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Nature Reviews Neuroscience
  • Review Article
  • Published:

Animal models of pain: progress and challenges

Nature Reviews Neurosciencevolume 10pages283–294 (2009)Cite this article

Key Points

  • Animal models of pain are crucially important for progress in the field, but the poor translation record of pain research has led to a re-evaluation of the appropriateness of current models.

  • The accuracy and relevance of data obtained using current animal pain assays can be improved by choosing subjects and conditions that have more in common, epidemiologically and contextually, with pain patients: both sexes, multiple strains, a wider age range, and with attention paid to social factors.

  • Pain assays have been developed in four successive and overlapping 'waves': acute assays, inflammatory assays, neuropathic assays and the modelling of diseases featuring pain.

  • Current animal models of pain are overly reliant on innate reflexes as dependent measures. Recently developed operant assays may provide a superior alternative.

  • Pain researchers seriously under-study spontaneous pain, and are overly reliant on the measurement of hypersensitivity states. A consensus as to which spontaneously emitted behaviours truly reflect pain in laboratory rodents is sorely needed.

  • Current animal studies of pain largely neglect to measure complex states comorbid with, affected by, and/or contributing to pain.

Abstract

Many are frustrated with the lack of translational progress in the pain field, in which huge gains in basic science knowledge obtained using animal models have not led to the development of many new clinically effective compounds. A careful re-examination of animal models of pain is therefore warranted. Pain researchers now have at their disposal a much wider range of mutant animals to study, assays that more closely resemble clinical pain states, and dependent measures beyond simple reflexive withdrawal. However, the complexity of the phenomenon of pain has made it difficult to assess the true value of these advances. In addition, pain studies are importantly affected by a wide range of modulatory factors, including sex, genotype and social communication, all of which must be taken into account when using an animal model.

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Figure 1: Species selected for pain experiments from 1963 to 2007.

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References

  1. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates?Nature Rev. Drug Discov.3, 711–716 (2004).

    Article CAS  Google Scholar 

  2. Langley, C. K. et al. Volunteer studies in pain research—opportunities and challenges to replace animal experiments: the report and recommendations of a Focus on Alternatives workshop.Neuroimage42, 467–473 (2008).

    Article CAS PubMed  Google Scholar 

  3. Hill, R. NK1 (substance P) receptor antagonists–why are they not analgesic in humans?Trends Pharmacol. Sci.21, 244–246 (2000).An interesting 'post-mortem' analysis of the failure of NK1 receptor antagonists to show efficacy in humans despite strong preclinical evidence.

    Article CAS PubMed  Google Scholar 

  4. Wallace, M. S. et al. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain.Neurology59, 1694–1700 (2002).

    Article CAS PubMed  Google Scholar 

  5. Wallace, M. S. et al. A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain.J. Pain2, 4227–4233 (2002).

    Google Scholar 

  6. Williams, J. A., Day, M. & Heavner, J. E. Ziconotide: an update and review.Expert Opin. Pharmacother.9, 1575–1583 (2008).

    Article CAS PubMed  Google Scholar 

  7. Kontinen, V. K. & Meert, T. F. inProceedings of the 10th World Congress on Pain (eds Dostrovsky, J. O., Carr, D. B. & Koltzenburg, M.) 489–498 (IASP, Seattle, 2002).The best counterevidence to the charge that animal models of pain fail to predict clinical efficacy; a meta-analysis showing that clinically efficacious treatments for neuropathic pain usually succeed in reversing thermal and mechanical hypersensitivity states in rats.

    Google Scholar 

  8. Whiteside, G. T., Adedoyin, A. & Leventhal, L. Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans.Neuropharmacology54, 767–775 (2008).

    Article CAS PubMed  Google Scholar 

  9. Campbell, J. N. & Meyer, R. A. Mechanisms of neuropathic pain.Neuron52, 77–92 (2006).

    Article CAS PubMed PubMed Central  Google Scholar 

  10. Rice, A. S. C. et al. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards.Pain139, 241–245 (2008).

    Article  Google Scholar 

  11. Wilson, S. G. & Mogil, J. S. Measuring pain in the (knockout) mouse: big challenges in a small mammal.Behav. Brain Res.125, 65–73 (2001).

    Article CAS PubMed  Google Scholar 

  12. Vierck, C. J., Hansson, P. T. & Yezierski, R. P. Clinical and pre-clinical pain assessment: are we measuring the same thing?Pain135, 7–10 (2008).A good review of operant measures and their importance.

    Article CAS PubMed  Google Scholar 

  13. Mogil, J. S. & Crager, S. E. What should we be measuring in behavioral studies of chronic pain in animals?Pain112, 12–15 (2004).A call to include spontaneously emitted behaviours as measures of chronic pain in animals.

    Article PubMed  Google Scholar 

  14. Blackburn-Munro, G. Pain-like behaviours in animals - how human are they?Trends Pharmacol. Sci.25, 299–305 (2004).

    Article CAS PubMed  Google Scholar 

  15. Stewart, W. F., Ricci, J. A., Chee, E., Morganstein, D. & Lipton, R. Lost productive time and cost due to common pain conditions in the US workforce.J. Am. Med. Assoc.290, 2443–2454 (2003).

    Article CAS  Google Scholar 

  16. Price, D. D., McGrath, P., Rafii, A. & Buckingham, B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain.Pain17, 45–56 (1983).

    Article CAS PubMed  Google Scholar 

  17. Borsook, D. & Becerra, L. Phenotyping central nervous system circuitry in chronic pain using functional MRI: considerations and potential implications in the clinic.Curr. Pain Headache Rep.11, 201–207 (2007).

    Article PubMed  Google Scholar 

  18. LaCroix-Fralish, M. L. & Mogil, J. S. Progress in genetic studies of pain and analgesia.Annu. Rev. Pharmacol. Toxicol.49, 97–121 (2009).The most current and comprehensive review of pain genetics in animals and humans.

    Article CAS PubMed PubMed Central  Google Scholar 

  19. Fields, H. L., Bry, J., Hentall, I. & Zorman, G. The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat.J. Neurosci.3, 2545–2552 (1983).

    Article CAS PubMed PubMed Central  Google Scholar 

  20. Mogil, J. S., Simmonds, K. & Simmonds, M. J. Pain research from 1975 to 2007: a categorical and bibliometric meta-trend analysis of every Research Paper published in the journal,Pain.Pain142, 48–58 (2009).

    Article PubMed  Google Scholar 

  21. Lariviere, W. R., Chesler, E. J. & Mogil, J. S. Transgenic studies of pain and analgesia: mutation or background phenotype?J. Pharmacol. Exp. Ther.297, 467–473 (2001).

    CAS PubMed  Google Scholar 

  22. LaCroix-Fralish, M. L., Ledoux, J. B. & Mogil, J. S. ThePain Genes Database: an interactive web browser of pain-related transgenic knockout studies.Pain131, 3.e1–4 (2007).

    Article  Google Scholar 

  23. Casas, C. et al. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Aβ42 accumulation in novel Alzheimer transgenic model.Am. J. Pathol.165, 1289–1300 (2004).

    Article CAS PubMed PubMed Central  Google Scholar 

  24. Indo, Y. et al. Mutations in theTRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.Nature Genet.13, 485–488 (1996).

    Article CAS PubMed  Google Scholar 

  25. Smeyne, R. J. et al. Severe sensory neuropathies in mice carrying a disrupted Trk/NGF receptor gene.Nature368, 246–249 (1994).

    Article CAS PubMed  Google Scholar 

  26. Nyholt, D. R. et al. A high-density association screen of 155 ion transport genes for involvement with common migraine.Hum. Mol. Genet.17, 3318–3331 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

  27. Gagliese, L. & Melzack, R. Chronic pain in elderly people.Pain70, 3–14 (1997).

    Article CAS PubMed  Google Scholar 

  28. Berkley, K. J. Sex differences in pain.Behav. Brain Sci.20, 371–380 (1997).The review paper that first brought the field's attention to the existence of sex differences in pain.

    Article CAS PubMed  Google Scholar 

  29. Edwards, R. R., Doleys, D. M., Fillingim, R. B. & Lowery, D. Ethnic differences in pain tolerance: clinical implications in a chronic pain population.Psychosom. Med.63, 316–323 (2001).

    Article CAS PubMed  Google Scholar 

  30. Mogil, J. S. & Chanda, M. L. The case for the inclusion of female subjects in basic science studies of pain.Pain117, 1–5 (2005).

    Article PubMed  Google Scholar 

  31. Mogil, J. S., Chesler, E. J., Wilson, S. G., Juraska, J. M. & Sternberg, W. F. Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype.Neurosci. Biobehav. Rev.24, 375–389 (2000).

    Article CAS PubMed  Google Scholar 

  32. Craft, R. M. Sex differences in drug- and non-drug-induced analgesia.Life Sci.72, 2675–2688 (2003).

    Article CAS PubMed  Google Scholar 

  33. Kest, B., Wilson, S. G. & Mogil, J. S. Sex differences in supraspinal morphine analgesia are dependent on genotype.J. Pharmacol. Exp. Ther.289, 1370–1375 (1999).

    CAS PubMed  Google Scholar 

  34. Terner, J. M., Lomas, L. M., Smith, E. S., Barrett, A. C. & Picker, M. J. Pharmacogenetic analysis of sex differences in opioid antinociception in rats.Pain106, 381–391 (2003).

    Article CAS PubMed  Google Scholar 

  35. Mogil, J. S. Sex, gender and pain.Handb. Clin.Neurol.81, 325–341 (2006).

    Google Scholar 

  36. Urca, G., Segev, S. & Sarne, Y. Footshock-induced analgesia: its opioid nature depends on the strain of rat.Brain Res.329, 109–116 (1985).

    Article CAS PubMed  Google Scholar 

  37. Proudfit, H. K. The challenge of defining brainstem pain modulation circuits.J. Pain3, 350–354 (2002).

    Article PubMed  Google Scholar 

  38. Mogil, J. S. & Belknap, J. K. Sex and genotype determine the selective activation of neurochemically-distinct mechanisms of swim stress-induced analgesia.Pharmacol. Biochem. Behav.56, 61–66 (1997).

    Article CAS PubMed  Google Scholar 

  39. Le Bars, D., Gozariu, M. & Cadden, S. W. Animal models of nociception.Pharmacol. Rev.53, 597–652 (2001).A stunningly comprehensive review of acute and tonic algesiometric assays.

    CAS PubMed  Google Scholar 

  40. Shir, Y., Ratner, A., Raja, S. N., Campbell, J. N. & Seltzer, Z. Neuropathic pain following partial nerve injury in rats is suppressed by dietary soy.Neurosci. Lett.240, 73–76 (1998).

    Article CAS PubMed  Google Scholar 

  41. Perez, J., Ware, M. A., Chevalier, S., Gougeon, R. & Shir, Y. Dietary omega-3 fatty acids may be associated with increased neuropathic pain in nerve-injured rats.Anesth. Analg.101, 444–448 (2005).

    Article CAS PubMed  Google Scholar 

  42. Shir, Y. & Seltzer, Z. Heat hyperalgesia following partial sciatic ligation in rats: interacting nature and nurture.Neuroreport12, 809–813 (2001).

    Article CAS PubMed  Google Scholar 

  43. Terman, G. W., Shavit, Y., Lewis, J. W., Cannon, J. T. & Liebeskind, J. C. Intrinsic mechanisms of pain inhibition: activation by stress.Science226, 1270–1277 (1984).

    Article CAS PubMed  Google Scholar 

  44. Imbe, H., Iwai-Liao, Y. & Senba, E. Stress-induced hyperalgesia: animal models and putative mechanisms.Front. Biosci.11, 2179–2192 (2006).

    Article CAS PubMed  Google Scholar 

  45. Balcombe, J. P., Barnard, N. D. & Sandusky, C. Laboratory routines cause animal stress.Contemp. Top. Lab. Anim. Sci.43, 42–51 (2004).

    CAS PubMed  Google Scholar 

  46. Robinson, I., Dowdall, T. & Meert, T. F. Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats.Neurosci. Lett.368, 107–111 (2004).

    Article CAS PubMed  Google Scholar 

  47. Tjolsen, A. & Hole, K. The tail-flick latency is influenced by skin temperature.APS J.2, 107–111 (1993).

    Article  Google Scholar 

  48. Pitcher, G. M., Ritchie, J. & Henry, J. L. Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands.J. Neurosci. Methods87, 185–193 (1999).

    Article CAS PubMed  Google Scholar 

  49. Berman, D. & Rodin, B. E. The influence of housing condition on autotomy following dorsal rhizotomy in rats.Pain13, 307–311 (1982).

    Article CAS PubMed  Google Scholar 

  50. Raber, P. & Devor, M. Social variables affect phenotype in the neuroma model of neuropathic pain.Pain97, 139–150 (2002).An intriguing demonstration of the power of environmental (social) factors to produce effects in a pain assay equal to those of genetic factors.

    Article PubMed  Google Scholar 

  51. Callahan, B. L., Gil, A. S. C., Levesque, A. & Mogil, J. S. Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state.J. Pain9, 174–184 (2008).

    Article PubMed  Google Scholar 

  52. Chesler, E. J., Wilson, S. G., Lariviere, W. R., Rodriguez-Zas, S. L. & Mogil, J. S. Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive.Neurosci. Biobehav. Rev.26, 907–923 (2002).

    Article PubMed  Google Scholar 

  53. Langford, D. L. et al. Social modulation of pain as evidence for empathy in mice.Science312, 1967–1970 (2006).

    Article CAS PubMed  Google Scholar 

  54. Price, D. D. Psychological and neural mechanisms of the affective dimension of pain.Science288, 1769–1772 (2000).

    Article CAS PubMed  Google Scholar 

  55. Braz, J. M., Nassar, M. A., Wood, J. N. & Basbaum, A. I. Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor.Neuron47, 787–793 (2005).This paper suggested that, even in the mouse, the sensory/discriminative component of pain and the motivational/affective component may be dissociable even at the level of primary afferent nociceptor subpopulations.

    Article CAS PubMed  Google Scholar 

  56. Hardy, J. D., Wolff, H. G. & Goodell, H. A new method for measuring pain threshold: observations on spatial summation of pain.J. Clin. Invest.19, 649–657 (1940).

    Article CAS PubMed PubMed Central  Google Scholar 

  57. Mogil, J. S. et al. Screening for pain phenotypes: analysis of three congenic mouse strains on a battery of nine nociceptive assays.Pain126, 24–34 (2006).

    Article PubMed  Google Scholar 

  58. Dubner, R. inTextbook of Pain (eds Wall, P. D. & Melzack, R.) 247–256 (Churchville Livingstone, Edinburgh, 1989).

    Google Scholar 

  59. Berkley, K. J., Wood, E., Scofield, S. L. & Little, M. Behavioral responses to uterine or vaginal distension in the rat.Pain61, 121–131 (1995).

    Article CAS PubMed  Google Scholar 

  60. Ness, T. J. & Gebhart, G. F. Colorectal distention as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective responses in the rat.Brain Res.450, 153–169 (1988).

    Article CAS PubMed  Google Scholar 

  61. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.Pain32, 77–88 (1988).

    Article CAS PubMed  Google Scholar 

  62. Koltzenburg, M., Wall, P. D. & McMahon, S. B. Does the right side know what the left is doing?Trends. Neurol. Sci.22, 122–127 (1999).

    Article CAS  Google Scholar 

  63. Dubuisson, D. & Dennis, S. G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats.Pain4, 161–174 (1977).

    Article CAS PubMed  Google Scholar 

  64. Dennis, S. G. & Melzack, R. inAdvances in Pain Research and Therapy vol.3 (ed. Bonica, J. J.) 747–760 (Raven, New York, 1979).

    Google Scholar 

  65. Mogil, J. S., Kest, B., Sadowski, B. & Belknap, J. K. Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay.J. Pharmacol. Exp. Ther.276, 532–544 (1996).

    CAS PubMed  Google Scholar 

  66. McNamara, C. R. et al. TRPA1 mediates formalin-induced pain.Proc. Natl Acad. Sci. USA104, 13525–13530 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  67. Macpherson, L. J. et al. An ion channel essential for sensing chemical damage.J. Neurosci.27, 11412–11415 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  68. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature389, 816–824 (1997).

    Article CAS PubMed  Google Scholar 

  69. Neugebauer, V., Han, J. S., Adwanikar, H., Fu, Y. & Ji, G. Techniques for assessing knee joint pain in arthritis.Mol. Pain3, 8 (2007).

    Article PubMed PubMed Central  Google Scholar 

  70. Rang, H. P., Bevan, S. & Dray, A. Chemical activation of nociceptive peripheral neurones.Br. Med. Bull.47, 534–548 (1991).

    Article CAS PubMed  Google Scholar 

  71. Beecher, H. K. The measurement of pain: prototype for the quantitative study of subjective responses.Pharmacol. Rev.9, 59–209 (1957).

    CAS PubMed  Google Scholar 

  72. Chapman, C. R. et al. Pain measurement: an overview.Pain22, 1–31 (1985).

    Article CAS PubMed  Google Scholar 

  73. Wall, P. D. et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa.Pain7, 103–113 (1979).

    Article CAS PubMed  Google Scholar 

  74. Kauppila, T. Correlation between autotomy-behavior and current theories of neuropathic pain.Neurosci. Biobehav. Rev.23, 111–129 (1998).

    Article CAS PubMed  Google Scholar 

  75. Bennett, G. J. inMolecular Neurobiology of Pain. Progress in Pain Research and Management vol.9 (ed. Borsook, D.) 109–113 (IASP, Seattle, 1997).

    Google Scholar 

  76. Bennett, G. J. & Xie, Y.-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.Pain33, 87–107 (1988).The first partial nerve injury animal model; the second most cited research paper ever published in the journalPain.

    Article CAS PubMed  Google Scholar 

  77. Eliav, E., Herzberg, U., Ruda, M. A. & Bennett, G. J. Neuropathic pain from an experimental neuritis of the rat sciatic nerve.Pain83, 169–182 (1999).

    Article CAS PubMed  Google Scholar 

  78. Chacur, M. et al. A new model of sciatic inflammatory neuritis (SIN): induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats.Pain94, 231–244 (2001).

    Article CAS PubMed  Google Scholar 

  79. DeLeo, J. A. et al. Characterization of a neuropathic pain model: sciatic cryoneurolysis in the rat.Pain56, 9–16 (1994).

    Article CAS PubMed  Google Scholar 

  80. Gazelius, B., Cui, J.-G., Svensson, M., Meyerson, B. & Linderoth, B. Photochemically induced ischaemic lesion of the rat sciatic nerve. A novel method providing high incidence of mononeuropathy.Neuroreport7, 2619–2623 (1996).

    Article CAS PubMed  Google Scholar 

  81. Kupers, R., Yu, W., Persson, J. K. E., Xu, X.-J. & Wiesenfeld-Hallin, Z. Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain.Pain76, 45–59 (1998).

    Article CAS PubMed  Google Scholar 

  82. Kim, S. H. & Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.Pain50, 355–363 (1992).

    Article CAS  Google Scholar 

  83. Walczak, J.-S., Pichette, V., Leblond, F., Desbiens, K. & Beaulieu, P. Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain.Neuroscience132, 1093–1102 (2005).

    Article CAS PubMed  Google Scholar 

  84. Mosconi, T. & Kruger, L. Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induced a painful neuropathy: ultrastructural morphometric analysis of axonal alterations.Pain64, 37–57 (1996).

    Article CAS PubMed  Google Scholar 

  85. Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain.Pain87, 149–158 (2000).

    Article CAS PubMed  Google Scholar 

  86. Seltzer, Z., Dubner, R. & Shir, Y. A novel behavioral model of causalgiform pain produced by partial sciatic nerve injury in rats.Pain43, 205–218 (1990).

    Article CAS PubMed  Google Scholar 

  87. Djouhri, L., Koutsikou, S., Fang, X., McMullan, S. & Lawson, S. N. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors.J. Neurosci.26, 1281–1292 (2006).

    Article CAS PubMed PubMed Central  Google Scholar 

  88. Kawakami, M. et al. Experimental lumbar radiculopathy, behavior and histologic changes in a model of radicular pain after spinal nerve root irritation with chronic gut ligatures in the rat.Spine19, 1795–1802 (1994).

    Article CAS PubMed  Google Scholar 

  89. Malmberg, A. B. & Basbaum, A. I. Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates.Pain76, 215–222 (1998).

    Article CAS PubMed  Google Scholar 

  90. Vos, B. P., Strassman, A. M. & Maciewicz, R. J. Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve.J. Neurosci.14, 2708–2723 (1994).

    Article CAS PubMed PubMed Central  Google Scholar 

  91. Dowdall, T., Robinson, I. & Meert, T. F. Comparison of five different rat models of peripheral nerve injury.Pharmacol. Biochem.Behav.80, 93–108 (2005).

    Google Scholar 

  92. Zeltser, R., Beilin, B.-Z., Zaslansky, R. & Seltzer, Z. Comparison of autotomy behavior induced in rats by various clinically-used neurectomy methods.Pain89, 19–24 (2000).

    Article CAS PubMed  Google Scholar 

  93. Kim, K. J., Yoon, Y. W. & Chung, J. M. Comparison of three rodent neuropathic models.Exp. Brain Res.1113, 200–206 (1997).

    Article  Google Scholar 

  94. Walczak, J.-S. & Beaulieu, P. Comparison of three models of neuropathic pain in mice using a new method to assess cold allodynia: the double plate technique.Neurosci. Lett.399, 240–244 (2006).

    Article CAS PubMed  Google Scholar 

  95. Cui, J.-G., Holmin, S., Mathiesen, T., Meyerson, B. A. & Linderoth, B. Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy.Pain88, 239–248 (2000).

    Article CAS PubMed  Google Scholar 

  96. Hall, G. C., Carroll, D., Parry, D. & McQuay, H. J. Epidemiology and treatment of neuropathic pain: the UK primary care perspective.Pain122, 156–162 (2006).

    Article PubMed  Google Scholar 

  97. Kehlet, H., Jensen, T. S. & Woolf, C. J. Persistent postsurgical pain: risk factors and prevention.Lancet367, 1618–1625 (2006).

    Article PubMed  Google Scholar 

  98. Nozaki-Taguchi, N. & Yaksh, T. L. A novel model of primary and secondary hyperalgesia after mild thermal injury in the rat.Neurosci. Lett.254, 25–28 (1998).

    Article CAS PubMed  Google Scholar 

  99. Wang, S. et al. A rat model of unilateral hindpaw burn injury: slowly developing rightwards shift of the morphine dose-response curve.Pain116, 87–95 (2005).

    Article CAS PubMed  Google Scholar 

  100. Pacharinsak, C. & Beitz, A. Animal models of cancer pain.Comp. Med.58, 220–233 (2008).A comprehensive review of an exciting new field of pain research.

    CAS PubMed PubMed Central  Google Scholar 

  101. Coderre, T. J., Xanthos, D. N., Francis, L. & Bennett, G. J. Chronic post-ischemia pain (CPIP): a novel animal model of complex regional pain syndrome-Type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat.Pain112, 94–105 (2004).

    Article PubMed  Google Scholar 

  102. Siegel, S. M., Lee, J. W. & Oaklander, A. L. Needlestick distal nerve injury in rats models symptoms of complex regional pain syndrome.Anesth. Analg.105, 1820–1829 (2007).

    Article PubMed  Google Scholar 

  103. Bon, K., Lanteri-Minet, M., de Pommery, J., Michiels, J. F. & Menetrey, D. Cyclophosphamide cystitis as a model of visceral pain in rats. A survey of hindbrain structures involved in visceroception and nociception using the expression of c-Fos and Krox-24 proteins.Exp. Brain Res.108, 404–416 (1996).

    Article CAS PubMed  Google Scholar 

  104. Kuraishi, Y., Nagasawa, T., Hayashi, K. & Satoh, M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice.Eur. J. Pharmacol.275, 229–233 (1995).

    Article CAS PubMed  Google Scholar 

  105. Wallace, V. C. J. et al. Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain.Brain130, 2688–2702 (2007).

    Article PubMed  Google Scholar 

  106. Joseph, E. K., Chen, X., Khasar, S. G. & Levine, J. D. Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat.Pain107, 147–158 (2004).

    Article PubMed  Google Scholar 

  107. Tong, C., Conklin, D. R., Liu, B., Ririe, D. G. & Eisenach, J. C. Assessment of behavior during labor in rats and effect of intrathecal morphine.Anesthesiology108, 1081–1086 (2008).

    Article CAS PubMed  Google Scholar 

  108. Lynch, J. L., Gallus, N. J., Ericson, M. E. & Beitz, A. J. Analysis of nociception, sex and peripheral nerve innervation in the TMEV animal model of multiple sclerosis.Pain136, 293–304 (2008).

    Article PubMed  Google Scholar 

  109. Aicher, S. A., Silverman, M. B., Winkler, C. W. & Bebo, B. F. Jr. Hyperalgesia in an animal model of multiple sclerosis.Pain110, 560–570 (2004).

    Article CAS PubMed  Google Scholar 

  110. Vera-Portocarrero, L. P., Lu, Y. & Westlund, K. N. Nociception in persistent pancreatitis in rats: effects of morphine and neuropeptide alterations.Anesthesiology98, 474–484 (2003).

    Article CAS PubMed  Google Scholar 

  111. Fleetwood-Walker, S. M. et al. Behavioral changes in the rat following infection with varicella-zoster virus.J. Gen. Virol.80, 2433–2436 (1999).

    Article CAS PubMed  Google Scholar 

  112. Brennan, T. J., Vandermeulen, E. P. & Gebhart, G. F. Characterization of a rat model of incisional pain.Pain64, 493–502 (1996).

    Article CAS PubMed  Google Scholar 

  113. Martin, T. J., Buechler, N. L., Kahn, W., Crews, J. C. & Eisenach, J. C. Effects of laparotomy on spontaneous exploratory activity and conditioned operant responding in the rat: a model for postoperative pain.Anesthesiology101, 191–203 (2004).

    Article CAS PubMed  Google Scholar 

  114. Gonzalez, M. I., Field, M. J., Bramwell, S., McCleary, S. & Singh, L. Ovariohysterectomy in the rat: a model of surgical pain for evaluation of pre-emptive analgesia?Pain88, 79–88 (2000).

    Article CAS PubMed  Google Scholar 

  115. Wright-Williams, S. L., Courade, J.-P., Richardson, C. A., Roughan, J. V. & Flecknell, P. A. Effects of vasectomy surgery and meloxicam treatment on faecal corticosterone levels and behaviour in two strains of laboratory mouse.Pain130, 108–118 (2007).

    Article CAS PubMed  Google Scholar 

  116. Rosenzweig, E. S. & McDonald, J. W. Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair.Curr. Opin. Neurol.17, 121–131 (2004).

    Article PubMed  Google Scholar 

  117. Koo, S. T., Park, Y. I., Lim, K. S., Chung, K. & Chung, J. M. Acupuncture analgesia in a new rat model of ankle sprain pain.Pain99, 423–431 (2002).

    Article PubMed  Google Scholar 

  118. Fernihough, J. et al. Pain related behaviour in two models of osteoarthritis in the rat knee.Pain112, 83–93 (2004).

    Article PubMed  Google Scholar 

  119. Bove, S. E. et al. Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.Osteoarthr. Cartil.14, 1041–1048 (2006).

    Article CAS  Google Scholar 

  120. Seo, H.-S. et al. A new rat model for thrombus-induced ischemic pain (TIIP); development of bilateral mechanical allodynia.Pain139, 520–532 (2008).

    Article PubMed  Google Scholar 

  121. Giamberardino, M. A., Valente, R., de Bigontina, P. & Vecchiet, L. Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia.Pain61, 459–469 (1995).

    Article CAS PubMed  Google Scholar 

  122. Courteix, C., Eschalier, A. & Lavarenne, J. Streptozotocin-induced diabetic rats: behavioural evidence for a model of chronic pain.Pain53, 81–88 (1993).

    Article CAS PubMed  Google Scholar 

  123. Tesch, G. H. & Allen, T. J. Rodent models of streptozotocin-induced diabetic nephropathy.Nephrology12, 261–266 (2007).

    Article PubMed  Google Scholar 

  124. Sullivan, K. A., Lentz, S. I., Roberts, J. L. Jr. & Feldman, E. L. Criteria for creating and assessing mouse models of diabetic neuropathy.Curr. Drug Targets9, 3–13 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

  125. Fox, A., Eastwood, C., Gentry, C., Manning, D. & Urban, L. Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat.Pain81, 307–316 (1999).

    Article CAS PubMed  Google Scholar 

  126. Hashizume, H., DeLeo, J. A., Colburn, R. W. & Weinstein, J. N. Spinal glial activation and cytokine expression following lumbar root injury in the rat.Spine25, 1206–1217 (2000).

    Article CAS PubMed  Google Scholar 

  127. Hu, S.-J. & Xing, J.-L. An experimental model for chronic compression of dorsal root ganglion produced by intervertebral foramen stenosis in the rat.Pain77, 15–23 (1998).

    Article CAS PubMed  Google Scholar 

  128. Olmarker, K., Iwabuchi, M., Larsson, K. & Rydevik, B. Walking analysis of rats subjected to experimental disc herniation.Eur.Spine J.7, 394–399 (1998).

    CAS  Google Scholar 

  129. Olmarker, K. Puncture of a lumbar intervertebral disc induces changes in spontaneous pain behavior: an experimental study in rats.Spine33, 850–855 (2008).

    Article PubMed  Google Scholar 

  130. Kawakami, M. et al. Pathomechanism of pain-related behavior produced by allografts of intervertebral disc in the rat.Spine21, 2101–2107 (1996).

    Article CAS PubMed  Google Scholar 

  131. Cuellar, J. M., Montesano, P. X. & Carstens, E. Role of TNF-alpha in sensitization of nociceptive dorsal horn neurons induced by application of nucleus pulposus to L5 dorsal root ganglion in rats.Pain110, 578–587 (2004).

    Article CAS PubMed  Google Scholar 

  132. Kauppila, T., Kontinen, V. K. & Pertovaara, A. Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat.Brain Res.797, 234–242 (1998).

    Article CAS PubMed  Google Scholar 

  133. Franklin, K. B. J. & Abbott, F. V. inNeuromethods, Vol. 13: Psychopharmacology (eds Boulton, A. A., Baker, G. B. & Greenshaw, A. J.) (Humana, Clifton, New Jersey, 1989).

    Google Scholar 

  134. Matthies, B. K. & Franklin, K. B. J. Formalin pain is expressed in decerebrate rats but not attenuated by morphine.Pain51, 199–206 (1992).

    Article CAS PubMed  Google Scholar 

  135. Woolf, C. J. Long term alterations in excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat.Pain18, 325–343 (1984).

    Article CAS PubMed  Google Scholar 

  136. Guilbaud, G. et al. Time course of degeneration and regeneration of myelinated nerve fibres following chronic loose ligatures of the rat sciatic nerve: can nerve lesions be linked to the abnormal pain-related behaviours.Pain53, 147–158 (1993).

    Article CAS PubMed  Google Scholar 

  137. Kauppila, T., Kontinen, V. K. & Pertovaara, A. Weight bearing of the limb as a confounding factor in assessment of mechanical allodynia in the rat.Pain74, 55–59 (1998).

    Article CAS PubMed  Google Scholar 

  138. Backonja, M.-M. & Stacey, B. Neuropathic pain symptoms relative to overall pain rating.J. Pain5, 491–497 (2004).A survey of the clinical symptoms of neuropathic pain patients. It revealed that spontaneous pain is more prevalent, and more reflective of overall pain ratings, than mechanical and thermal hypersensitivities.

    Article PubMed  Google Scholar 

  139. Gottrup, H., Nielsen, J., Arendt-Nielsen, L. & Jensen, T. S. The relationship between sensory thresholds and mechanical hyperalgesia in nerve injury.Pain75, 321–329 (1998).

    Article CAS PubMed  Google Scholar 

  140. Rowbotham, M. C. & Fields, H. L. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia.Brain119, 347–354 (1996).

    Article PubMed  Google Scholar 

  141. Kupers, R. C., Nuytten, D., De Castro-Costa, M. & Gybels, J. M. A time course analysis of the changes in spontaneous and evoked behaviour in a rat model of neuropathic pain.Pain50, 101–111 (1992).

    Article CAS PubMed  Google Scholar 

  142. Meller, S. T. Thermal and mechanical hyperalgesia: a distinct role for different excitatory amino acid receptors and signal transduction pathways?APS J.3, 215–231 (1994).

    Article  Google Scholar 

  143. Mogil, J. S. et al. Heritability of nociception. II. “Types” of nociception revealed by genetic correlation analysis.Pain80, 83–93 (1999).

    Article CAS PubMed  Google Scholar 

  144. Hansson, P. Difficulties in stratifying neuropathic pain by mechanisms.Eur. J. Pain7, 353–357 (2003).

    Article PubMed  Google Scholar 

  145. Field, M. J., Bramwell, S., Hughes, J. & Singh, L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones?Pain83, 303–311 (1999).

    Article CAS PubMed  Google Scholar 

  146. Loeser, J. D. Pain and suffering.Clin. J. Pain16 (Suppl. 2), S2–S6 (2000).

    Article CAS PubMed  Google Scholar 

  147. Warner, L. H. The association span of the white rat.J. Genet. Psychol.41, 57–89 (1932).

    Google Scholar 

  148. Weiss, B. & Laties, V. G. Fractional escape and avoidance on a titration schedule.Science128, 1575–1576 (1958).

    Article CAS PubMed  Google Scholar 

  149. Bodnar, R. J., Kelly, D. D., Brutus, M., Mansour, A. & Glusman, M. 2-Deoxy-D-glucose-induced decrements in operant and reflex pain thresholds.Pharmacol. Biochem. Behav.9, 543–549 (1978).

    Article CAS PubMed  Google Scholar 

  150. Ross, E. L., Komisaruk, B. R. & O'Donnell, D. Evidence that probing the vaginal cervix is analgesic in rats, using an operant paradigm.J. Comp. Physiol. Psychol.93, 330–336 (1979).

    Article CAS PubMed  Google Scholar 

  151. Mauderli, A. P., Acosta-Rua, A. & Vierck, C. J. An operant assay of thermal pain in conscious, unrestrained rats.J. Neurosci. Methods97, 19–29 (2000).

    Article CAS PubMed  Google Scholar 

  152. Baliki, M., Calvo, O., Chialvo, D. R. & Apkarian, A. V. Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape task.Mol. Pain1, 18 (2005).

    PubMed PubMed Central  Google Scholar 

  153. Ding, H. K., Shum, F. W., Ko, S. W. & Zhuo, M. A new assay of thermal-based avoidance test in freely moving mice.J. Pain6, 411–416 (2005).

    Article PubMed  Google Scholar 

  154. Dubner, R., Beitel, R. E. & Brown, F. J. inPain: New Perspectives in Therapy and Research (eds Weisenberg, M. & Tursky, B.) 155–170 (Plenum, New York, 1976).

    Book  Google Scholar 

  155. Sufka, K. J., Brockel, B. J., Liou, J.-R. & Fowler, S. C. Functional deficits following bilateral forelimb adjuvant inflammation assessed by operant methodology: effects of indomethacin and morphine on recovery of function.Exp. Clin. Psychopharmacol.4, 336–343 (1996).

    Article CAS  Google Scholar 

  156. Neubert, J. K. et al. Use of a novel thermal operant behavioral assay for characterization of orofacial pain sensitivity.Pain116, 386–395 (2005).

    Article PubMed  Google Scholar 

  157. Thut, P. D., Hermanstyne, T. O., Flake, N. M. & Gold, M. S. An operant conditioning model to assess changes in feeding behavior associated with temporomandibular joint inflammation in the rat.J. Orofac. Pain21, 7–18 (2007).

    PubMed  Google Scholar 

  158. Martin, T. J. & Ewan, E. Chronic pain alters drug self-administration: implications for addiction and pain mechanisms.Exp. Clin. Psychopharmacol.16, 357–366 (2008).

    Article PubMed PubMed Central  Google Scholar 

  159. Sufka, K. J. Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain.Pain58, 355–366 (1994).

    Article CAS PubMed  Google Scholar 

  160. Johansen, J. P., Fields, H. L. & Manning, B. H. The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex.Proc. Natl Acad. Sci. USA98, 8077–8082 (2001).

    Article CAS PubMed PubMed Central  Google Scholar 

  161. LaBuda, C. J. & Fuchs, P. N. A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats.Exp. Neurol.163, 490–494 (2000).

    Article CAS PubMed  Google Scholar 

  162. Colpaert, F. C. et al. Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats.Pain92, 33–45 (2001).

    Article  Google Scholar 

  163. Neubert, J. K., Rossi, H. L., Malphurs, W., Vierck, C. J. Jr. & Caudle, R. M. Differentiation between capsaicin-induced allodynia and hyperalgesia using a thermal operant assay.Behav. Brain Res.170, 308–315 (2006).

    Article CAS PubMed  Google Scholar 

  164. Morton, D. B. & Griffiths, P. H. Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment.Vet. Rec.116, 431–436 (1985).

    Article CAS PubMed  Google Scholar 

  165. Stasiak, K. L., Maul, D., French, E., Hellyer, P. W. & Vandewoude, S. Species-specific assessment of pain in laboratory animals.Contemp. Top. Lab. Anim. Sci.42, 13–20 (2003).

    CAS PubMed  Google Scholar 

  166. Williams, W. O., Riskin, D. K. & Mott, K. M. Ultrasonic sound as an indicator of acute pain in laboratory mice.J. Am. Assoc. Lab. Anim. Sci.47, 8–10 (2008).

    CAS PubMed PubMed Central  Google Scholar 

  167. Jourdan, D., Ardid, D. & Eschalier, A. Analysis of ultrasonic vocalisation does not allow chronic pain to be evaluated in rats.Pain95, 165–173 (2002).

    Article PubMed  Google Scholar 

  168. Han, J. S., Bird, G. C., Li, W., Jones, J. & Neugebauer, V. Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior.J. Neurosci. Methods141, 261–269 (2005).

    Article PubMed  Google Scholar 

  169. Calvino, B., Besson, J. M., Boehrer, A. & Depaulis, A. Ultrasonic vocalization (22–28 kHz) in a model of chronic pain, the arthritic rat: effects of analgesic drugs.Neuroreport7, 581–584 (1996).

    Article CAS PubMed  Google Scholar 

  170. Wallace, V. C. J., Norbury, T. A. & Rice, A. S. C. Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain.Eur. J. Pain9, 445–452 (2005).

    Article PubMed  Google Scholar 

  171. Roughan, J. V. & Flecknell, P. A. Evaluation of a short duration behaviour-based post-operative pain scoring system in rats.Eur. J. Pain7, 397–406 (2003).

    Article PubMed  Google Scholar 

  172. Tjolsen, A., Berge, O.-G., Hunskaar, S., Rosland, J. H. & Hole, K. The formalin test: an evaluation of the method.Pain51, 5–17 (1992).

    Article CAS PubMed  Google Scholar 

  173. Mogil, J. S., Lichtensteiger, C. A. & Wilson, S. G. The effect of genotype on sensitivity to inflammatory nociception: characterization of resistant (A/J) and sensitive (C57BL/6) inbred mouse strains.Pain76, 115–125 (1998).

    Article CAS PubMed  Google Scholar 

  174. Gould, H. J. Complete Freund's adjuvant-induced hyperalgesia: a human perception.Pain85, 301–303 (2000).An intriguing and amusing first-person recounting of symptoms following accidental injection of the inflammatory compound.

    Article PubMed  Google Scholar 

  175. Olmarker, K., Storkson, R. & Berge, O.-G. Pathogenesis of sciatic pain: a study of spontaneous behavior in rats exposed to experimental disc herniation.Spine27, 1312–1317 (2002).

    Article PubMed  Google Scholar 

  176. Roughan, J. V. & Flecknell, P. A. Behavioural effects of laparotomy and analgesic effects of ketoprofen and carprofen in rats.Pain90, 65–74 (2001).

    Article CAS PubMed  Google Scholar 

  177. Na, H. S., Yoon, Y. W. & Chung, J. M. Both motor and sensory abnormalities contribute to changes in foot posture in an experimental rat neuropathic model.Pain67, 173–178 (1996).

    Article CAS PubMed  Google Scholar 

  178. van Loo, P. L. P. et al. Analgesics in mice used in cancer research: reduction of discomfort?Lab. Anim.31, 318–325 (1997).

    Article CAS PubMed  Google Scholar 

  179. D'Almeida, J. A. C. et al. Behavioral changes of Wistar rats with experimentally-induced painful diabetic neuropathy.Arq. Neuropsiquiatr.57, 746–752 (1999).

    Article CAS PubMed  Google Scholar 

  180. Loeser, J. D., Butler, S. H., Chapman, C. R. & Turk, D. C. (eds)Bonica's Management of Pain 3rd edn (Lippincott Williams & Wilkins, New York, 2000).

    Google Scholar 

  181. Hummel, M., Lu, P., Cummons, T. A. & Whiteside, G. T. The persistence of a long-term negative affective state following the induction of either acute or chronic pain.Pain140, 436–445 (2008).

    Article PubMed  Google Scholar 

  182. Benbouzid, M. et al. Sciatic nerve cuffing in mice: a model of sustained neuropathic pain.Eur. J. Pain12, 591–599 (2007).

    Article PubMed  Google Scholar 

  183. Narita, M. et al. Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala.Neuropsychopharmacology31, 739–750 (2006).

    Article CAS PubMed  Google Scholar 

  184. Suzuki, T. et al. Experimental neuropathy in mice is associated with delayed behavioral changes related to anxiety and depression.Anesth. Analg.104, 1570–1577 (2007).

    Article PubMed  Google Scholar 

  185. Hasnie, F. S. et al. Further characterization of a rat model of varicella zoster virus-associated pain: relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs.Neuroscience144, 1495–1508 (2007).

    Article CAS PubMed  Google Scholar 

  186. Stevenson, G. W., Bilsky, E. J. & Negus, S. S. Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/56J mice.J. Pain7, 408–416 (2006).

    Article CAS PubMed  Google Scholar 

  187. Malick, A., Jakubowski, M., Elmquist, J. K., Saper, C. B. & Burstein, R. A neurochemical blueprint for pain-induced loss of appetite.Proc. Natl Acad. Sci. USA98, 9930–9935 (2001).

    Article CAS PubMed PubMed Central  Google Scholar 

  188. Millecamps, M., Etienne, M., Jourdan, D., Eschalier, A. & Ardid, D. Decrease in non-selective, non-sustained attention induced by a chronic visceral inflammatory state as a new pain evaluation in rats.Pain109, 214–224 (2004).

    Article PubMed  Google Scholar 

  189. Vierck, C. J., Yezierski, R. P. & Light, A. R. Long-lasting hyperalgesia and sympathetic dysregulation after formalin injection into the rat hind paw.Neuroscience153, 501–506 (2008).

    Article CAS PubMed  Google Scholar 

  190. Cain, C. K., Francis, J. M., Plone, M. A., Emerich, D. F. & Lindner, M. D. Pain-related disability and effects of chronic morphine in the adjuvant-induced arthritis model of chronic pain.Physiol. Behav.62, 199–205 (1997).

    Article CAS PubMed  Google Scholar 

  191. Messaoudi, M. et al. Behavioral evaluation of visceral pain in a rat model of colonic inflammation.Neuroreport10, 1137–1141 (1999).

    Article CAS PubMed  Google Scholar 

  192. Rodriguez, R. & Pardo, E. G. Drug reversal of pain induced functional impairment.Arch. int. Pharmacodyn. Ther.172, 148–160 (1968).

    CAS  Google Scholar 

  193. Houghton, A. K., Kadura, S. & Westlund, K. N. Dorsal column lesions reverse the reduction of homecage activity in rats with pancreatitis.Neuroreport8, 3795–3800 (1997).

    Article CAS PubMed  Google Scholar 

  194. Bon, K., Lichtensteiger, C. A., Wilson, S. G. & Mogil, J. S. Characterization of cyclophosphamide cystitis, a model of visceral and referred pain in the mouse: species and strain differences.J. Urol.170, 1008–1012 (2003).

    Article PubMed  Google Scholar 

  195. Zhao, M.-G. et al. Enhanced presynaptic neurotransmitter release in the anterior cingulate cortex of mice with chronic pain.J. Neurosci.26, 8923–8930 (2006).

    Article CAS PubMed PubMed Central  Google Scholar 

  196. Monassi, C. R., Bandler, R. & Keay, K. A. A subpopulation of rats show social and sleep-waking changes typical of chronic neuropathic pain following peripheral nerve injury.Eur. J. Neurosci.17, 1907–1920 (2003).

    Article PubMed  Google Scholar 

  197. Farabollini, F., Giordano, G. & Carli, G. Tonic pain and social behavior in male rabbits.Behav. Brain Res.31, 169–175 (1988).

    Article CAS PubMed  Google Scholar 

  198. Andersen, M. L. & Tufik, S. Sleep patterns over 21-day period in rats with chronic constriction of sciatic nerve.Brain Res.984, 84–92 (2003).

    Article CAS PubMed  Google Scholar 

  199. Guevara-Lopez, U., Ayala-Guerrero, F., Covarrubias-Gomez, A., Lopez-Munoz, F. J. & Torres-Gonzalez, R. Effect of acute gouty arthritis on sleep patterns: a preclinical study.Eur. J. Pain13, 146–153 (2009).

    Article PubMed  Google Scholar 

  200. Landis, C. A., Robinson, C. R. & Levine, J. D. Sleep fragmentation in the arthritic rat.Pain34, 93–99 (1988).

    Article CAS PubMed  Google Scholar 

  201. Munro, G., Erichsen, H. K. & Mirza, N. R. Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety.Neuropharmacology53, 609–618 (2007).

    Article CAS PubMed  Google Scholar 

  202. Kontinen, V. K., Ahnaou, A., Drinkenburg, W. H. & Meert, T. F. Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain.Physiol. Behav.78, 241–246 (2003).

    Article CAS PubMed  Google Scholar 

  203. Tokunaga, S. et al. Changes of sleep patterns in rats with chronic constriction injury under aversive conditions.Biol. Pharm. Bull.30, 2088–2090 (2007).

    Article CAS PubMed  Google Scholar 

  204. Cryan, J. F. & Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety.Nature Rev. Drug Discov.4, 775–790 (2005).

    Article CAS  Google Scholar 

  205. Hasnie, F. S., Wallace, V. C. J., Hefner, K., Holmes, A. & Rice, A. S. C. Mechanical and cold hypersensitivity in nerve-injured C57BL/56J mice is not associated with fear-avoidance- and depression-related behaviour.Br. J. Anaesth.98, 816–822 (2007).

    Article CAS PubMed  Google Scholar 

  206. Kontinen, V. K., Kauppila, T., Paananen, S., Pertovaara, A. & Kalso, E. Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy.Pain80, 341–346 (1999).

    Article CAS PubMed  Google Scholar 

  207. Jourdan, D., Ardid, D. & Eschalier, A. Automated behavioural analysis in animal pain studies.Pharmacol. Res.43, 103–110 (2001).

    Article CAS PubMed  Google Scholar 

  208. Roughan, J. V., Wright-Williams, S. L. & Flecknell, P. A. Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice.Lab. Anim.43, 17–26 (2009).The future of algesiometry in the laboratory animal?

    Article CAS PubMed  Google Scholar 

  209. Chesler, E. J., Wilson, S. G., Lariviere, W. R., Rodriguez-Zas, S. L. & Mogil, J. S. Influences of laboratory environment on behavior.Nature Neurosci.5, 1101–1102 (2002).

    Article CAS PubMed  Google Scholar 

  210. Ueta, K. et al. Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki rats.Life Sci.76, 2655–2668 (2005).

    Article CAS PubMed  Google Scholar 

  211. Cimino-Brown, D. et al. Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model.Anesthesiology103, 1052–1059 (2005).

    Article  Google Scholar 

  212. Mizisin, A. P., Shelton, G. D., Burgers, M. L., Powell, H. C. & Cuddon, P. A. Neurological complications associated with spontaneously occurring feline diabetes mellitus.J. Neuropathol. Exp. Neurol.61, 872–884 (2002).

    Article PubMed  Google Scholar 

  213. Mao, J. NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity.Brain Res. Rev.30, 289–304 (1999).

    Article CAS PubMed  Google Scholar 

  214. Elliott, K., Kest, B., Man, A., Kao, B. & Inturrisi, C. E. N-Methyl-D-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development.Neuropsychopharmacology13, 347–356 (1995).

    Article CAS PubMed  Google Scholar 

  215. Kozela, E. & Popik, P. The effects of NMDA receptor antagonists on acute morphine antinociception in mice.Amino Acids23, 163–168 (2002).

    Article CAS PubMed  Google Scholar 

  216. Kemp, J. A. & McKernan, R. M. NMDA receptor pathways as drug targets.Nature Neurosci.5, 1039–1042 (2002).

    Article CAS PubMed  Google Scholar 

  217. Chizh, B. A., Headley, P. M. & Tzschentke, T. M. NMDA receptor antagonists as analgesics: focus on the NR2B subtype.Trends Pharmacol. Sci.22, 636–642 (2001).

    Article CAS PubMed  Google Scholar 

  218. Monck, N. Morphine/dextromethorphan - endo: E 3231, Morphidex.Drugs R D4, 55–56 (2003).

    Article  Google Scholar 

  219. Lipa, S. M. & Kavaliers, M. Sex differences in the inhibitory effects of the NMDA antagonist, MK-801, on morphine and stress-induced analgesia.Brain Res. Bull.24, 627–630 (1990).

    Article CAS PubMed  Google Scholar 

  220. Nemmani, K. V. S., Grisel, J. E., Stowe, J. R., Smith-Carliss, R. & Mogil, J. S. Modulation of morphine analgesia by site-specificN-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time.Pain109, 274–283 (2004).

    Article CAS PubMed  Google Scholar 

  221. Grisel, J. E., Allen, S., Nemmani, K. V. S., Fee, J. R. & Carliss, R. The influence of dextromethorphan on morphine analgesia in Swiss Webster mice is sex-specific.Pharmacol. Biochem. Behav.81, 131–138 (2005).

    Article CAS PubMed  Google Scholar 

  222. Craft, R. M. & Lee, D. A. NMDA antagonist modulation of morphine antinociception in female vs. male rats.Pharmacol. Biochem. Behav.80, 639–649 (2005).

    Article CAS PubMed  Google Scholar 

  223. Bryant, C. D., Eitan, S., Sinchak, K., Fanselow, M. S. & Evans, C. J. NMDA receptor antagonism disrupts the development of morphine analgesic tolerance in male, but not female C57BL/56J mice.Am. J. Physiol. Regul. Integr. Comp. Physiol.291, R315–R326 (2006).

    Article CAS PubMed  Google Scholar 

  224. Holtman, J. R. Jr., Jing, X. & Wala, E. P. Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats.Pharmacol. Biochem. Behav.76, 285–293 (2003).

    Article CAS PubMed  Google Scholar 

  225. Holtman, J. R. Jr. & Wala, E. P. Characterization of morphine-induced hyperalgesia in male and female rats.Pain114, 62–70 (2005).

    Article CAS PubMed  Google Scholar 

  226. Juni, A., Klein, G., Kowalczyk, B., Ragnauth, A. & Kest, B. Sex differences in hyperalgesia during morphine infusion: effect of gonadectomy and estrogen treatment.Neuropharmacology54, 1264–1270 (2008).

    Article CAS PubMed  Google Scholar 

  227. Levine, J. D., Fields, H. L. & Basbaum, A. I. Peptides and the primary afferent nociceptor.J. Neurosci.13, 2273–2286 (1993).

    Article CAS PubMed PubMed Central  Google Scholar 

  228. Nakamura-Craig, M. & Gill, B. K. Effect of neurokinin A, substance P and calcitonin gene related peptide in peripheral hyperalgesia in the rat paw.Neurosci. Lett.124, 49–51 (1991).

    Article CAS PubMed  Google Scholar 

  229. Gamse, R. & Saria, A. Nociceptive behavior after intrathecal injections of substance P, neurokinin A and calcitonin gene-related peptide.Neurosci. Lett.70, 143–147 (1986).

    Article CAS PubMed  Google Scholar 

  230. Pedersen-Bjergaard, U. et al. Calcitonin gene-related peptide, neurokinin A and substance P: effects on nociception and neurogenic inflammation in human skin and temporal muscle.Peptides12, 333–337 (1991).

    Article CAS PubMed  Google Scholar 

  231. Saxen, M. A., Welch, S. P. & Dewey, W. L. The mouse paw withdrawal assay: a method for determining the effect of calcitonin gene-related peptide on cutaneous heat nociceptive latency time.Life Sci.53, 397–405 (1993).

    Article CAS PubMed  Google Scholar 

  232. Mogil, J. S. et al. Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene.Proc. Natl Acad. Sci. USA102, 12938–12943 (2005).

    Article CAS PubMed PubMed Central  Google Scholar 

  233. MacIntyre, L. C. et al. Sex-dependent fear of human experimenters and facsimiles thereof in laboratory mice.Soc. Neurosci. Abstr. 33 (2007).

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Acknowledgements

The author would like to thank G. Bennett and the anonymous reviewers for helpful comments on this manuscript.

Author information

Authors and Affiliations

  1. Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, H3A 1B1, Quebec, Canada

    Jeffrey S. Mogil

Authors
  1. Jeffrey S. Mogil

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FURTHER INFORMATION

Jeffrey S. Mogil's homepage

Pain Genes Database

Glossary

Therapeutic index

The ratio of the minimum dose of a drug that causes toxic effects to the therapeutic dose, used as a relative measure of drug safety.

Neuropathic pain

Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.

Reflexive measures

Measures of involuntary movements made in response to a stimulus. For example, the nociceptive withdrawal reflex is a spinal (segmental) reflex intended to protect the body from potentially damaging noxious stimuli. Spino-bulbospinal reflexes, lost after spinal transection but preserved after decerebration, include licking, guarding, vocalizing and jumping.

Non-reflexive (operant) measures

Measures of behaviours that require spinal-cerebrospinal integration, which are lost after decerebration. The use of operant measures specifically requires a learned, motivated behaviour that terminates exposure to the noxious stimulus.

Biomarker

A specific physical or chemical entity used to measure or indicate the effects or progress of a disease or condition.

Face validity

A property of a model that seems to obviously ('on its face') measure what it is supposed to measure.

Small interfering RNA knockdown technology

A sequence-specific gene-silencing tool used for RNA interference. Small interfering RNAs are short fragments of synthetic double-stranded RNA with 21–23 pairs of nucleotides that have sequence specificity to the gene of interest. They trigger degradation of the target RNA, thereby creating a partial loss-of-function by decreasing the amount of translatable RNA.

Hyperalgesia

An increased response to a stimulus which is normally painful.

Nociceptive pain

Somatic or visceral pain processed by a normal, unaltered nervous system.

Quantitative trait locus (QTL) mapping

A statistical technique used to identify particular regions of the genome containing DNA variants responsible for between-strain variation on a quantitative (complex) trait.

Formalin test

An assay of acute and tonic pain in which a dilute solution of formalin (37% w/w formaldehyde) is injected into the dorsal or plantar hindpaw. Formalin produces two 'phases' of pain behaviour separated by a quiescent period: the early phase is probably due to direct activation of nociceptors through TRPA1 channels; the second phase is due to ongoing inflammatory input and central sensitization.

Allodynia

Pain resulting from a stimulus that does not normally provoke pain.

von Frey fibres

Nylon monofilaments that, when pressed against tissue until they bend, exert a calibrated amount of force. They are used to measure mechanical sensibility.

Conditioned place preference or aversion

A behavioural task during which a subject learns to associate an experience with a specific physical environment. A subject will choose to spend more time in an environment in which it previously had a rewarding experience (for example, an analgesic drug) and less time in an environment in which it had an aversive experience (for example, inflammatory pain).

Ethogram

A catalogue of discrete behaviours displayed by an organism.

Anthropomorphism

The attribution of human characteristics to non-human organisms. Whereas this attribution is often mistaken, people can also make the opposite error, anthropodenial, denying our commonalities with other species.

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