Editorial Bhattacharjee
“If we can disrupt channel trafficking mechanisms that result from prostaglandininduced inflammatory signaling for example, we could produce an analgesic-specific effect without the side effects, such as addiction, of current analgesics.”
200
opioids act centrally, they also produce sedation, euphoria or dysphoria, nausea and vomiting, and in overdose, deadly respiratory depression. Nonsteroidal antiflammatory drugs and opiods are very good for relieving inflammatory pain states: pain that arises from acute tissue injury or trauma. However, there are limitations to these drugs when pain results from nerve injury. Nerve injury pain, called neuropathic pain, can be caused by nerve compression, spinal cord injury, diabetes, alcoholism, cancer chemotherapy and postherpectic neuralgia. Nerve damage results in the persistent action potential firing of primary nociceptive afferents. The continual input from discharging nociceptors induces synaptic changes in the spinal cord, causing central sensitization. It is important to realize that continual discharging afferents are required for maintenance of central sensitization [2] . Therefore, for neuropathic pain, alternative types of analgesics are required. Antiepileptic drugs such as carbamazepine, phenytoin and valproate are used. These drugs directly target ion channels, particularly sodium channels, to reduce excitability. However, they are antiepileptic drugs acting centrally and, as such, are also associated with many side effects. Are there any similarities between chronic inflammatory pain and neuropathic pain? Both pain states depend on nociceptor hyperexcitability [3–5] . Therefore, developing drugs that act peripherally, targeting ion channels and thereby reducing primary afferent sensitization, is a logical analgesic approach to take to minimize side effects and prevent addiction. Which ion channel(s) should we target? The answer to this question is not so simple. There has been extensive research trying to determine the principle ion channels that are responsible for nociceptor hyperexcitability in animal models of inflammatory and neuropathic pain. Heavy emphasis has been placed on the central role of voltage-dependent sodium channels in primary afferent hyperexcitability. However, recent transgenic animal studies indicate that increased sodium channel activity may not be essential in the pathophysiology of inflammatory and neuropathic pain [6] . Calcium channels, in particular T‑type calcium channels, have drawn considerable attention because they are upregulated in neuropathic pain [7] , and specific T‑type calcium channel antagonists have been tested for their abilities to treat neuropathic pain [8] . However, targeting sodium and calcium channels poses
Pain Manage. (2011) 1(3)
toxicity issues, because many of the same channel subtypes expressed in nociceptors are also expressed in other neuronal and non-neuronal tissues. Potassium channels also offer unique analgesic targets. Potassium currents in nociceptors are also affected by inflammation and neuropathy, and therefore developing potassium channel openers to increase their activity will impact nociceptor hyperexcitability. Potassium channels are far more diverse than sodium and calcium channels, and the unique repertoire of potassium channels that are expressed in nociceptors could be of considerable pharmacological interest [9] . From my 11 years of experience studying sodium-activated potassium (K Na) channels, I have found their expression in rats to be the highest in trigeminal and dorsal root ganglion neurons [10,11] . Why sensory neurons express high levels of K Na channels still remains to be fully answered. However, my research team has recently demonstrated that PKA activation results in the internalization of K Na channels from the dorsal root ganglia neuronal membrane and this was associated with hyperexcitability [12] . The most remarkable aspect of these findings is that there is a robust ion channel trafficking capacity in nociceptive neurons: signal activation causes ion channels to move in and out of the nociceptor membrane [12–15] . Ion channel trafficking offers nociceptive neurons a rapid but prolonged method for changing their firing properties. Up until this point, many have assumed that inflammatory mediators modulate nociceptors primarily through phosphorylation-/dephosphorylation-dependent changes in ion channel gating. While this process is important, I would like to highlight that phosphorylation-dependent changes in channel gating are transient. Dorsal root ganglia neuronal hyperexcitability in either neuropathic pain or inflammatory pain occurs in the magnitude of hours, days, weeks or even years. We need to appreciate the long-term regulation of ion channels at the plasma membrane in pain-sensing neurons. This is akin to the understanding of ion channel clustering and trafficking during synaptic plasticity in the CNS. It is within the context of ion channel trafficking that I think efficacious, nontoxic analgesics can be developed. Merely applying channel blockers or channel openers will inevitably lead to adverse side effects. If we can disrupt channel trafficking mechanisms that result from prostaglandin-induced inflammatory
future science group
Targeting ion channel trafficking mechanisms for novel analgesics signaling for example, we could produce an analgesic-specific effect without the side effects, such as addiction, of current analgesics. Indeed, this may be how the well-tolerated drug gaba pentin, which controls the trafficking of calcium channels [16] , is efficacious for neuropathic pain. Future research is still required to understand nociceptor hyperexcitability during inflammatory and neuropathic pain signaling; we need to identify the dynamic ion channel processes associated with hyperexcitability. If we can elucidate the molecular underpinnings of nociceptor hyperexcitability, it will lead to better and safer analgesics. Unfortunately, within the USA, the NIH devotes only a fraction of a percentage of its total budget to pain research and, given the recent decline in interest for developing new therapeutics by pharmaceutical companies, it is unclear where the impetus will come for the Bibliography 1
2
3
4
5
6
7
Green GA: Understanding NSAIDs: from aspirin to COX-2. Clin. Cornerstone 3(5), 50–60 (2001). Pitcher GM, Henry JL: Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy. Exp. Neurol. 214, 219–228 (2008). Reichling DB, Levine JD: Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 32, 611–618 (2009). Xu J, Brennan TJ: Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision. Anesthesiology 112, 153–164 (2010). Wu G, Ringkamp M, Murinson BB et al.: Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J. Neurosci. 22, 7746–7753 (2002). Krafte DS, Bannon AW: Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8, 50–56 (2008).
future science group
8
development of novel channel targeted drugs. Perhaps the Drug Enforcement Agency, with its billion-dollar budget, could devote a portion of its resources to fund research whose sole purpose is to develop nonaddictive analgesics. It may be as cost effective as trying to protect pharmacies from bandits gallivanting down the Oxy Express. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert te stimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Jagodic MM, Pathirathna S, Joksovic PM et al.: Upregulation of the T‑type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J. Neurophysiol. 99, 3151–3156 (2008).
13 Ji RR, Samad TA, Jin SX, Schmoll R,
Todorovic SM, Jevtovic-Todorovic V: T‑type voltage-gated calcium channels as targets for the development of novel pain therapies. Br. J. Pharmacol. DOI: 10.1111/j.1476-5381.2011.01256.x (2011) (Epub ahead of print).
14
Zhang X, Huang J, McNaughton PA: NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 24, 4211–4223 (2005).
15
Fabbretti E, D’Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R: Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J. Neurosci. 26, 6163–6171 (2006).
16
Bauer CS, Tran-Van-Minh A, Kadurin I, Dolphin AC: A new look at calcium channel a2d subunits. Curr. Opin. Neurobiol. 20, 563–571 (2010).
9
Ocana M, Cendan CM, Cobos EJ, Entrena JM, Baeyens JM: Potassium channels and pain: present realities and future opportunities. Eur. J. Pharmacol. 500, 203–219 (2004).
10
Bhattacharjee A, Gan L, Kaczmarek LK: Localization of the Slack potassium channel in the rat central nervous system. J. Comp. Neurol. 454, 241–254 (2002).
11
Editorial
Tamsett TJ, Picchione KE, Bhattacharjee AL: NAD + Activates K Na channels in dorsal root ganglion neurons. J. Neurosci. 29, 5127–5134 (2009).
12 Nuwer MO, Picchione KE, Bhattacharjee A:
PKA-induced internalization of Slack K Na channels produces dorsal root ganglion
neuron hyperexcitability. J. Neurosci. 30, 14165–14172 (2010). Woolf CJ: p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36, 57–68 (2002).
Website 101 Illegal prescription-drug trade now epidemic
www.dispatch.com/live/content/local_news/ stories/2010/02/07/OXYCONTIN.ART_ ART_02-07-10_A1_HGGH7K4.html
www.futuremedicine.com
201
“If we can disrupt channel trafficking mechanisms that result from prostaglandininduced inflammatory signaling for example, we could produce an analgesic-specific effect without the side effects, such as addiction, of current analgesics.”
200
opioids act centrally, they also produce sedation, euphoria or dysphoria, nausea and vomiting, and in overdose, deadly respiratory depression. Nonsteroidal antiflammatory drugs and opiods are very good for relieving inflammatory pain states: pain that arises from acute tissue injury or trauma. However, there are limitations to these drugs when pain results from nerve injury. Nerve injury pain, called neuropathic pain, can be caused by nerve compression, spinal cord injury, diabetes, alcoholism, cancer chemotherapy and postherpectic neuralgia. Nerve damage results in the persistent action potential firing of primary nociceptive afferents. The continual input from discharging nociceptors induces synaptic changes in the spinal cord, causing central sensitization. It is important to realize that continual discharging afferents are required for maintenance of central sensitization [2] . Therefore, for neuropathic pain, alternative types of analgesics are required. Antiepileptic drugs such as carbamazepine, phenytoin and valproate are used. These drugs directly target ion channels, particularly sodium channels, to reduce excitability. However, they are antiepileptic drugs acting centrally and, as such, are also associated with many side effects. Are there any similarities between chronic inflammatory pain and neuropathic pain? Both pain states depend on nociceptor hyperexcitability [3–5] . Therefore, developing drugs that act peripherally, targeting ion channels and thereby reducing primary afferent sensitization, is a logical analgesic approach to take to minimize side effects and prevent addiction. Which ion channel(s) should we target? The answer to this question is not so simple. There has been extensive research trying to determine the principle ion channels that are responsible for nociceptor hyperexcitability in animal models of inflammatory and neuropathic pain. Heavy emphasis has been placed on the central role of voltage-dependent sodium channels in primary afferent hyperexcitability. However, recent transgenic animal studies indicate that increased sodium channel activity may not be essential in the pathophysiology of inflammatory and neuropathic pain [6] . Calcium channels, in particular T‑type calcium channels, have drawn considerable attention because they are upregulated in neuropathic pain [7] , and specific T‑type calcium channel antagonists have been tested for their abilities to treat neuropathic pain [8] . However, targeting sodium and calcium channels poses
Pain Manage. (2011) 1(3)
toxicity issues, because many of the same channel subtypes expressed in nociceptors are also expressed in other neuronal and non-neuronal tissues. Potassium channels also offer unique analgesic targets. Potassium currents in nociceptors are also affected by inflammation and neuropathy, and therefore developing potassium channel openers to increase their activity will impact nociceptor hyperexcitability. Potassium channels are far more diverse than sodium and calcium channels, and the unique repertoire of potassium channels that are expressed in nociceptors could be of considerable pharmacological interest [9] . From my 11 years of experience studying sodium-activated potassium (K Na) channels, I have found their expression in rats to be the highest in trigeminal and dorsal root ganglion neurons [10,11] . Why sensory neurons express high levels of K Na channels still remains to be fully answered. However, my research team has recently demonstrated that PKA activation results in the internalization of K Na channels from the dorsal root ganglia neuronal membrane and this was associated with hyperexcitability [12] . The most remarkable aspect of these findings is that there is a robust ion channel trafficking capacity in nociceptive neurons: signal activation causes ion channels to move in and out of the nociceptor membrane [12–15] . Ion channel trafficking offers nociceptive neurons a rapid but prolonged method for changing their firing properties. Up until this point, many have assumed that inflammatory mediators modulate nociceptors primarily through phosphorylation-/dephosphorylation-dependent changes in ion channel gating. While this process is important, I would like to highlight that phosphorylation-dependent changes in channel gating are transient. Dorsal root ganglia neuronal hyperexcitability in either neuropathic pain or inflammatory pain occurs in the magnitude of hours, days, weeks or even years. We need to appreciate the long-term regulation of ion channels at the plasma membrane in pain-sensing neurons. This is akin to the understanding of ion channel clustering and trafficking during synaptic plasticity in the CNS. It is within the context of ion channel trafficking that I think efficacious, nontoxic analgesics can be developed. Merely applying channel blockers or channel openers will inevitably lead to adverse side effects. If we can disrupt channel trafficking mechanisms that result from prostaglandin-induced inflammatory
future science group
Targeting ion channel trafficking mechanisms for novel analgesics signaling for example, we could produce an analgesic-specific effect without the side effects, such as addiction, of current analgesics. Indeed, this may be how the well-tolerated drug gaba pentin, which controls the trafficking of calcium channels [16] , is efficacious for neuropathic pain. Future research is still required to understand nociceptor hyperexcitability during inflammatory and neuropathic pain signaling; we need to identify the dynamic ion channel processes associated with hyperexcitability. If we can elucidate the molecular underpinnings of nociceptor hyperexcitability, it will lead to better and safer analgesics. Unfortunately, within the USA, the NIH devotes only a fraction of a percentage of its total budget to pain research and, given the recent decline in interest for developing new therapeutics by pharmaceutical companies, it is unclear where the impetus will come for the Bibliography 1
2
3
4
5
6
7
Green GA: Understanding NSAIDs: from aspirin to COX-2. Clin. Cornerstone 3(5), 50–60 (2001). Pitcher GM, Henry JL: Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy. Exp. Neurol. 214, 219–228 (2008). Reichling DB, Levine JD: Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 32, 611–618 (2009). Xu J, Brennan TJ: Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision. Anesthesiology 112, 153–164 (2010). Wu G, Ringkamp M, Murinson BB et al.: Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J. Neurosci. 22, 7746–7753 (2002). Krafte DS, Bannon AW: Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8, 50–56 (2008).
future science group
8
development of novel channel targeted drugs. Perhaps the Drug Enforcement Agency, with its billion-dollar budget, could devote a portion of its resources to fund research whose sole purpose is to develop nonaddictive analgesics. It may be as cost effective as trying to protect pharmacies from bandits gallivanting down the Oxy Express. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert te stimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Jagodic MM, Pathirathna S, Joksovic PM et al.: Upregulation of the T‑type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J. Neurophysiol. 99, 3151–3156 (2008).
13 Ji RR, Samad TA, Jin SX, Schmoll R,
Todorovic SM, Jevtovic-Todorovic V: T‑type voltage-gated calcium channels as targets for the development of novel pain therapies. Br. J. Pharmacol. DOI: 10.1111/j.1476-5381.2011.01256.x (2011) (Epub ahead of print).
14
Zhang X, Huang J, McNaughton PA: NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 24, 4211–4223 (2005).
15
Fabbretti E, D’Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R: Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J. Neurosci. 26, 6163–6171 (2006).
16
Bauer CS, Tran-Van-Minh A, Kadurin I, Dolphin AC: A new look at calcium channel a2d subunits. Curr. Opin. Neurobiol. 20, 563–571 (2010).
9
Ocana M, Cendan CM, Cobos EJ, Entrena JM, Baeyens JM: Potassium channels and pain: present realities and future opportunities. Eur. J. Pharmacol. 500, 203–219 (2004).
10
Bhattacharjee A, Gan L, Kaczmarek LK: Localization of the Slack potassium channel in the rat central nervous system. J. Comp. Neurol. 454, 241–254 (2002).
11
Editorial
Tamsett TJ, Picchione KE, Bhattacharjee AL: NAD + Activates K Na channels in dorsal root ganglion neurons. J. Neurosci. 29, 5127–5134 (2009).
12 Nuwer MO, Picchione KE, Bhattacharjee A:
PKA-induced internalization of Slack K Na channels produces dorsal root ganglion
neuron hyperexcitability. J. Neurosci. 30, 14165–14172 (2010). Woolf CJ: p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36, 57–68 (2002).
Website 101 Illegal prescription-drug trade now epidemic
www.dispatch.com/live/content/local_news/ stories/2010/02/07/OXYCONTIN.ART_ ART_02-07-10_A1_HGGH7K4.html
www.futuremedicine.com
201
