and psychosocial stress converge on higher brain centers, such as the hippocampus, which is capable of processing both types of stimuli (Duric and McCarson, 2005, 2006b; Kramer et al., 1998). Clinical depression has a strong influence on a patient’s perception of pain intensity; thus, depressed patients will often suffer from allodynia (Blackburn-Munro and Blackburn-Munro, 2001; Wilson et al., 2001). This implies that depression precedes the pain disorder. On the other hand, a meta-analysis suggested that depression results from chronic pain (Dworkin and Gitlin, 1991). Interestingly, with increasing severity of pain or depression, the pain/depression association becomes stronger; but, it is not clear whether pain causes depression or depression amplifies the pain (Bair et al., 2003). There are five hypotheses that have been put forth to explain the comorbidity of chronic pain and depression: 1 – the ‘antecedent hypothesis’ states that depression precedes the development of chronic pain; 2 – the ‘consequence hypothesis’ in which depression is a consequence of chronic pain symptoms; 3 – the ‘scar hypothesis’ states that previous episodes of depression occurring before the onset of chronic pain predispose the patient to depression after the onset of chronic pain; 4 – the ‘cognitive mediation’ hypothesis suggests that psychological factors, such as poor coping strategies mediate the reciprocal interaction between chronic pain and depression; and 5 – the ‘independent hypothesis’ in which the diseases remain distinct diseases without any interaction although they share some pathogenic mechanisms (Blackburn-Munro and Blackburn-Munro, 2001; Maletic et al., 2007; Martelli et al., 2004). Therefore, while it is well-documented that chronic pain can trigger depressive symptoms and that depression manifests as both physical and emotional pain, there is still a lack of agreement on a definitive hypothesis to explain the comorbidity of chronic pain and depression. 4.2. Hippocampus in pain and depression There is evidence that persistent noxious stimuli result in molecular changes in the hippocampus that mediate the affectivecognitive component of pain, such as pain-associated mood changes, individual coping strategies, and formation of memories about painful stimuli (Bair et al., 2003). An example for these molecular changes is the increases in hippocampal levels of TNF␣ secondary to the afferent barrage that occurs during the development of neuropathic pain (Spengler et al., 2007). The elevated level of TNF␣ in turn suppresses NE production in the hippocampus (Covey et al., 2000; Ignatowski et al., 1999, 2005). Similar molecular and physiologic changes are proposed to occur during depressive illness (Fig. 1) (Ignatowski et al., 1997; Ignatowski and Spengler, 1994; Reynolds et al., 2004b, 2005a). During both chronic pain and depression, long-term neurochemical, autonomic, and HPA axis dysfunction inspire the progression of neuronal changes, such as hippocampal atrophy. It is likely that neurochemical and morphological changes in the hippocampal network contribute to the similar symptoms seen in chronic pain and depression (McEwen, 2001). For example, the disrupted feedback mechanism of the hippocampus and subsequent HPA axis dysfunction are factors that underlie the comorbidity

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Fig. 1. Links common to chronic pain and depression. The relationship between chronic pain and depression, while complex, shares similar pathologic changes, both structural and physiological in nature, within the limbic system anatomic structure, the hippocampus. Likewise, an increase in the pro-inflammatory cytokine and neural mediator TNF␣ is common to both disorders, providing a mechanism underlying the increased incidence of co-morbidity.

of chronic pain and depression (Blackburn-Munro and BlackburnMunro, 2001; Duric and McCarson, 2006b). 4.3. Cognitive dysfunction in comorbid pain and depression Cognition, or the brain’s ability to acquire, process, store, and retrieve information (Lawlor, 2002), is negatively affected in chronic pain conditions. Chronic pain is often a sympton of complex disorders such as fibromyalagia, migraine headaches, irritable bowel syndrome, and diabetes, which also express comorbid depression. Thus, it is not surprising that chronic pain, depression, and cognition share inherent overlap in that all require attention, learning, and memory, and all share similar brain regions (anterior cingulate cortex, prefrontal cortex, periaqueductal gray, hippocampus) for processing (Kennedy et al., 2012; Moriarty et al., 2011). In particular, the hippocampus is traditionally associated with learning and memory, cognitive functions that are disturbed during chronic pain. Long-term potentiation (LTP), a type of synaptic plasticity associated with learning and memory formation, is impaired in hippocampal slices from nerve-injured mice (Kodama et al., 2007). Likewise, the spared nerve injury model of neuropathic pain in rodents increased TNF␣ production in the hippocampus leading to memory impairment and hippocampal dysfunction (Ren et al., 2011). Hippocampal neurogenesis is decreased in rodents experiencing pain and stress-induced depressive behavior (Czeh et al., 2001; Duric and McCarson, 2006b); this would be expected to negatively impact both learning and memory. Cognitive impairment is further demonstrated in transgenic mice that over-express TNF␣ (Aloe et al., 1999). Interestingly, animals with increased TNF␣ are susceptible to developing chronic pain and depressive behaviors (Felger and Lotrich, 2013; Kaster et al., 2012; Ren et al., 2011). These findings point toward a common potential mechansim contributing to the emotional/affective component of pain and its impact on cognitive functioning. Major changes in cortical and subcortical structures of the brain, which are areas that are responsible for cognitive and emotional components of pain, have been described in neuropathic pain in both human and animal studies (Baliki et al., 2008; Gore et al., 2012; Metz et al., 2009). Chronic pain patients seem to suffer as much from the emotional disturbance as from the pain itself supporting the role of the hippocampus in the processing of chronic pain (Ren et al., 2006). Comorbidities such as fatigue, anxiety and depression that we often see in neuropathic pain patients could be justified with the affective component of pain (Jensen et al., 2007).

4.4. HPA axis and comorbid pain and depression The neuroendocrine HPA stress axis is a well-characterized pathway whereby the CNS communicates with the rest of the body via substrates that support proper functioning of the sympathetic nervous system. Monoamines secreted from the autonomic nervous system, along with serotonin play a major role in the pathophysiology of depression and chronic pain. Within the HPA axis the CNS communicates with the endocrine system through production of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal gland to produce glucocorticoids, which are virtually inhibitory to all aspects of the immune system. Indirect, long-term activation of the HPA axis via nociceptive input can manifest as depressive symptoms in chronic pain patients (Blackburn-Munro and Blackburn-Munro, 2001), thus eliciting a comorbid profile. 4.4.1. Glucocorticoids and glucocorticoid receptors in pain and depression Natural endogenous glucocorticoids function as ligand to both mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) with almost an equal affinity (Pariante and Miller, 2001; Raison and Miller, 2003). The hippocampus shows a higher number of MR and GR than any other brain region, thereby playing a crucial role in the negative feedback control of HPA axis activity (Blackburn-Munro and Blackburn-Munro, 2001; Lathe, 2001). Imbalance between concentrations of glucocorticoid and the availability and/or sensitivity of MRs and GRs may result in neuronal damage of hippocampus (de Kloet et al., 2007; Maletic et al., 2007). In fact, excess levels of glucocorticoid observed during recurrent depressive illness or chronic pain leads to dystrophic changes of dendritic processes, which is more prominent in the hippocampus than the other regions of the brain (McEwen, 2001, 2005; Sheline et al., 1996; Watanabe et al., 1992). In animal studies, stress and corticosterone administration induce a remodeling of the apical dendrites of the hippocampal CA3 pyramidal neurons, and increased glucocorticoid is the vital event that initiates stress-induced atrophy seen in the CA3 pyramidal dendrites (Magarinos et al., 1999). Conversely, patients who show a decrease in glucocorticoid after pharmacotherapy tend toward higher hippocampal volumes (Colla et al., 2007). Chronic stress results in a decrease in GR sensitivity, hence GR receptor stimulation will not be able to produce negative feedback (Maletic et al., 2007; Raison et al., 2006; Raison and Miller, 2003). Excessive secretion of glucocorticoids along with the decrease in GR


responsiveness leads to the adverse behavioral and psychological sequelae seen in MDD that result from chronic stress (Holsboer, 2000; McEwen and Seeman, 1999b; Pariante and Miller, 2001; Raison and Miller, 2003). Chronic pain, another form of chronic stress, leads to a downregulation of glucocorticoid-mediated activity of the inhibitory connection, thereby leading to an increase in pain perception. Chronic constriction injury (CCI), a model of neuropathic pain, is associated with decreased GR mRNA expression in the hippocampus, suggesting that increased nociception during chronic pain is associated with hippocampal alterations that may disrupt the negative HPA axis feedback system (Ulrich-Lai et al.,

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2006). Chronic pain also leads to a depressed mood (BlackburnMunro and Blackburn-Munro, 2001). A preclinical study showed that mice receiving sciatic nerve cuffing to induce neuropathic pain developed depressive-like behaviors 6–8 weeks after cuff placement (Yalcin et al., 2011). Whereas HPA-axis dysfunction did not contribute to the development of comorbid depressive symptoms in this model, the contribution of hippocampal GR contribution was not evaluated. Elevated glucocorticoid level and an unrestrained immune response further the metabolic and neuroendocrine disruption manifest in chronic pain and depression (see Fig. 2) (Maletic et al., 2007; Raison and Miller, 2003).

Fig. 2. Diagram illustrating pathophysiological mechanisms underlying chronic pain and depression. Chronic stress leads to prolonged activation of the hypothalamuspituitary-adrenal (HPA) axis and excess production of glucocorticoids (a). Excess glucocorticoid acts by desensitizing glucocorticoid receptors (GR) (b), which results in neuronal damage and atrophy of dendritic processes in the hippocampus and eventually disturbs the normal negative feedback from the hippocampus (c) (Blackburn-Munro and Blackburn-Munro, 2001; Maletic et al., 2007; McEwen, 2001; Raison et al., 2006; Raison and Miller, 2003; Sapolsky, 1996; Sapolsky et al., 1990). Unrestrained glucocorticoid concentration also decreases NE production in the hippocampus (d) (Pacak et al., 1995; Raison and Miller, 2003). Any kind of injury activates the immune/inflammatory system (e) that leads to pro-inflammatory cytokine (TNF, IL-1, IL-6) production (f); cytokines are active at the level of the hypothalamus and hippocampus (g) and also activate afferent autonomic nerve pathways involved in transducing cytokine signals to the CNS (h) (Blackburn-Munro and Blackburn-Munro, 2001; Maier and Watkins, 1998; Maletic et al., 2007; Raison et al., 2006; Raison and Miller, 2003). Increased TNF level in the hippocampus decreases the hippocampal NE level (i) and decreases BDNF (j) (see Fig. 3), effects involved in the development of chronic pain and depression (Covey et al., 2000; Ignatowski et al., 1999; Reynolds et al., 2005a; Sud et al., 2007, 2008). Cytokines reduce both the number and the function of GRs and play a role in altering the negative feedback from the hippocampus (k) (Pariante et al., 1997; Raison et al., 2006; Raison and Miller, 2003). Loss of negative feedback control of glucocorticoid production is responsible for the continual increase in cytokine activity and in adrenal medulla production of epinephrine and NE (l) (Blackburn-Munro and Blackburn-Munro, 2001), which may increase the production of pro-inflammatory cytokine by macrophages (m) (f) (Maletic et al., 2007; Spengler et al., 1990; Sud et al., 2008). Stress/pain-induced sympathetic outflow similarly influences cytokine production from immune/inflammatory cells. Taken together, dysregulation of the HPA axis and an unrestrained immune response are responsible for chronic pain and depression (Maletic et al., 2007; Raison and Miller, 2003).

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4.4.2. Stress-induced excitatory amino acids common to pain and depression The HPA axis and excitatory amino acids play a role in mediating changes in the hippocampus (McEwen, 2001), including the structural plasticity that is observed during depression and chronic pain. Excitatory amino acids and glucocorticoids that are produced during stressful experiences are capable of suppressing the ongoing neurogenesis that normally occurs in the granular neurons within the dentate gyrus (McEwen, 1999a, 2001). Together excitatory amino acids and glucocorticoids act as mediators during stressinduced remodeling of CA3 pyramidal neurons (Magarinos et al., 1999; McEwen et al., 1997), and their concerted actions generate a shortening and debranching of the apical dendrites (Magarinos et al., 1999; McEwen, 1999a, 2001). Stress-related plasticity associated with the concerted effort of excitatory amino acids and glucocorticoids is reversible as long as the stress is discontinued after 21 days (Conrad et al., 1999; McEwen, 2001). Moreover, activation of NMDA and AMPA receptors leads to a cascade of events resulting in hippocampal plasticity, such as LTP and long-term depression (LTD) (McEwen, 2001). Blockade of NMDA receptors prevents the stress-induced CA3 apical atrophy (Magarinos et al., 1999; McEwen et al., 1997). During stress, glucocorticoids increase hippocampal expression of NMDA receptor subunits (Weiland et al., 1997) and induce the enhancement of hippocampal glutamate release (Magarinos et al., 1999; McEwen, 2001; Moghaddam et al., 1994). Stress-induced excitatory amino acids dysregulation results in damage to the hippocampus and failure to shut-off glutamate release after stress (McEwen, 2001). Excessive glutamate activation results in tissue edema and degeneration, similar to as occurs with unrestricted glucocorticoid production (Duric and McCarson, 2005). It is well accepted that glutamate is the main excitatory neurotransmitter in the brain. Glutamate plays a key role in changes in excitatory processes involved in psychiatric and neurological disorders (Spooren et al., 2003). Restraint stress that is used to induce depressive-like behavior causes an increase in extracellular glutamate levels, which leads to hippocampal dendritic remodeling (McEwen, 2001). Similarly, glutamate in the hippocampus plays a role in chronic pain. Formalin-related nociceptive behaviors are reduced by microinjections of glutamate receptor antagonists, such as AP5, directly into the dorsal hippocampal formation or the dentate gyrus (Al Amin et al., 2004; Duric and McCarson, 2007; McKenna and Melzack, 1992, 2001). Antisense oligonucleotides against metabotropic glutamate 1 receptor (mGlu1R) prolonged thermal analgesia in the tail flick model and reduced the development of neuropathic pain in CCI model of chronic pain (Fundytus et al., 2001). Likewise, anti-rat mGlu1R antibodies induced antinociception in models for chronic pain (Fundytus et al., 2001; Spooren et al., 2003). Although mGluRs are expressed throughout the brain, high levels of mGlu1R expression are concentrated in the hippocampus. While high levels of mGlu1Rs are particularly evident in the dendritic field and the hilum of the dentate gyrus, as well as in the CA3 region, mGlu1R expression is not observed in the CA1 region. In comparison, the mGlu5Rs are highly expressed in the CA1, CA3, and the hilum and molecular layers of the dentate gyrus (Spooren et al., 2003). Therefore, in both depression and chronic pain models, glutamate appears to play a pivotal role in disease pathogenesis, especially at the level of the hippocampus. 4.5. Animal models of comorbid pain and depression Preclinical studies provide detailed information regarding mechanisms mediating the development of chronic pain and depressive behavior in separate, well-validated animal models. However, there is a noticeable gap in basic research regarding

comorbid chronic pain and depression due to few studies modeling the clinical profiles of both chronic pain and depression in laboratory animals. One such study sought to model comorbid pain and depression by pairing chronic constriction injury (CCI), a neuropathic pain model, with unpredictable chronic mild stress, an experimental model of depression. Rats subjected to sciatic nerve injury and stress-induced to express depressive behavior showed that stress did heighten aversion to certain sensory pain stimuli, i.e., enhancing cold allodynia, but not mechanical allodynia. Further, a chronic mild stress-induced depressive state did negatively impact the affective component of chronic pain. In contrast, chronic pain did not cause exaggerated depressive behaviors (anhedonia and forced swim-induced immobility) in rats subjected to chronic mild stress (Bravo et al., 2012). Interestingly, in this study, it was shown that HPA axis dysfunction did not contribute to the comorbid condition. These findings reinforce the idea that comorbidity of chronic pain and depression leads to a more negative perception of painful stimuli than perceived during chronic pain in the absence of depression. Another study assessed whether depressive behaviors developed in rats following spared nerve injury (SNI), another neuropathic pain model. Indeed, SNI rats exhibited depression-like behavior (increased forced swimming immobility and decreased sucrose preference, a measure of anhedonia) that was long-lasting when compared to sham-operated rats (Wang et al., 2011). In fact, as recently reviewed by Yalcin et al. (2014), many early studies modeling depressive consequences of chronic pain utilized animal neuropathic pain models, but yielded conflicting results. Of these studies, those that assessed pain-induced depressive behaviors at later times (>3 weeks) following peripheral nerve injury reported development of a depression-related phenotype (Yalcin et al., 2014). Many parameters in addition to time, such as the specific model used, the side on which the injury is instigated, and the strain/species of animal used, are important factors influencing whether depressive behaviors are observed in neuropathic pain models; however, if carefully controlled, it is feasible to reliably model comorbid depressive behavior in animals with neuropathic pain (Yalcin et al., 2014). An animal model for fibromyalgia, a chronic pain condition often comorbid with depression, was developed whereby rats receive subcutaneous injections of reserpine, which depletes biogenic amines (NE, serotonin, dopamine) from the nervous system (Nagakura et al., 2009). Reserpineadministered rats developed long-lasting muscular mechanical hyperalgesia, tactile allodynia, and comorbid depressive behavior (prolonged forced swim test immobility) that was accompanied by chronic decreases in dopamine, NE, and serotonin in brain regions involved in pain control and processing. Reserpine-induced pain and depressive-like behaviors were also accompanied by increased production of pro-inflammatory cytokines, including TNF␣, in both the cerebral cortex and hippocampus (Arora and Chopra, 2013; Arora et al., 2011; Xu et al., 2013). Ferulic acid, curcumin, and berberine, naturally occurring anti-inflammatory and antioxidant agents derived from plant extracts, dose-dependently ameliorated the reserpine-induced pain and depressive-like behaviors, significantly reduced TNF␣ and IL-1␤ levels in the rodent cortex and hippocampus, and increased monoamine transmission (Arora and Chopra, 2013; Arora et al., 2011; Xu et al., 2013). Since these agents target multiple steps in the inflammatory and oxidative-nitrosative pathways, whether it is the combination of targeted effects or a single initiating effect that sets into motion antioxidant/antiinflammatory cascade activation has yet to be determined. This is especially important in light of the finding that a selective increase in CNS levels of the monoamine norepinephrine was sufficiently efficacious in several models of pain and depression (Whiteside et al., 2010). However, these findings do support a role for hippocampal expressed TNF␣ in the rodent reserpine model of comorbid pain and depression.


Recent investigations into the brain-gut-microbe axis and irritable bowel syndrome have identified animal models of comorbid pain and depression. Preclinical studies using early-life stress paradigms have demonstrated utility as models for comorbid pain and depression. The rodent maternal separation model is a well-validated model for depression whereby animals also display visceral hypersensitivity in adulthood (Moloney et al., 2012; O’Mahony et al., 2009). Likewise, the Wistar Kyoto (WKY) rat that is genetically predisposed to express heightened behavioral responses to stress also displays abdominal visceral pain (Hyland et al., 2015; O’Mahony et al., 2011). Using these animal models, researchers are unraveling the complex pathways and multidirectional communication networks that are common to pain and depression symptomology. Future studies utilizing distinct animal models of comorbid chronic pain and depression will be vital to elucidating the mediators and mechanisms common to both conditions that can be targeted for effective therapies. 5. Immune-neural interactions common to chronic pain and depression Almost all stressors, including psychological insults and pain, are associated with activation of the immune system and release of pro-inflammatory cytokines, such as TNF␣, IL-1, and IL-6 (Maier and Watkins, 1998; Raison and Miller, 2003). Stress-activation of the pro-inflammatory cytokine cascade initially increases the production of TNF␣, the first cytokine to appear in the cascade (O’Connor et al., 2003). The brain is normally protected from immune-mediated damage by glucocorticoids, which mobilize and shape the immune response during times of stress. Glucocorticoids are responsible for returning the levels of cytokines to homeostatic concentrations after removal of the stress stimuli (McEwen et al., 1997; Raison and Miller, 2003). Unrelieved or chronic stresses lead to inappropriate or de-regulation of the neural-immune systems, thereby perpetuating pathophysiologic changes that underlie the development of chronic pain and depression. Discussion of some of the neural/immune mediators common to chronic pain and depression, with emphasis on their effects within the hippocampus follows. 5.1. Proinflammatory cytokine TNF˛ in pain and depression Constitutive levels of TNF␣ are present in the hippocampus (Ignatowski et al., 1997), but higher induced levels of this cytokine are associated with the development of chronic pain (Covey et al., 2000; Ignatowski et al., 1999; Sud et al., 2007). This higher pathological level of TNF␣ can be elicited experimentally; an increase in hippocampal TNF␣ levels temporally coincides with the development of thermal hyperalgesia in the CCI neuropathic pain model (Covey et al., 2000). Furthermore, microinfusion of TNF␣ into the lateral cerebral ventricle (proximal to the hippocampus) results in hyperalgesia in normal, naive rats and enhances the hyperalgesia present in rats subjected to CCI (Covey et al., 2000; Ignatowski et al., 1999; Oka et al., 1996). In fact, localized increase in TNF␣ production in the hippocampus induces persistent pain behavior similar to that observed during CCI (Martuscello et al., 2012). It has been suggested that the memory deficits that are observed in animals experiencing pain is due to the overproduction of TNF␣ in the hippocampus (Ren et al., 2011). These rodent models of pain show the importance of the hippocampus as a site within the brain for the nociceptive effect of TNF␣, via TNF␣-mediated signal translation/transduction. Depression is also associated with an increase in serum levels of TNF␣ (Mikova et al., 2001) as well as interleukins, specifically with increased IL-1 levels in the CNS and IL-6 in the plasma

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(Raison and Miller, 2003). In pre-clinical experiments, animals displayed depressive behavior following intracerebroventricular (i.c.v.) microinfusion of TNF␣ (adjacent to the hippocampus) (Reynolds et al., 2004b). Taken together, it appears that cytokines, and TNF␣ in particular, are pivotal in the pathogenesis of both depression and chronic pain, which are effects of hippocampal function. TNF␣ (Clark et al., 2010; Ren et al., 2011) and interleukin-1 (IL-1) (del Rey et al., 2011) may also be involved in the decrease of neurogenesis evidenced in pain and depression models. Mice receiving sciatic nerve CCI to induce neuropathic pain developed depressive-like behavior 4 weeks following ligature placement that was associated with increased hippocampal TNF and impaired dentate gyrus neurogenesis dependent on TNF receptor-1 signaling (Dellarole et al., 2014). In addition to various harmful effects of cytokines on neurons, depression mediates the activation of resident brain macrophages including microglia, which contribute to the existing immune disruption by releasing more cytokines (Frank et al., 2007; Maletic et al., 2007). Glial cells interact with neurons to maintain neuronal homeostasis via modulation of neurotransmitters, cytokines, and neurotrophic factors (Bessis et al., 2007; Maletic et al., 2007). Neurons reciprocate this glial support via neurotrophic signaling. Alterations in the production and levels of cytokines may diminish neurotrophic support as well as monoamine neurotransmission, which can lead to neuronal and glial damage and ultimately atrophy (Maletic et al., 2007). Consequently, the previous discussion (see Section 4.4) regarding the effects of glucocorticoids at the level of the hippocampus indicates that reduced glucocorticoid inhibitory feedback signaling may subsequently lead to uncontrolled inflammatory responses, with deleterious effects, including impaired cell survival in the brain (Nadeau and Rivest, 2003; Raison and Miller, 2003). 5.2. Monoamines common to pain and depression Pro-inflammatory cytokines, such as TNF␣, influence monoamine turnover in the hippocampus (Maier and Watkins, 1998; Raison and Miller, 2003). Therefore, pro-inflammatory dysfunction leads to deregulation of monoamines in the hippocampus, which suggests a possible mechanism underlying pathophysiology of chronic pain and depression (Blackburn-Munro and Blackburn-Munro, 2001; Maletic et al., 2007). The monoamines represent a class of hormones or neurotransmitters, such as the catecholamines (epinephrine, NE and dopamine) and indoleamines (serotonin) following decarboxylation of their respective amino acids. These monoamines are the main neurotransmitters within the sympathetic nervous system and are responsible for the “fight or flight” response as the first defense against homeostatic challenge (Blackburn-Munro and Blackburn-Munro, 2001). They are also endogenous neurotransmitters of the CNS involved in pain control (Millan, 2002; Ren and Dubner, 2002; Wood, 2008). 5.2.1. Agmatine Agmatine (4-aminobutyl-guanidine) is a lesser known monoamine derived from decarboxylation of arginine, and it is distinguished from other monoamines by a strong basic guanidine group (Halaris and Plietz, 2007). Various cell stressors induce synthesis of agmatine by neurons (Iyo et al., 2006) and astrocytes (Halaris and Plietz, 2007; Regunathan and Piletz, 2003). Once released, agmatine acts on different transmembrane receptors, including the imidazoline receptor (Aricioglu et al., 2003; Wu et al., 2005), the ␣2 -adrenergic receptor (␣2 -AR) and the glutamatergic NMDA receptor (Halaris and Plietz, 2007; Yang and Reis, 1999). Agmatine has both anti-neurotoxic (Gilad et al., 2005; Zhu et al., 2006) and antidepressant actions (Halaris and Piletz, 2003) thereby helping to relieve psychological stress (Halaris and Plietz, 2007).

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Agmatine acts to reduce glutamate release (Feng et al., 2005); this may explain its anti-neurotoxic action as well as its antidepressant action due to the alleviation of glutaminergic neurotransmission, a neuromodulator that is indicated in the pathogenesis of depression (Halaris and Plietz, 2007; Himmerich et al., 2008). Agmatine is able to cross the blood brain barrier (Piletz et al., 2003), therefore antidepressant-like effects are produced rapidly when low-dose agmatine is administered peripherally or centrally (Halaris and Plietz, 2007; Li et al., 2003). Agmatine inhibits and down-regulates inducible nitric oxide synthase (Satriano et al., 2001), which is likely a feed-forward inhibitor of nitric oxide synthase induction (Auguet et al., 1995; Halaris and Plietz, 2007). Interestingly, various forms of chronic pain are associated with increased inducible nitric oxide synthase activity and nitric oxide production (LaBuda et al., 2006), which may be mediated by loss of inhibition by agmatine (Halaris and Plietz, 2007). Inhibitors of nitric oxide synthase have antidepressant-like activity and increase the efficacy of antidepressant drugs that are used clinically to treat both depression and chronic neuropathic pain (Harkin et al., 2004; Heiberg et al., 2002). Recently, Uzbay reviewed the substantial evidence regarding multiple CNS effects induced by agmatine, including its interaction with ␣2 -ARs and antinociceptive action (Uzbay, 2012). Therefore, the agmatinergic system may be a promising therapeutic target of chronic pain and depression.

5.2.2. NE and serotonin According to the classic monoamine theory, depression is mediated by an imbalance of NE and/or serotonin levels in the CNS (Harro and Oreland, 2001; Meyer et al., 2006). Also the ‘dysregulation hypothesis’ has been proposed, whereby inappropriate NE release results from impaired negative feedback onto presynaptic neurons (Siever and Davis, 1985). This hypothesis indicates the importance of presynaptic ␣2 -AR regulation of neurotransmitter release in the pathophysiology of MDD. The hippocampus contains a high density of auto-regulatory (presynaptic) ␣2 -ARs (Curet and de Montigny, 1988; Unnerstall et al., 1984). Whereas NE is primarily a facilitator through the activation of ␣1 -AR (Blackburn-Munro and Blackburn-Munro, 2001; Holsboer and Barden, 1996), the ␣2 -AR, an autoreceptor, is the primary inhibitory regulator of NE release through a feedback mechanism (Dixon et al., 1979). The presynaptic ␣2 -ARs are sensitive to stimulation by NE and, in fact, inhibit further monoamine release, thus carefully regulating release of these neurotransmitters, which are important in regulation of mood and pain. For example, ␣2 -adrenergic hetero-receptors inhibit release of serotonin from serotonergic neurons (Raiteri et al., 1990). Chronic stress-induced elevations in glucocorticoid and subsequent decreases in NE and serotonin are events that play a role in the development of depressive symptoms. Chronic stress also leads to a glucocorticoid-induced down-regulation of post-synaptic serotonergic receptors in the hippocampus, central depletion of serotonin, and an up-regulation of pre-synaptic serotonin receptors in the brainstem (Blackburn-Munro and Blackburn-Munro, 2001). Disturbances in serotonergic transmission are commonly observed in chronic stress and depression (Lopez et al., 1998; Magarinos et al., 1999). It has been reported that brain indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, was increased in patients with comorbid pain and depression. Cytokines enhance IDO1 activity, thereby decreasing serotonin availability (Schrocksnadel et al., 2006). In fact, intra-hippocampal administration of IL-6 in rats induced IDO1 expression (Kim et al., 2012). Also, chronic pain in rats caused depressive behavior and up-regulation of IDO1 that resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio bilaterally in both hippocampi. The present findings may suggest a new strategy of clinical intervention.

Although more well-known for their role in depressive symptoms, NE and serotonin also play a role in pain processing. When injected into the ventral hippocampus, NE and serotonin have opposite effects on nociceptive responses to painful stimuli; NE increases the response, while serotonin decreases it (Al Amin et al., 2004; Gage and Springer, 1981). As occurs during depression, ␣2 adrenergic activity also modulates pain through auto-regulation of NE in the CNS (Covey et al., 2000). In hippocampi harvested from naïve animals, electrical field stimulation inhibits NE release, and activation of the ␣2 -AR further inhibits this release (Covey et al., 2000; Ignatowski et al., 1996a). Experimentally, during the development of neuropathic pain, inhibition of NE release from the hippocampus is more pronounced and NE concentrations released upon neuron stimulation remain low in the hippocampus due to enhanced ␣2 -AR activity (Covey et al., 2000; Spengler et al., 2007; Sud et al., 2007). 5.3. Reciprocal interactions between TNF˛ and the ˛2 -AR in pain and depression The sympathetic nervous system and immune system interact during the processing of stress stimuli. Whereas activation of ␤-ARs results in anti-inflammatory effects (Severn et al., 1992), activation of ␣2 -ARs is generally considered pro-inflammatory by triggering or enhancing an immune/inflammatory response (Spengler et al., 1990; Sud et al., 2007). Development of neuropathic pain is associated with enhanced sympathetic activity (Sasaki et al., 1997) and increased activation of ␣2 -ARs, which contributes to the increased production of TNF␣ (Spengler et al., 2007). TNF␣ production leads to remodeling of the ␣2 -adrenergic regulation of NE release in the CNS, which contributes to the development of central sensitization, a characteristic of neuropathic pain (Covey et al., 2000). During peak hyperalgesia associated with CCI, an experimental model of neuropathic pain, TNF␣ and ␣2 -adrenergic inhibition of NE release is at its maximum in the hippocampus (Spengler et al., 2007). A decrease in NE release results in decreased activation of ␣2 -ARs; this brings about a further increase of TNF␣ levels in the brain, which maintains low levels of NE and subsequent high production of TNF␣ (Covey et al., 2000). Following peak hyperalgesia of the CCI pain model, there is a loss of this up-regulated inhibition of NE release, which coincides with resolution of hyperalgesia (Spengler et al., 2007). The decrease in pain is associated with a full switch in ␣2 -adrenergic and TNF␣ regulation of NE release from inhibition to potentiation of NE release from adrenergic neurons in the hippocampus. This switch or reversal of function counteracts the decrease in NE release that occurs during the development of hyperalgesia (Covey et al., 2000; Ignatowski et al., 2005; Spengler et al., 2007). During the development of neuropathic pain in the CCI model, which is a unilateral injury model, the ␣2 -AR undergoes a functional switch in the contralateral hippocampus, e.g. a switch in the regulation of cAMP production from inhibition to potentiation (Sud et al., 2007, 2008). The generation of cAMP results in a decrease in the production of TNF␣ (Renauld et al., 2004; Severn et al., 1992) and an increase in production of growth factors, such as BDNF (Duric and McCarson, 2006b, 2007; Maletic et al., 2007). Thus, the TNF␣induced switch in ␣2 -AR function (regulation of NE release and cAMP production) in the hippocampus in this chronic pain model may provide translational evidence for future treatments of chronic pain and depression. Conflicting results have been reported for TNF␣ regulation of BDNF production by neurons. Inflammatory (TNF␣) stimulation of sensory neurons in vitro and of dorsal root ganglion neurons in vivo increased BDNF production (Balkowiec-Iskra et al., 2011; Onda et al., 2004). However, studies have shown decreased production of BDNF in the hippocampus during animal models of inflammatory


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Fig. 3. Proposed hippocampal commonalities of chronic pain and depression, and brain TNF function in the pathophysiology and treatment of these disorders. (A) TNF mediates neuroplastic changes in the brain during neuropathic pain and induction of depressive behavior. (a) Nerve injury induces an inflammatory response in the CCI model (DeLeo et al., 1997; Sommer et al., 1998). Inflammatory mediators generate hyperexcitable sensory neurons (Xiao et al., 1996) that over-load CNS sensory input. The increased levels of brain-TNF mediate a decrease in NE release (Covey et al., 2000; Ignatowski et al., 2005), thereby inactivating the descending inhibitory pathway, which may serve to facilitate pain transmission and intensify pain sensation. (b) Stressors, including pain, activate the pro-inflammatory cytokine cascade, with TNF being the proximal cytokine (Madrigal et al., 2002; O’Connor et al., 2003; Raison et al., 2006). (c) TNF inhibits stimulated NE release (Elenkov et al., 1992a, 1992b; Ignatowski et al., 1996a, 1997; Ignatowski and Spengler, 1994; Nickola et al., 2001), and TNF enhances G␣i protein expression (Klein et al., 1995; Reithmann et al., 1991; Scherzer et al., 1997). The presynaptic ␣2 -adrenergic receptor (␣2 -AR) that normally favors coupling to G␣i and inhibition of NE release becomes supersensitized, which allows for greater inhibition of NE release (Covey et al., 2000; Ignatowski et al., 1999, 2005; Nickola et al., 2000; Reynolds et al., 2004b). (d) A deficiency in bioavailable NE results in the attenuation of ␣2 -AR stimulation that upon activation normally inhibits TNF expression (Ignatowski et al., 1996a; Nickola et al., 2000; Renauld and Spengler, 2002; Reynolds et al., 2005a; Spengler et al., 2007); therefore, ␣2 -AR-mediated decrease in TNF is also attenuated, and a sustained elevation in TNF ensues. (e) TNF causes a decrease in hippocampal BDNF, CREB, and ␤-arrestin activity; the decrease in ␤-arrestin activity prevents desensitization of the G-protein-coupled receptor (␣2 -AR-G␣i/o ) (Khoa et al., 2006). We propose that low (physiological) levels of TNF stimulate BDNF production, while elevated levels of TNF inhibit BDNF production (Aloe et al., 1999; Duric and McCarson, 2005, 2007; Onda et al., 2004; Schulte-Herbruggen et al., 2005). Similarly, TNF produces a decrease in CREB (Arai et al., 2005). (f) Taken together, the elevated TNF levels, decreases in ␤-arrestin, BDNF, and CREB are all associated with the attenuated neurogenesis of depression and chronic pain (Duric and McCarson, 2006b; Warner-Schmidt and Duman, 2006). (B) The role of TNF in antidepressant therapeutic drug action. (a) Initially (acute), upon dosing, some antidepressants indirectly decrease TNF through blockade of monoamine reuptake or monoamine oxidase inhibition. This blockade increases NE availability allowing for ␣2 -AR activation (it is coupled to G␣i/o protein); the ␣2 -AR-G␣i/o configuration supports a decrease in TNF (see ‘d’ above) (Ignatowski et al., 1996a; Nickola et al., 2000; Renauld and Spengler, 2002; Reynolds et al., 2005a; Spengler et al., 2007). Also, tricyclic antidepressants, atypical antidepressants (bupropion, rolipram), and electroconvulsive therapy directly reduce TNF levels in the brain (Brustolim et al., 2006; Buttini et al., 1997; Hestad et al., 2003; Ignatowski et al., 1996b; Ignatowski and Spengler, 1994; Nickola et al., 2001). The initial antidepressant-induced decrease in TNF expression is a cAMP-mediated event (Maes et al., 2005; Renauld et al., 2004; Sud et al., 2007). (b) Since TNF normally inhibits NE release, the initial decrease in TNF levels allows for an increase in NE release (Reynolds et al., 2004b). Also, TNF produces an increase in G␣i/o protein expression (Klein et al., 1995; Reithmann et al., 1991; Scherzer et al., 1997); therefore, decreased TNF would be associated with decreased G␣i/o protein expression (Reynolds et al., 2005b) and increase of ␣2 -AR coupling to G␣s proteins (Chabre et al., 1994; Chen and Rasenick, 1995b; Eason et al., 1992, 1994; Pauwels et al., 2001), which upon activation facilitates NE release (Ignatowski and Spengler, 1994; Nickola et al., 2001; Reynolds et al., 2004b, 2005b). (c) The increase in bioavailable NE allows for enhanced ␣2 -AR activation that not only serves to further increase NE release, but also now supports an increase in TNF production (Nickola et al., 2000; Renauld and Spengler, 2002; Spengler et al., 2007). In turn, TNF increases NE release (directly) (Ignatowski et al., 1996b, 1997, 2005; Ignatowski and Spengler, 1994; Nickola et al., 2001; Reynolds et al., 2004a, 2005a). A new baseline is thus established between TNF production and ␣2 -AR coupling for balanced regulation of NE release. (d) The overall decrease in TNF (from pathological to physiological levels) allows for increased ␤-arrestin activity, and BDNF and CREB production. (e) Together, the enhanced BDNF, CREB, ␤-arrestin activity, monoamine levels, and lowered TNF levels support neurogenesis (Avissar et al., 2004; Duric and McCarson, 2006b; Gould, 1999; Iosif et al., 2006; Nakagawa et al., 2002; Pencea et al., 2001; Thome et al., 2000). Step (a) is proposed to occur within minutes to hours, while steps (b)–(e) would take days to weeks to be accomplished. NE, norepinephrine; SC, spinal cord; BDNF, brain-derived neurotrophic factor; CREB, cAMP response element binding protein.

pain and depressive behavior/stress (Duric and McCarson, 2005, 2006a, 2006b, 2007). We propose that similar to the ␣2 -AR regulation of cAMP in the hippocampus versus peripheral nerve (Sud et al., 2007) and to the ␣2 -AR regulation of TNF␣ production in the hippocampus versus peripheral macrophage (Nickola et al., 2000; Spengler et al., 1990), TNF␣ most likely regulates the production of BDNF differentially in the hippocampus versus in the spinal cord/peripheral sensory neurons. Based on the preponderance of

findings in regards to chronic pain and depression, we predict that in the hippocampus, an increase in TNF␣ beyond physiological levels will decrease BDNF production (Fig. 3). The guanine nucleotide protein (G-protein) second messenger system provides a mechanism that explains ␣2 -adrenergic and TNF␣ regulation of the monoamine NE within the hippocampus during neuropathic pain. The ␣2 -AR couples to either G␣i or G␣s proteins to elicit opposing effects (Chabre et al., 1994; Eason et al.,

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1992, 1994; Pauwels et al., 2001). TNF␣ differentially modulates the expression of the G-proteins, thereby regulating intracellular signaling of the ␣2 -ARs (Reynolds et al., 2005b; Spengler et al., 2007). A switch in the availability of G␣i or G␣s -proteins allows for a change of AR-coupling and the corresponding switch of ␣2 adrenergic regulation of TNF␣ production (Nickola et al., 2000; Renauld et al., 2004; Renauld and Spengler, 2002; Reynolds et al., 2005b) and NE release, as verified by the CCI model (Spengler et al., 2007). The importance of the G-proteins was shown by the administration of pertussis toxin, which inactivates G␣i proteins and thereby switched the inhibition of NE release to potentiation (a G␣s -protein function); subsequent exposure to TNF␣ reversed this response back to inhibition (Reynolds et al., 2005b). Therefore, TNF␣ regulation of G-proteins may underlie the pathophysiological change in monoamine functioning that is observed during chronic pain and depression. Taken together, the articles reviewed above provide support for a model of hippocampal TNF involvement in chronic pain and depression that is illustrated in Fig. 3. Left untreated or under-treated, both chronic pain and depression become self-sustaining and persistent; similar pathologic changes predicted to occur within the hippocampus for chronic pain are indicated for depression (Fig. 3A), providing a theoretical link for their comorbidity. 5.4. Trophic factors and transcription factors common to pain and depression The extracellular signal-regulated protein kinase/CREB (ERK/CREB) cascade may be a common intracellular transduction mechanism between various CNS events that lead to central sensitization, stress-evoked hippocampal plasticity, and/or the LTP associated with memory formation (Duric and McCarson, 2007; Mizuno et al., 2002; Ying et al., 2002). ERK and CREB are thought to play a role in the conversion of acute stimuli into long-term events, such as that observed in the development and maintenance of chronic pain or depression (Duric and McCarson, 2007). Activation of CREB is coupled to various transduction factors, besides ERK. The ERK/CREB cascade is one of many intracellular pathways in which extracellular stimulation (e.g. pain) is transduced to posttranslational and transcriptional responses within neuronal tissue (Duric and McCarson, 2007). Genes such as those for neurokinin-1 receptor (NK-1R), tyrosine protein kinase B (trkB) and BDNF have the CRE sites present in their promoter regions (Duric and McCarson, 2007; Lonze and Ginty, 2002) allowing them to be co-regulated via a CREB-dependent mechanism during pain or stress (Duman and Charney, 1999; Duman et al., 1997; Duric and McCarson, 2005; Nibuya et al., 1995). SP, a major nociceptive neuropeptide, its receptor NK-1R, and the neurotrophic factor BDNF are ubiquitously expressed throughout the hippocampus, including the granular layer and hilum of the dentate gyrus and the pyramidal cells of the CA1 and CA3 regions (Duric and McCarson, 2005, 2007; Yan et al., 1997). NK-1R and BDNF are involved in neuronal plasticity of the CNS, particularly stress-induced hippocampal plasticity (Duric and McCarson, 2006b, 2007). SP has the trophic ability to stimulate the growth of axons (De Felipe et al., 1995; Herpfer and Lieb, 2005); however, BDNF is proposed to be the primary neurotrophin of the hippocampus (Maletic et al., 2007) and is involved in the regulation of neurogenesis (Duric and McCarson, 2006b; Scharfman et al., 2005). BDNF is responsible for trimming neuronal networks via an activity-dependent mechanism regulated by neurotransmitters, such as glutamate, ␥-aminobutyric acid, serotonin, NE, acetylcholine, and hormones (Maletic et al., 2007). BDNF also plays an integral role in maintaining the health of the glial-neuronal interactions (Duman et al., 1997; Duric and McCarson, 2007; Maletic et al., 2007). The pain-induced down-regulation of hippocampal NK-1R

and BDNF gene expression is in stark contrast to the up-regulation that is observed in the spinal cord (Duric and McCarson, 2006b). The disparity in hippocampal versus spinal cord pain-induced gene expression of NK-1R and BDNF lies in their distinct modulating effects on the hippocampus (i.e., mood, affect) versus on the development of central sensitization in the sensory components of the CNS (Duric and McCarson, 2006b). Similar to chronic pain, depression results in down-regulation of hippocampal expression of NK-1R and BDNF (Duric and McCarson, 2005, 2006a, 2006b; Maletic et al., 2007). The chronic pain- and stress-induced downregulation of NK-1R and BDNF gene expression suggest that these pathways converge on non-sensory higher brain regions (Duric and McCarson, 2007), such as the hippocampus (Duric and McCarson, 2005, 2006b). Also, the SP/NK-1R system overlaps with that of serotonin (dorsal raphe nucleus) and NE (locus coeruleus), which are known for their involvement in regulation of mood and stress. Therefore, SP, as a co-transmitter, may modulate the effect of these (NE, serotonin) neurotransmitters during depression and chronic pain (Feuerstein et al., 1996; Herpfer and Lieb, 2005). Moreover, clinical observations support involvement of SP/NK1R and BDNF/trkB in the processing of mood/disposition (Duman et al., 1997; Duric and McCarson, 2007; Kramer et al., 1998; Rupniak and Kramer, 1999). For example, fibromyalgia is a chronic pain syndrome often associated with depressive symptoms (Ackenheil, 1998) that frequently presents with elevated cerebrospinal fluid (CSF) levels of SP (Herpfer and Lieb, 2005; Russell, 2002). Stressinduced down-regulation of BDNF is evident in patients with untreated MDD, as shown by significantly lower levels of serum BDNF (Maletic et al., 2007; Shimizu et al., 2003). Post-mortem analysis of individuals who committed suicide showed a decrease in hippocampal BDNF levels compared with non-suicide individuals (Karege et al., 2005; Maletic et al., 2007). In fact, BDNF is associated with the reversal of stress-related pathophysiology seen in the hippocampus (Duric and McCarson, 2006a; Nibuya et al., 1995) such that intra-hippocampal injections of BDNF result in antidepressantlike behaviors (Herpfer and Lieb, 2005; Shirayama et al., 2002). Furthermore, post-mortem analysis of depressed patients who were receiving antidepressant therapy at the time of death had a greater BDNF expression than untreated depressed individuals (Chen et al., 2001; Maletic et al., 2007). Additionally, SP and NK1R interfere with the regulation and physiological effects of the HPA axis (Duric and McCarson, 2005; Jessop et al., 2000; Nussdorfer and Malendowicz, 1998). For example, the acute actions of SP are inhibitory on HPA axis activity (Blackburn-Munro and BlackburnMunro, 2001; Nussdorfer and Malendowicz, 1998). 6. Treatments and medications Often temporary pain relief is achieved through analgesics, such as morphine, non-steroidal anti-inflammatory drugs, and anticonvulsants; however, these therapies have long-term complications and short-term efficacy that leaves patients with untreated and constant pain (Blackburn-Munro and Blackburn-Munro, 2001). Important goals in pain management are to avoid chronicity and to reduce the functional disability of the patient; this would require that the treatment prevent development of central sensitization by minimizing physical as well as cognitive and emotional distress caused by pain (Martelli et al., 2004). Although the mechanism of action is not well understood, it is common practice to use the same medications to treat both chronic pain and depression. The neuromodulators and primaryaffected brain regions shared between these two disease states allow the same drugs, such as certain classes of antidepressants, to be effective for both disorders. The hippocampus is a target of many antidepressants. For example, SNRIs, which target both serotonin and NE pathways, improve core features of MDD, including


restoration of physiologic functioning in the hippocampus, as well as provide relief of associated physical symptoms (Maletic et al., 2007). However, analgesic effects of antidepressants may occur at a much more rapid onset, at lower dose, and independently of antidepressant effects (Duric and McCarson, 2006a; Lynch, 2001; McQuay et al., 1996). These differences in the treatment of chronic pain and depression suggest that the mechanism mediating the analgesic and antidepressant effects of antidepressants may be monoamineindependent or involve more important determinants. 6.1. Antidepressants and mechanisms A majority of current antidepressants (e.g. SSRIs, SNRIs, triand tetra-cyclic, and MAOIs) target the monoamine pathway, to enhance synaptic levels of NE and serotonin in the brain (Duman et al., 1997; Duric and McCarson, 2006a; Herpfer and Lieb, 2005). Monoamine oxidase inhibitors block the enzyme that breaks down monoamines. The reuptake inhibitors (SSRI, SNRI) are thought to block the reuptake of monoamines at the level of the reuptake transporters. Tricyclic antidepressants (e.g. desipramine, amitriptyline, and fluoxetine) alleviate the symptoms of chronic pain and depression by increasing monoamine release in the hippocampus, which would likely alter ␣2 -AR number and sensitivity, decrease hippocampal TNF␣ and/or affect the interaction between TNF␣ and ␣2 -ARs (Covey et al., 2000; Ignatowski et al., 1996a, 1997; Ignatowski and Spengler, 1994; Spengler et al., 2007). Fluoxetine inhibits the production of pro-inflammatory cytokines, thereby alleviating chronic pain symptoms (Blackburn-Munro and Blackburn-Munro, 2001). As expected, plasma levels of cytokines were elevated in patients who did not respond to antidepressant treatment (Maletic et al., 2007; O’Brien et al., 2007). Based on the theoretical model for common pathophysiological mechanisms underlying both diseases (Fig. 3A), a mechanism is proposed for comorbid treatment involving modification of the interaction between TNF␣ levels and functioning of ␣2 -ARs. Antidepressant-induced inhibition of TNF␣ production may induce a decrease in G␣i proteins and increase monoamine bioavailability. These events would oppose the changes in the hippocampus during the development of chronic pain and depression that increase G␣i proteins and decrease monoamine bioavailability (see Fig. 3B) (Reynolds et al., 2004b, 2005a; Spengler et al., 2007; Sud et al., 2008). Support for this was demonstrated by using the CCI model of chronic pain. Amitriptyline inhibited CCI pain-induced increases in TNF␣ (Sud et al., 2008) and modified ␣2 -adrenergic regulation of NE release (Ignatowski et al., 2005) and cAMP production in the hippocampus (Sud et al., 2007); these changes were associated with analgesic effects. Administration of recombinant rat TNF␣ into the cerebral ventricles opposed the analgesic effects of intraperitoneal amitriptyline administration, indicating that inhibition of TNF␣ production in the brain is required for the analgesic actions of this drug (Sud et al., 2007). Unfortunately, antidepressants that affect monoaminergic pathways tend to have a slow onset of action and limited efficacy in protecting against relapse of depressive symptoms following cessation of therapy; moreover they are not effective in patients suffering from severe depressive symptoms (Andrews and Pinder, 2000; Blackburn-Munro and Blackburn-Munro, 2001). Clonidine, an ␣2 -AR agonist that possesses analgesic properties, as well as acute antidepressant qualities in the CNS (Ignatowski et al., 1996a), affects the production of TNF␣ (Ignatowski et al., 1996a; Nader et al., 2001; Nickola et al., 2000). Clonidine, like desipramine and amitriptyline, alters the ␣2 -adrenergic sensitivity to TNF␣ and transforms TNF␣ regulation of NE release from inhibition to potentiation at the time when CCI-induced pain is alleviated (Ignatowski et al., 2005; Spengler et al., 2007). Based on these and other findings, there is a focus on targeting cytokines and/or their

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receptors in the development of effective therapies for both chronic pain and depression (Iannone et al., 2007; Mulleman et al., 2006; Sasaki et al., 2007). 6.2. Anti-TNF drugs The findings that healthy volunteers administered TNF␣ develop symptoms of depression (Dantzer et al., 1999; Meyers, 1999; Wichers and Maes, 2002), and as mentioned before, that TNF has been shown to be increased in patients experiencing chronic pain and depression, point toward TNF␣ as a target for therapy. Both preclinical and clinical studies have shown that blocking TNF alleviates symptoms of chronic pain and depression (Krugel et al., 2013; Lichtenstein et al., 2002; Mathias et al., 2000; Sommer et al., 2001). For example, animal studies show that i.c.v. administration of polyclonal anti-TNF␣ antibodies to rats abolishes hyperalgesia in the CCI pain model (Ignatowski et al., 1999) and increases mobility in the forced swim test, similar to antidepressant administration (Reynolds et al., 2004b). Clinically, a perispinal method was used to administer etanercept, a human TNF receptor-2 antagonist, to chronic pain patients; a subset of these patients exhibited physical and cognitive improvement (Tobinick and Davoodifar, 2004; Tobinick, 2003). Interestingly, patients that received perispinal etanercept for stroke/traumatic brain injury reported alleviation of pain and an improved mood/affect (Tobinick et al., 2012). Likewise, results from a double-blind, placebo-controlled study showed that epidural etanercept was effective in alleviating chronic sciatica (Cohen et al., 2009). However, in a clinical trial whereby infliximab (monoclonal anti-TNF antibody, administered by i.v. infusion) was used for treatment of chronic sciatica, some patients did not receive benefit (Korhonen et al., 2005, 2006; IOM, 2011). Similarly, a recent randomized, controlled trial of infliximab for treatment-resistant depression by Raison and colleagues showed no overt efficacy in treatment-resistant depression, but did find that infliximab improved depressive symptoms in patients expressing a high baseline of inflammatory markers (Raison et al., 2013). These conflicting reports of lack of anti-TNF␣ efficacy for chronic pain and depression could be due to the prediction that targeting TNF centrally is necessary. In fact, functional MRI confirmed that the rapid relief of chronic pain (within 24 h) following TNF neutralization via i.v. infliximab was due to CNS effects, including blockade of pain-induced limbic system activation (Hess et al., 2011). Thus, it is apparent that TNF plays a pivotal role in chronic pain and depression, and therapies aimed at decreasing not just systemic, but perhaps more importantly, central levels of TNF may provide more efficacious treatment modalities. 6.3. Enhancing neurogenesis It has been hypothesized that impaired neurogenesis has an essential role in the pathogenesis of both MDD and chronic pain syndrome (Kempermann and Kronenberg, 2003; Mutso et al., 2012). Antidepressants are able to prevent and sometimes reverse structural plasticity in the hippocampus that is mediated by chronic pain or depression. The alleviation of depressive symptoms by antidepressants involves an increase in neurogenesis and angiogenesis (Santarelli et al., 2003), as well as preventing and/or reversing hippocampal volume loss (Bremner et al., 2000; Herpfer and Lieb, 2005). For instance, dual-reuptake inhibitors (Duman et al., 1997; Maletic et al., 2007) show an improvement in depressive symptoms that not only correlates with increased availability of NE and serotonin, but also increased activation of cAMP and subsequent increases in expression of growth factors necessary for neuronal survival, such as BDNF and its receptor, trkB (Chen et al., 2001; Maletic et al., 2007; Nibuya et al., 1995; Sairanen et al., 2005). Phenytoin, an NMDA receptor blocker (Magarinos et al.,

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1999; McEwen et al., 1997), and tianeptine, a serotonin-reuptake enhancer, block stress-induced atrophy of CA3 dendrites (McEwen, 1999a, 2001). Furthermore, tianeptine partially reverses the stress induced presynaptic ultrastructural rearrangement at the level of the mossy fiber terminals (Magarinos et al., 1997, 1999). 6.4. Increasing BDNF levels Experiments using animal models of chronic stress and pain demonstrated decreased BDNF expression in the hippocampus (Duric and McCarson, 2005, 2006b, 2007; Russo-Neustadt et al., 2001). Thus, the administration of 4-methylcatechol, a potent stimulator of BDNF synthesis (Furukawa et al., 1989; Kourounakis et al., 1997), may exert antidepressant and analgesic effects on chronic pain via induction of BDNF in the brain (Fukuhara et al., 2012). Therefore, specifically increasing BDNF may be a novel treatment strategy for chronic pain associated with depression. 6.5. Modulation of the HPA axis The HPA axis is also a target of antidepressants, such as tianeptine and fluoxetine. Chronic antidepressant therapy reduces CSF concentrations of corticotrophin releasing hormone and upregulates the expression of MR and GR (Blackburn-Munro and Blackburn-Munro, 2001; Holsboer and Barden, 1996). Tianeptine counteracts stress-induced activation of the HPA axis that result from GR dysfunction and also prevents and reverses structural remodeling of hippocampal neurons (Delbende et al., 1991; Holsboer, 2000; Magarinos et al., 1999; Pariante and Miller, 2001; Raison and Miller, 2003). Chronic antidepressant therapy may be a result of the drug’s effects on second messengers that are involved in the regulation of GR expression, such as activation of cAMP (Maletic et al., 2007; Pace et al., 2007; Raison and Miller, 2003). An additional benefit of antidepressants in the HPA axis is restoration of the glucocorticoid-mediated inhibition of the immune system (Holsboer, 2000; Pariante and Miller, 2001; Raison and Miller, 2003). 6.6. Other mechanisms 6.6.1. Other enzyme and receptor targets Indoleamine 2,3-dioxygenase-1 (IDO1) has as an important role in the tryptophan metabolic pathway, therefore alteration of IDO1 changes the level of kynurenine and serotonin. Moreover, inhibition of IDO-1 activity or IDO gene knockout decreased the serotonin/tryptophan ratio that had been increased by hippocampal IDO up-regulation and, at the same time, improved pain and depression. This raises the possibility that an IDO1 inhibitor, or any other agent blocking IDO1 up-regulation or regulating tryptophan metabolism, would be able to achieve concurrent alleviation of clinical pain and depression (Kim et al., 2012). Antagonism or genetic inactivation of SP receptor (NK-1R) leads to alterations in serotonin and NE transmission, which likely contributes to the antidepressant efficacy of NK-1R antagonists (Duric and McCarson, 2005; Herpfer and Lieb, 2005). SP receptor antagonists, such as aprepitant, attenuate stress-induced behavioral responses and produce antidepressant-like activity in experimental models. Aprepitant produced improvements in depressive symptoms are similar to those seen with paroxetine, a SSRI. Unlike most antidepressant treatments, SP antagonists did not cause motor impairment or sedation in the tested animals. SP antagonists may modulate mood responses to stressful stimuli independently of other neurotransmitter pathways (Herpfer and Lieb, 2005). Studies suggest that SP antagonists involve complex interactions with the HPA axis (Lieb et al., 2002; Rupniak, 2002), neurotransmitters, and/or neurogenesis (Herpfer and Lieb, 2005).

6.6.2. Ketamine and NMDA antagonism There is a need for more efficacious medical treatments for MDD that exhibit a faster onset of action and sustained effects of hours or even days. One of the drugs with above-mentioned properties is an NMDA antagonist, ketamine (Sanacora et al., 2008), which has both analgesic and antidepressant effects, making ketamine ideally suited for co-occurring depression and pain (Correll et al., 2004; Garcia et al., 2008). By antagonizing NMDA receptors in the spinal dorsal horn neurons, ketamine can decrease central sensitization (Jorum et al., 2003; Sawynok and Reid, 2002), thereby providing descending monoaminergic inhibition of pain (Sawynok and Reid, 2002). Unlike the short-term analgesic properties of ketamine that are mediated at peripheral and spinal levels, its long-term antidepressant properties involve frontal and limbic structures (Correll et al., 2004; Garcia et al., 2008). Lowdose ketamine appears to have an important role in treating the depressive symptoms of neuropathic pain (Wang et al., 2011). Besides its effects on the inhibition of NMDA, ketamine stimulates AMPA receptors (Koike et al., 2011; Maeng et al., 2008); a recent study showed that chronic low-dose ketamine administration was associated with an increase in the AMPA/NMDA receptor density ratio in the hippocampus and had a significant and lasting antidepressant effect in WKY rats (Tizabi et al., 2012). Also, it was demonstrated that chronic AMPA alone, or in combination with ketamine at doses that were ineffective on their own, resulted in a significant antidepressant effect (Akinfiresoye and Tizabi, 2013). An underlying mechanism for the rapid antidepressant effect of ketamine is mTOR-(serine/threonine protein kinase) induced rapid formation of synapses. In other words, neurogenesis is most likely the underlying mechanism of antidepressant effects of ketamine, through increased expression of BDNF and mTOR (Li et al., 2010; Yang et al., 2013).

6.6.3. Non-pharmacologic alternative therapies Non-pharmacologic interventions are used to treat depression, especially refractory or treatment-resistant depression, and hard-to-treat chronic pain. Whereas electroconvulsive therapy and vagal nerve stimulation are FDA-approved for the treatment of refractory depression (George et al., 2005; Rush et al., 2005), these procedures also reduce pain in patients suffering from chronic pain induced by migraines and cluster headaches (Hord et al., 2003; Multon and Schoenen, 2005) and from chronic pelvic pain (Napadow et al., 2012). Several case reports demonstrate electroconvulsive therapy effectiveness in the treatment of comorbid chronic pain and depression (Suzuki et al., 2009; Wasan et al., 2004). Interestingly, both electroconvulsive therapy and vagal nerve stimulation affect the hippocampus: clinical and experimental studies exploring the antidepressant and/or analgesic mechanism(s) of electroconvulsive therapy and vagal nerve stimulation action consistently demonstrate increased hippocampal BDNF production (Furmaga et al., 2012; Kuwatsuka et al., 2013; Li et al., 2007; Taliaz et al., 2013), CREB activation (Gebhardt et al., 2013), noradrenergic transmission (Manta et al., 2013) and neurogenesis (Gebhardt et al., 2013; Ito et al., 2010). Electroconvulsive therapy and vagal nerve stimulation mediate anti-inflammation processes that decrease levels of TNF␣ in blood serum/plasma (Bansal et al., 2012; Hestad et al., 2003). Based on the evidence to date, normalization of hippocampal TNF␣ levels will restore brain function that is key to effective treatment of chronic pain and depression. Therefore, we predict that the effective treatment of chronic pain and depression with electroconvulsive therapy and vagal nerve stimulation intervention will be associated with a putative decrease in hippocampal TNF␣ production.


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Table 1 Database search results for number of peer-reviewed articles pertaining to indicated subjects. Main focus (total # of studies) Hippocampus TNF Hippocampus + TNF

– 133,510 [123,979] 174,740 [163,111] 1350 [1140]

Chronic pain

Depression

Chronic pain + depression

37,071 [32,169] 231 [209] 534 [439] 17 [16]

320,220 [266,929] 8654 [7524] 1657 [1484] 113 [93]

3944 [3257] 43 [39] 16 [9] 3 [2]

Articles in PubMed and OVID Medline databases, since 1946, were searched using Mesh keywords. Based on our search (performed on January 15, 2015), only 3 papers were found for (chronic pain + depression + hippocampus + TNF). TNF: tumor necrosis factor; for search purposes included (“tumor necrosis factor alpha” or “tumor necrosis factor” or TNF or “TNF alpha”). As illustrated, keywords consisting of more than one word were placed within quotation marks, e.g., “tumor necrosis factor”, to ensure a combined keyword search, thereby limiting inclusion of single word citations (e.g., necrosis) deemed non-relevant to the search parameter. Multiple phrases or keywords defined as a single entity were grouped within parentheses, e.g., (“tumor necrosis factor alpha” or “tumor necrosis factor” or TNF or “TNF alpha”), for searching purposes to ensure a complete and focused search. Depression was searched using (depression or “major depressive disorder”); chronic pain used (“chronic pain” or “neuropathic pain” or “persistent pain”); Hippocampus was searched using (hippocampus or hippocampal). Values are presented for PubMed results with OVID Medline results in brackets.

7. Conclusion Chronic pain and depression are debilitating diseases that are commonly comorbid such that chronic pain can lead to depressive symptoms, and patients with depression suffer from physical pain as well as emotional disturbances. The mechanism of this comorbidity is unknown, however, the hippocampus, which is a primary region within the limbic system that regulates mood/affect, is a key structural common denominator. The hippocampus is necessary both for a stimulus to be perceived as painful and for emotion-based disorders, such as depression. Stresses that include psychosocial stress and chronic pain induce structural and chemical plasticity or flexibility in hippocampal neurons. Chronic pain and depressive illness have been shown to produce neuroplastic changes including atrophy of the hippocampus. Another common denominator of both disorders is the induction of the pro-inflammatory and pleiotropic cytokine TNF␣. This TNF␣ induction activates the HPA axis, elevates glucocorticoids that are potent endogenous anti-inflammatory hormones, and decreases glucocorticoid responsiveness. This reduced glucocorticoid-responsiveness of chronic pain and depressive illness results in loss of glucocorticoidmediated suppression of pro-inflammatory cytokine production. Pro-inflammatory cytokines contribute to the increased glucocorticoids, setting up a vicious cycle that elevates levels of TNF␣ and glucocorticoids. Using the keywords chronic pain, depression, hippocampus, and TNF, a search was performed via the HUBNET/OVID and PubMed databases for related articles. The numbers of studies found, for any keyword alone and in combination, are shown in Table 1. When searched as a single entity or as simple combinations, such as “chronic pain and hippocampus” or “depression and hippocampus”, there were plenty of published studies related to these topics. However, as the search parameters became more focused, the search yielded only 43 studies focused on “chronic pain and depression and hippocampus” and just 16 articles searched by the “chronic pain and depression and TNF” combination. TNF, for search purposes, in each case included ‘tumor necrosis factor alpha or tumor necrosis factor or TNF alpha or TNF’. ‘Depression’ was searched using ‘depression or major depressive disorder’, and chronic pain used ‘chronic pain or neuropathic pain or persistent pain’ (see Table 1 legend for detailed definition of search parameters). Therefore, despite the prevalence of these disorders and the importance of the topic, there is a shortage of studies focused on the pathophysiology underlying chronic pain and depression comorbidity. Many neurotransmitters, neuromodulators, cytokines, and their receptors that are common to and important in the pathophysiology of chronic pain and depression are produced/expressed in the hippocampus. Therefore, the morphological changes of the hippocampus and dysfunction of the production of or response to cytokines, neuromodulators, and neurotransmitters within the hippocampus are likely responsible for the pathophysiology seen in chronic pain and depression. As presented herein, a review

of the literature suggests that many of the pathological changes of the hippocampus that are observed during chronic pain and depression contribute to the comorbidity of these disorders. We propose that the neuroplasticity in structure and function of the hippocampus may explain the pathogenesis of this comorbidity. The evidence further indicates that therapeutic targeting of the common hippocampus pathological changes may be the key to designing strategies for better treatment of chronic pain and depression that would provide greater efficacy over current therapeutic approaches and would present fewer side-effects.

Acknowledgements This work was prepared in partial fulfillment of the requirements for the Master of Arts degree, Department of Pathology and Anatomical Sciences, University at Buffalo, State University of New York (V.F.). These authors contributed equally to the writing of the manuscript (V.F., R.N.S., and T.A.I.). In addition to her contributions to the content of this manuscript, the authors would like to thank Dr. Shabnam Samankan for her invaluable assistance in the production of Fig. 2.

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Relation between catastrophizing and depression in chronic pain patients.

Depression and the chronic pain experience.

Longitudinal associations between depression, anxiety, pain, and pain-related disability in chronic pain patients.

Differences in the Association between Depression and Opioid Misuse in Chronic Low Back Pain versus Chronic Pain at Other Locations.

Links between early post-partum mood and post-natal depression.

Associations Between Pain, Current Tobacco Smoking, Depression, and Fibromyalgia Status Among Treatment-Seeking Chronic Pain Patients.

Longitudinal Links Between Perfectionism and Depression in Children.

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Chronic idiopathic pain, mianserin and 'masked' depression.

The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain.

Common misconceptions about chronic pain.

Ethnic differences in the association between depression and chronic pain: cross sectional results from UK Biobank.

The Association between Chronic Widespread Musculoskeletal Pain, Depression and Fatigue Is Genetically Mediated.

The association between chronic pain and obesity.

Correction: Associations between Neuroticism and Depression in Relation to Catastrophizing and Pain-Related Anxiety in Chronic Pain Patients.

Chronic back pain. A common sense approach.

Gender Differences in the Developmental Links Between Conduct Problems and Depression Across Early Adolescence.

A difficult combination: chronic physical illness, depression, and pain.

Opioid use and depression in chronic pelvic pain.

Unlocking pain: deep brain stimulation might be the key to easing depression and chronic pain.

Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens.

Links Between the Microbiome and Bone.

Associations between pain appraisals and pain outcomes: meta-analyses of laboratory pain and chronic pain literatures.

Pain, kinesiophobia and quality of life in chronic low back pain and depression.