Behavioural Brain Research 286 (2015) 347–355

Contents lists available at ScienceDirect

Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr

Research report

Enduring attentional deficits in rats treated with a peripheral nerve injury夽 Guy A. Higgins a,b,∗ , Leo B. Silenieks a , Annalise Van Niekerk a , Jill Desnoyer a , Amy Patrick a , Winnie Lau a , Sandy Thevarkunnel a a b

InterVivo Solutions Inc., 120 Carlton Street, Toronto, ON Canada M5A 4K2 Dept. Pharmacology & Toxicology, U. Toronto, ON, Canada M5S 1A8

h i g h l i g h t s • • • • •

Rats prepared with spared nerve injury (SNI) as model of neuropathic pain. Rats evaluated daily for 3 months post surgery for food motivation (PR schedule) or attention/reaction time (serial 5-choice task). SNI rats show similar motivation for food compared to sham operated controls. SNI rats show deficits in attention and response speed compared to sham operated controls from 2 weeks post surgery. Implications for translational research into study of attention based deficits in neuropathic pain.

a r t i c l e

i n f o

Article history: Received 20 January 2015 Received in revised form 17 February 2015 Accepted 24 February 2015 Available online 5 March 2015 Keywords: Neuropathic pain Cognition 5-Choice serial reaction time task Progressive ratio task Translational research

a b s t r a c t The present study investigated the impact of a spared nerve injury (SNI) on the daily performance of rats tested in two instrumental conditioning procedures: the progressive ratio (PR) schedule of food reinforcement to study motivation for an appetitive stimulus, and the 5-choice serial reaction time task (5-CSRTT), a test of attention and reaction time. Separate groups of male, Sprague-Dawley rats of age 8–10 months were trained to asymptotic performance in either task, before undergoing either SNI or sham surgery. After a recovery period of 3–4 days the animals were run 5 days/week for 3 months in either task. Tests of responsivity to evoked tactile (Von Frey) and thermal (acetone) stimuli were also conducted over this period to check integrity of the model. Post SNI surgery, rats showed equivalent responding to sham controls for food available under a PR schedule throughout the test period, implying a similar level of motivation for a food reward. In contrast, a performance deficit emerged in SNI treated rats run in the 5CSRTT, consistent with an attentional deficit. This deficit emerged during the second month post-surgery and was characterized by slower response speed, reduced accuracy and increased trial omissions. Both SNI groups showed equivalent hypersensitivity to evoked sensory stimuli compared to controls. Since attention based deficits have been reported in individuals with clinical forms of neuropathic pain, the present studies suggest a novel approach to study this phenomena and a means to study the effect of treatments against this cognitive endpoint. © 2015 Elsevier B.V. All rights reserved.

1. Introduction

Abbreviations: NCE, new chemical entity; SNI, spared nerve injury; SNL, spinal nerve ligation; PR, progressive ratio; 5-CSRTT, 5-choice serial reaction time task; SD, stimulus duration; ITI, inter trial interval; LH, limited hold; ICSS, intracranial selfstimulation; NbM, nucleus basalis of Meynert; VTA, ventral tegmental area; FCA, Freunds complete adjuvant. 夽 The present study was funded entirely by InterVivo Solutions Inc. ∗ Corresponding author at: InterVivo Solutions Inc., 120 Carlton Street, Toronto, ON, Canada M5A 4K2. Fax: +1 416 920 1876. E-mail address: [email protected] (G.A. Higgins). http://dx.doi.org/10.1016/j.bbr.2015.02.050 0166-4328/© 2015 Elsevier B.V. All rights reserved.

Gaps in the translation between preclinical to clinical findings for new chemical entities (NCE’s) is a topic of significant concern, because failure to demonstrate clinical efficacy has become the most significant reason for program termination [1,2]. This trend is apparent across all therapeutic areas including NCE’s developed for pain management [2]. One counter approach is to reevaluate the animal models themselves and identify ways to improve their predictive power. Several key articles have been written about how pain models can be refined with a major theme being

348

G.A. Higgins et al. / Behavioural Brain Research 286 (2015) 347–355

the type of endpoint used to measure pain [3–10]. A significant ongoing research effort is to identify endpoints beyond the traditional evoked sensory responses which remain a mainstay yet do not capture the chronicity of a pain state or reflect clinical endpoints which tend to be measures of continuous spontaneous pain. Reflective of the fact that depression and cognitive decline are often associated with clinical forms of chronic pain [11–13], indirect measures of affect such as place conditioning and sucrose preference [14–19] and cognitive performance across multiple test designs [20–25] have been studied as endpoints in both neuropathic and inflammatory pain models. While many of these studies have identified behavioural deficits consistent with clinical experience, most of these tests are acute i.e. conducted on limited occasion, and in tests that are subject to both environmental factors, and critical details/variations in protocol. Taken together, these factors make consistent replication over time and between laboratories problematic [26]. One way to reduce these inconsistencies is to utilize instrumental conditioning procedures in which animals are trained to perform a specific task for food reinforcement. In addition to generating stable baselines within experiments enabling the detection of subtle performance changes, such tests can also be conducted daily to continuously measure performance in the same animals over days/weeks to establish reliability to any change [27,28]. Task contingencies can also be manipulated to measure specific aspects of behaviour. Examples of instrumental conditioning tasks include the progressive ratio (PR) and the 5-choice serial reaction time (5-CSRT) tasks. The progressive ratio schedule is an approach used to measure motivation to respond for a rewarding stimulus [29]. By training rats to lever press for a reward (e.g. food pellet) and progressively increasing the number of lever presses necessary for each subsequent reward, an index of the amount of effort that an animal will commit can be determined, with the final ratio achieved (i.e. the “break point”) providing an objective measure of the test subjects motivation to work for that reward. Since reduced motivation is a core symptom of depression [30,31], the PR test has been used to characterize animal models of depression, including chronic mild stress procedures [32–35]. In contrast, the 5-choice serial reaction time task measures the ability of a test subject to detect and respond to a brief visual stimulus presented in random location, and has become a task widely used to study attention and reaction time in rodents [36–38]. Primary outcome measures in this test include choice accuracy, response speed (reaction time), and premature responding, an index of response control. Both the PR and 5-CSRT tasks can be conducted across multiple species including humans raising a possibility for translational study. The purpose of the present studies was to adopt the PR and 5CSRT tasks as a means to measure the performance of rats following induction of a Spared Nerve Injury (SNI; [39]) model of neuropathic pain. This approach was selected due to the long term hypersensitivity to evoked sensory stimuli, consistent with the clinical pain state, and it was a specific purpose of these studies to continuously monitor performance of rats trained to either the PR or 5-CSRT for an extended post-surgical time period (3 months). It was thought that such studies could shed useful information about the long term impact of the SNI model on motivation for food reward (an index of affect), and on a core aspect of cognitive function. In recognition of the fact that neuropathic pain conditions are more prevalent in the ageing population [5,7,26], these studies were conducted in rats of mid-age, i.e. 8–12 months age. A previous study identified rats of this age group to be more susceptible to chronic pain-induced affective and cognitive deterioration compared to young (3 months) and aged (22 months) cohorts [24].

2. Methods 2.1. Animals and housing Test subjects were male Sprague-Dawley rats (source: Charles River, St. Constant, Quebec, Canada) of approximate age 8 months at the study start. Previous studies have shown this strain to give reliable tactile and thermal allodynia following SNI surgery [40,41]. Animals were singly housed in polycarbonate cages with sawdust bedding with water freely available. Food (LabDiet, 5001) availability was restricted to approximately 18–20 g at the end of each day, plus that earned during the daily operant session. The housing room was maintained at a constant temperature of 22 ± 2 ◦ C, under a 12 h light-dark cycle (lights on: 06:00–18:00 h). Testing was conducted under the light phase of the animals light/dark cycle. All studies were approved by an Institutional Animal Care and Use committee and conducted in accordance with guidelines established by the Canadian Council of Animal Care (CCAC). 2.2. Preparation of animals: spared nerve injury Following anaesthesia with ketamine (75 mg/kg IP) and xylazine (10 mg/kg IP), the skin on the lateral surface of the thigh was incised and a section made directly through the biceps femoris muscle to expose the sciatic nerve and its three terminal branches: the sural, common peroneal and tibial nerves. The common peroneal and the tibial nerves were tight ligated with 5–0 or 6–0 silk sutures and sectioned distal to the ligation, removing 2–4 mm of the distal nerve stump. Care was taken to avoid any contact with, or stretching of, the intact sural nerve. Sham controls involved exposure of the sciatic nerve without any lesion or further manipulation. At the completion of surgery, the muscles were sutured and the skin closed with silk sutures. Animals were returned to their home cage lined with soft sawdust bedding for the duration of study [42]. Post surgery, the animals tended to develop a change to the posture of the hindpaw ipsilateral to the nerve injury reflecting an avoidance of weight bearing on the lateral portion of the affected paw. Autotomy was not detected throughout the 3-month post-surgery period. A preliminary test was undertaken to assess mechanical allodynia (see below). Any non-responders (typically 30 s) [43]. The average score from three separate assessments was taken as the final measure for that animal. For all experiments only the treated paw was measured, the control response being derived from the corresponding paw from the sham operated animals. All evoked sensory responses were conducted by a single trained observer (JD). 2.4. Experiment 1 – assessment of motivated behaviour (progressive schedule of food reinforcement) Rats were first trained to respond for food in standard operant chambers (Med Associates Inc., St. Albans, VT) under a progressive ratio schedule as described in Higgins et al. [44]. The active response lever was positioned 7 cm above the grid floor. Briefly, following acquisition of lever pressing, rats were trained to respond on a single lever under a progressive ratio (PR) schedule in which the number of responses required to obtain a food pellet increased for successive reinforcers according to the progression 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, etc. A rat reached the break-point if it failed to receive a reward for 20 min. The rats were considered trained once they performed at asymptote, i.e. individual break-points did not vary by >15% over three consecutive sessions, which required 2–3 weeks of training. The number or reinforcers earned, i.e. break-point, and the total number of responses made was recorded. Once performance had stablised, the rats were allocated into 2 groups based on equivalent performance. Over a 2day period, the animals underwent surgical manipulation, i.e. either SNI surgery or sham surgery control according to group designation. Group sizes were N = 10 sham operated controls, N = 10 SNI surgery. After a recovery period of 2–3 days, the rats were returned to PR testing where they were run 5 days/week for 3 months. Tests of evoked responses to tactile and thermal stimuli were conducted on days pre-surgery, and D10, D20, D30, D60, D90 post-surgery. 2.5. Experiment 2 – assessment of cognitive behaviour (5-choice serial reaction time task) A separate cohort of rats to Experiment 1 were first trained in 5-choice operant chambers equipped with LED’s positioned in each of 5 niches (Med Associates Inc., St. Albans, VT), using techniques described previously [38,44]. Each training session ran for either 100 trials or 60 min, whichever was shorter. Initially, stimulus parameters were such that stimulus duration (SD) was set at 60 s, inter-trial interval (ITI) 5 s, and time-out (TO) and limited hold (LH) were 2 s. For all subjects the SD was progressively reduced until a final duration of 0.8 s was achieved. This SD was necessary in order to get the rats performing at target criterion. All other parameters remained at their initial levels throughout training and test. Training continued under the target stimulus parameters until subjects had achieved consistent performance above a threshold of 80% correct ([correct/(correct + incorrect)]*100) and 0.6) with power of 1.0 for both Experiments 1 and 2. Small effect sizes (partial 2 < 0.04) were measured for the interaction of time by lever presses and rewards in the progressive ratio model, and the power of this experiment for both factors (observed power 0.3) and observed power of >0.97. The striking differences in effect sizes for evoked pain measures for both Experiments 1 and 2 suggest that these measures are the most effective in determining group differences for neuropathic pain response. Although lower effect sizes were

352

G.A. Higgins et al. / Behavioural Brain Research 286 (2015) 347–355

Fig. 3. Effect of () sham, and ( ) SNI surgery on various performance measures of rats in the 5-choice serial reaction time task. On the LHS data are expressed as daily performance during a 5 day baseline phase immediately preceding surgery, and over the 12 week immediately after surgery. On the RHS, the data are grouped into time bins representing the baseline phase and months 1, 2 and 3 following surgery. Note that while performance on each measure was almost equivalent between sham and SNI operated rats over the first 4 weeks, during the weeks 5–12 performance began to diverge with the SNI operated rats having lower choice accuracy, number of correct responses, increased missed trials and incorrect responses and a slower response speed by comparison to sham controls. * P < 0.05 vs. pre-surgical (baseline) score for SNI rats, # P < 0.05 vs. sham rats at the equivalent timepoint (Fisher’s LSD following significant ANOVA).

G.A. Higgins et al. / Behavioural Brain Research 286 (2015) 347–355

found for the primary 5-CSRTT measures as compared to evoked pain responses, these measures were also reasonably powerful in identifying group differences between sham and SNI treated rats. 4. Discussion There are two main findings from the present studies. First, despite enduring hypersensitivity to tactile and thermal stimuli throughout the 90 day post-surgical period, SNI rats demonstrated equivalent motivation for a food reward compared to sham treated controls tested over this timespan. Second, a separate cohort of SNI rats showed a significant impairment in attentional function measured using the 5-CSRTT, which was characterized by reduced correct responses and % choice accuracy, and a slower response speed. This difference was found despite both groups of SNI treated rats having equivalent levels of hypersensitivity to both tactile and thermal stimuli relative to sham controls. 4.1. Assessment of motivated behaviour using the progressive ratio task In broad terms it has been estimated that over 50% of patients suffering from forms of chronic pain also express a clinical diagnosis of depression [11]. While some controversy may exist regarding the relationship between the two, i.e. cause vs. consequence, the weight of evidence would seem to support the view that depression is a consequence of the presence of chronic pain, rather than a predisposing factor [47]. Given this association there have been multiple attempts to incorporate measures of affect into pain models, including tests of sucrose preference, place conditioning, learned helplessness and measurement of ICSS threshold [7,14–19,48,49]. Some of these studies report a behavioural change in animal models of neuropathic pain compared to their sham controls, perhaps reflecting a state of anhedonia, (a loss of interest in rewards), which constitutes a core feature of depression [30,31]. We hypothesized that rats trained to respond for food reinforcement under the progressive ratio schedule, could provide a useful measure of anhedonia with an added advantage that the test subjects may be tested daily over a 3 month period to investigate the enduring nature of a chronic nociceptive state on this measure, and also the reliability of any detectable change [26]. The results from this study revealed that over the 3 month test period, rats treated with SNI surgeries showed equivalent responding to sham operated controls both in terms of break-point and absolute number of active lever presses. In other words the degree of motivation to respond for food reinforcement was unaffected. This was despite the evoked measures demonstrating that the SNI prepared rats had a robust sensory allodynia to both tactile and thermal stimuli over this time period. These null effects contrast with positive findings of others using alternative procedures. For example Wang et al. [18] reported rats treated with a spared nerve injury demonstrated a decrease in preference for a 1% sucrose solution compared to sham operated controls over a 2 month post-operative period. It may be the present study design where responding for food was driven by food deprivation as well as the appetitive nature of the reinforcer may have blunted task sensitivity. A greater emphasis on motivation being driven by hedonic quality of the primary reinforcer may have proved more fruitful. However it is interesting to note the recent studies of Ewan and Martin [50,51] who examined the sensitivity of rats with spinal nerve ligation surgery (SNL; [52]) to rewarding intracranial self-stimulation of the VTA. These authors reported a similar sensitivity to ICSS in both SNL and sham groups both in terms of current threshold to elicit 50% of maximal response, and maximal response rate measured up to 5 months post-surgery

353

[50]. Furthermore, studies measuring daily quality of life and affective state over 3 months failed to identify any robust changes in mice with tissue or nerve injury-induced mechanical hypersensitivity [53]. Together with the present studies, these data imply that peripheral nerve injury models of neuropathic pain may not necessarily elicit an altered sensitivity to a rewarding stimulus, suggesting that peripheral nerve injury models of neuropathic pain may not evoke a reliable “anhedonic” state, at least in rodents. In the immediate post-surgical period, both SNI and sham operated groups showed decreased break-point and number of lever presses compared to pre-surgical baseline. This decrease was transient with both groups showing a rapid recovery within the first week. As such, this likely reflects an effect of surgery itself to reduce operant responding for food, similar to what has been described following laparotomy in rats [54]. Acute pain, in the form of intraperitoneal injections of lactic acid to initiate GI discomfort, has also been reported to impact on ICSS threshold [48]. This demonstrates that certain pain states can affect these instrumental tests of reward. 4.2. Assessment of cognitive behaviour using the 5-choice serial reaction time task As an unpleasant sensory and emotional experience, pain undoubtedly places a demand on the attentional resources of an individual, consequently the influence of pain on attention has been assessed in several clinical studies. As reviewed by Moriarty et al. [13], chronic pain patients self-report difficulty with attention, and controlled clinical studies have demonstrated attentional deficits across multiple chronic pain states such as fibromyalgia, rheumatoid arthritis and diabetic neuropathy. Furthermore patients experiencing chronic pain conditions display slower reaction times compared to matched controls across multiple cognitive tests suggesting deficits in speed of information processing [13,55,56]. The 5-CSRTT measures both attentional performance and reaction time, and so represents a useful means to evaluate how these measures may be affected in animal models of pain. To the best of our knowledge such studies have not previously been reported in a model of neuropathic pain. The most interesting finding from this investigation was the emergence of a significant decrease in the frequency of correct responses, increased missed trials and an overall decline in choice accuracy in SNI treated rats compared to sham controls. Response speed was also slowed, which in the context of normal responding for food under the PR schedule, suggests this may reflect a decline in information processing speed rather than motivational change. This attention deficit emerged by the second week post SNI surgery but was most marked during the second and third months suggesting a longer term adaptive change. Interestingly there was no further performance decline during the third month, indeed there were some signs of behavioural adaptation by the end of week 12. Premature responding, a measure of impulsive action [57], was not affected suggesting that this index of executive function remained intact. Interestingly, Pais-Vieira et al. [22] also reported reduced accuracy and increased omissions in rats trained to this task, following treatment with an intra-articular injection of FCA designed to induce monoarthritis. Previous studies examining cognitive outcomes in rodents prepared with peripheral nerve injury have tended to focus on tests of working memory or executive function. For example, LeiteAlmeida and coworkers [24,25] reported that rats prepared one month previously with SNI surgeries demonstrated deficits both in spatial working memory in a water maze and executive function measured by reversal learning in water maze and a food reinforced set shifting task. Low et al. [58] described reduced exploration time of a novel object in rats 6 months post SNI surgery relative to sham

354

G.A. Higgins et al. / Behavioural Brain Research 286 (2015) 347–355

controls. While the findings of Low et al. [58] were interpreted as attention based, the novelty of the object introduced 24 h after the sample objects, undoubtedly imparts a significant mnemonic demand to the test [59]. The present studies in SNI treated rats using a well validated and widely used attention based task [36], appear to complement the findings of others [24,25,58] and together suggest rats prepared with this nerve injury model are impaired on multiple cognitive domains. Impairments to performance in the 5-CSRTT as measured by choice accuracy and response speed were not immediately evident following SNI surgery, but tended to emerge after 2–3 weeks suggesting an adaptive change subsequent to the peripheral nerve injury. In this context, studies looking at cortical changes post SNI surgery are of potential relevance because effective performance in the 5-CSRTT task is particularly sensitive to discrete lesion and pharmacological manipulations to this region [36,60,61]. For example, bilateral excitotoxin lesions to the medial prefrontal cortex produce a marked decline in choice accuracy and a concomitant slowing of response latency perhaps reflecting a speed-error tradeoff [61]. Furthermore, selective 192 IgG-saporin neurotoxin lesions to the cholinergic NbM-cortical pathway result in reduced accuracy, increased omissions and slowed response speed [62,63], again similar to that reported in the present study. Cholinergic input to the prefrontal cortex is considered an amplification mechanism for local glutamatergic circuits necessary for cue detection [64]. Thus, taken together these studies highlight the importance of the prefrontal cortex in attentional function. Emerging data in the rat suggest surgical injury to the sciatic nerve trunk results in both functional and structural changes within the prefrontal cortex [65–70]. At a structural level, Seminowicz et al. [65] reported decreased volumes in multiple cortical regions measured up to 6 months post SNI surgery using MRI. Metz et al. [66] described both functional and morphological changes to medial prefrontal cortex layer 2/3 pyramidal neurons 1 week post SNI surgery. More specifically, relative to sham operated controls, an increase in basal dendritic complexity and spine density of pyramidal neurons was reported in SNI prepared rats, which also showed heightened glutamatergic synaptic currents (EPSC’s) in response to afferent fibre stimulation. Upregulation of synaptic proteins and protein kinases associated with glutamate function may contribute to this change [67]. Furthermore, imaging and multielectrode recording techniques are also identifying changes in other brain structures connected to the prefrontal region following sciatic nerve damage, implying that multiple interconnected neuronal circuits may be ultimately be impacted [68–70]. Therefore, one reasonable hypothesis is that the attentional deficits evident in SNI treated rats, reflect an adaptive change in microcircuitry within cortical subregions such as medial prefrontal cortex. 4.3. Concluding comments The present studies attempted to identify any motivational and cognitive change following a peripheral nerve injury model of neuropathic pain. Despite clear evidence for hypersensitivity to sensory stimuli, no evidence for shift in break point for food reinforcement measured consistently over a 3 month period was found. This lack of motivational change served to highlight the attention deficit that was evident from the second month post SNI surgery – an adaptive change that may mirror the cognitive changes reported in individuals experiencing chronic forms of neuropathic pain. The work of Pais-Vieira et al. [22] suggests equivalent attentional changes may occur in rat models of chronic inflammatory pain. Current treatment strategies focus primarily on the sensory component rather than cognitive/affective components of pain, suggesting this feature is not necessarily well targeted by existing therapies [10,13,26,71]. This course of study may have value as

a means to study the aetiology of cognitive (attentional) deficits associated with chronic pain conditions, and also to serve as a novel endpoint for the study of pain therapeutics to complement sensory measures. These studies utilized instrumental conditioning procedures enabling daily measurement of performance within animals and across a relatively stable baseline. In theory this should enable the detection of subtle changes to behaviour and repeated testing to examine the reliability of any change [26]. Although power analyses identified these changes not to be as reliable as evoked measures, the consistency of deficit seems suitable for drug intervention studies. Furthermore the tests used may also be conducted in humans creating opportunity to directly translate studies between the preclinical and clinical test arenas and hopefully improve their predictive power. Conflict of interest The authors declare no conflict of interest outside of primary employment. References [1] Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3:711–5. [2] Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol 2014;32:40–51. [3] Blackburn-Munro G. Pain-like behaviours in animals – how human are they? Trends Pharmacol Sci 2004;25:299–305. [4] Negus SS, Vanderah TW, Brandt MR, Bilsky EJ, Becerra L, Borsook D. Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. J Pharmacol Exp Ther 2006;319:507–14. [5] Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I, et al. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain 2008;139:243–7. [6] Whiteside GT, Adedoyin A, Leventhal L. Predictive validity of animal pain models? A comparison of the pharmacokinetic–pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology 2008;54:767–75. [7] Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci 2009;10:283–94. [8] Mogil JS, Davis KD, Derbyshire SW. The necessity of animal models in pain research. Pain 2010;151:12–7. [9] Berge OG. Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol 2011;164:1195–206. [10] Navratilova E, Porreca F. Reward and motivation in pain and pain relief. Nat Neurosci 2014;17:1304–12. [11] Dworkin RH, Gitlin MJ. Clinical aspects of depression in chronic pain patients. Clin J Pain 1991;7:79–94. [12] Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288(5472):1769–72. [13] Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol 2011;93:385–404. [14] LaBuda CJ, Fuchs PN. A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats. Exp Neurol 2000;163:490–4. [15] Pedersen LH, Blackburn-Munro G. Pharmacological characterisation of place escape/avoidance behaviour in the rat chronic constriction injury model of neuropathic pain. Psychopharmacology (Berl) 2006;185:208–17. [16] Hummel M, Lu P, Cummons TA, Whiteside GT. The persistence of a long-term negative affective state following the induction of either acute or chronic pain. Pain 2008;140:436–45. [17] Shi M, Wang JY, Luo F. Depression shows divergent effects on evoked and spontaneous pain behaviors in rats. J Pain 2010;11:219–29. [18] Wang J, Goffer Y, Xu D, Tukey DS, Shamir DB, Eberle SE, et al. A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology 2011;115:812–21. [19] Navratilova E, Xie JY, King T, Porreca F. Evaluation of reward from pain relief. Ann N Y Acad Sci 2013;1282:1–11. [20] Cain CK, Francis JM, Plone MA, Emerich DF, Lindner MD. Pain-related disability and effects of chronic morphine in the adjuvant-induced arthritis model of chronic pain. Physiol Behav 1997;62:199–205. [21] Pais-Vieira M, Aguiar P, Lima D, Galhardo V. Inflammatory pain disrupts the orbitofrontal neuronal activity and risk-assessment performance in a rodent decision-making task. Pain 2012;153:1625–35. [22] Pais-Vieira M, Lima D, Galhardo V. Sustained attention deficits in rats with chronic inflammatory pain. Neurosci Lett 2009;463:98–102. [23] Pais-Vieira M, Mendes-Pinto MM, Lima D, Galhardo V. Cognitive impairment of prefrontal-dependent decision-making in rats after the onset of chronic pain. Neuroscience 2009;161:671–9.

G.A. Higgins et al. / Behavioural Brain Research 286 (2015) 347–355 [24] Leite-Almeida H, Almeida-Torres L, Mesquita AR, Pertovaara A, Sousa N, Cerqueira JJ, et al. The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats. Pain 2009;144:57–65. [25] Leite-Almeida H, Cerqueira JJ, Wei H, Ribeiro-Costa N, Anjos-Martins H, Sousa N, et al. Differential effects of left/right neuropathy on rats’ anxiety and cognitive behavior. Pain 2012;153:2218–25. [26] Percie du Sert N, Rice ASC. Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain. Br J Pharmacol 2014;171:2951–63. [27] Wenger GR. Operant behavior as a technique for toxicity testing. Neurotox Teratol 1990;12:515–21. [28] Li J-X. The application of conditioning paradigms in the measurement of pain. Eur J Pharmacol 2013;716:158–68. [29] Hodos W. Progressive ratio as a measure of reward strength. Science 1961;134:943–4. [30] Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology 2004;10:1765–81. [31] Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol 2007;21:461–71. [32] Barr AM, Phillips AG. Withdrawal following repeated exposure to damphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 1999;141:99–106. [33] Willner P, Benton D, Brown E, Cheeta S, Davies G, Morgan J, et al. Depression increases craving for sweet rewards in animal and human models of depression and craving. Psychopharmacology (Berl) 1998;136:272–83. [34] Vollmayr B, Bachteler D, Vengeliene V, Gass P, Spanagel R, Henn F. Rats with congenital learned helplessness respond less to sucrose but show no deficits in activity or learning. Behav Brain Res 2004;150:217–21. [35] Rüedi-Bettschen D, Pedersen EM, Feldon J, Pryce CR. Early deprivation under specific conditions leads to reduced interest in reward in adulthood in Wistar rats. Behav Brain Res 2005;156:297–310. [36] Robbins TW. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 2002;163:362–80. [37] Bari A, Dalley JW, Robbins TW. The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc 2008;3:759–67. [38] Higgins GA, Breysse N. Rodent model of attention: the 5-choice serial reaction time task. Curr Protoc Pharmacol 2008 [chapter 5: unit 5.49]. [39] Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000;87:149–58. [40] Rode F, Thomsen M, Broløs T, Jensen DG, Blackburn-Munro G, Bjerrum OJ. The importance of genetic background on pain behaviours and pharmacological sensitivity in the rat spared serve injury model of peripheral neuropathic pain. Eur J Pharmacol 2007;564:103–11. [41] Lau W, Dykstra C, Thevarkunnel S, Silenieks LB, de Lannoy IA, Lee DK, et al. A back translation of pregabalin and carbamazepine against evoked and nonevoked endpoints in the rat spared nerve injury model of neuropathic pain. Neuropharmacology 2013;73:204–15. [42] Robinson I, Dowdall T, Meert TF. Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats. Neurosci Lett 2004;368:107–11. [43] Erichsen HK, Blackburn-Munro G. Pharmacological characterisation of the spared nerve injury model of neuropathic pain. Pain 2002;98:151–61. [44] Higgins GA, Silenieks LB, Rossmann A, Rizos Z, Noble K, Soko AD, et al. The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse control. Neuropsychopharmacology 2012;62:2288–98. [45] Cohen J. Eta-squared and partial eta-squared in fixed factor ANOVA design. Educ Psychol Meas 1973;33:107–12. [46] Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 2010;160:1577–9. [47] Blackburn-Munro G, Blackburn-Munro RE. Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 2001;13:1009–23. [48] Pereira Do Carmo G, Stevenson GW, Carlezon WA, Negus SS. Effects of painand analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior. Pain 2008;144:170–7.

355

[49] Gonc¸alves L, Silva R, Pinto-Ribeiro F, Pêgo JM, Bessa JM, Pertovaara A, et al. Neuropathic pain is associated with depressive behaviour and induces neuroplasticity in the amygdala of the rat. Exp Neurol 2008;213:48–56. [50] Ewan EE, Martin TJ. Opioid facilitation of rewarding electrical brain stimulation is suppressed in rats with neuropathic pain. Anesthesiology 2011;114:624–32. [51] Ewan EE, Martin TJ. Rewarding electrical brain stimulation in rats after peripheral nerve injury: decreased facilitation by commonly abused prescription opioids. Anesthesiology 2011;115:1271–80. [52] Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355–63. [53] Urban R, Scherrer G, Goulding EH, Tecott LH, Basbaum AI. Behavioral indices of ongoing pain are largely unchanged in male mice with tissue or nerve injuryinduced mechanical hypersensitivity. Pain 2011;152:990–1000. [54] Martin TJ, Kahn WR, Eisenach JC. Abdominal surgery decreases food-reinforced operant responding in rats. Anesthesiology 2005;103:629–37. [55] Harman K, Ruyak P. Working through the pain: a controlled study of the impact of persistent pain on performing a computer task. Clin J Pain 2005;21:216–22. [56] Lee DM, Pendleton N, Tajar A, O’Neill TW, O’Connor DB, Bartfai G, et al. Chronic widespread pain is associated with slower cognitive processing speed in middle-aged and older European men. Pain 2010;151:30–6. [57] Winstanley CA. The utility of rat models of impulsivity in developing pharmacotherapies for impulse control disorders. Br J Pharmacol 2011;164:1301–21. [58] Low LA, Millecamps M, Seminowicz DA, Naso L, Thompson SJ, Stone LS, et al. Nerve injury causes long-term attentional deficits in rats. Neurosci Lett 2012;529:103–7. [59] Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1 Behavioral data. Behav Brain Res 1988;31:47–59. [60] Muir JL, Everitt BJ, Robbins TW. The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cereb Cortex 1996;6:470–81. [61] Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW. Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 2003;146:105–19. [62] McGaughy J, Dalley JW, Morrison CH, Everitt BJ, Robbins TW. Selective behavioral and neurochemical effects of cholinergic lesions produced by intrabasalis infusions of 192 IgG-saporin on attentional performance in a five-choice serial reaction time task. J Neurosci 2002;22:1905–13. [63] Lehmann O, Grottick AJ, Cassel JC, Higgins GA. A double dissociation between serial reaction time and radial maze performance in rats subjected to 192 IgGsaporin lesions of the nucleus basalis and/or the septal region. Eur J Neurosci 2003;18:651–66. [64] Sarter M, Paolone G. Deficits in attentional control: cholinergic mechanisms and circuitry-based treatment approaches. Behav Neurosci 2011;125:825–35. [65] Seminowicz DA, Laferriere AL, Millecamps M, Yu JS, Coderre TJ, Bushnell MC. MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage 2009;47:1007–14. [66] Metz AE, Yau HJ, Centeno MV, Apkarian AV, Martina M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc Natl Acad Sci 2009;106:2423–8. [67] Hung KL, Wang SJ, Wang YC, Chiang TR, Wang CC. Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain. Pain 2014;155:377–87. [68] Kim CE, Kim YK, Chung G, Jeong JM, Lee DS, Kim J, et al. Large-scale plastic changes of the brain network in an animal model of neuropathic pain. Neuroimage 2014;98:203–15. [69] Cardoso-Cruz H, Lima D, Galhardo V. Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus–prefrontal cortex connectivity. J Neurosci 2013;33:2465–80. [70] Thompson SJ, Millecamps M, Aliaga A, Seminowicz DA, Low LA, Bedell BJ, et al. Metabolic brain activity suggestive of persistent pain in a rat model of neuropathic pain. Neuroimage 2014;91:344–52. [71] Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73.