Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Innovations and advances in modelling and measuring pain in animals

Nature Reviews Neuroscience volume 23, pages 70–85 (2022)Cite this article

Subjects

Abstract

Best practices in preclinical algesiometry (pain behaviour testing) have shifted over the past decade as a result of technological advancements, the continued dearth of translational progress and the emphasis that funding institutions and journals have placed on rigour and reproducibility. Here we describe the changing trends in research methods by analysing the methods reported in preclinical pain publications from the past 40 years, with a focus on the last 5 years. We also discuss how the status quo may be hampering translational success. This discussion is centred on four fundamental decisions that apply to every pain behaviour experiment: choice of subject (model organism), choice of assay (pain-inducing injury), laboratory environment and choice of outcome measures. Finally, we discuss how human tissues, which are increasingly accessible, can be used to validate the translatability of targets and mechanisms identified in animal pain models.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Analysis of rodent use in pain studies from 1980 to 2020.
Fig. 2: Analysis of animal pain assays used from 1980 to 2020.
Fig. 3: Environmental considerations for pain testing.
Fig. 4: Behavioural measures of pain and an analysis of their use in studies from 1980 to 2020.
Fig. 5: Recommendations for increased translational relevance of animal pain models.

Similar content being viewed by others

Data availability

The data supporting the findings of the analysis described in this Review are available in the files in Supplementary information.

References

  1. Rice, A. S. C., Smith, B. H. & Blyth, F. M. Pain and the global burden of disease. Pain 157, 791–796 (2016).

    PubMed  Google Scholar 

  2. Woolf, C. J. Capturing novel non-opioid pain targets. Biol. Psychiatry 87, 74–81 (2020).

    PubMed  Google Scholar 

  3. Gregory, N. S. et al. An overview of animal models of pain: disease models and outcome measures. J. Pain 14, 1255–1269 (2013).

    PubMed  Google Scholar 

  4. Mogil, J. S. Animal models of pain: progress and challenges. Nat. Rev. Neurosci. 10, 283–294 (2009).

    CAS  PubMed  Google Scholar 

  5. Yuan, H., Spare, N. M. & Silberstein, S. D. Targeting CGRP for the prevention of migraine and cluster headache: a narrative review. Headache 59, 20–32 (2019).

    PubMed  Google Scholar 

  6. Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990).

    CAS  PubMed  Google Scholar 

  7. Lassen, L. H. et al. CGRP may play a causative role in migraine. Cephalalgia 22, 54–61 (2002).

    CAS  PubMed  Google Scholar 

  8. Levy, D., Burstein, R. & Strassman, A. M. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann. Neurol. 58, 698–705 (2005).

    CAS  PubMed  Google Scholar 

  9. Wattiez, A. S., Wang, M. & Russo, A. F. CGRP in animal models of migraine. Handb. Exp. Pharmacol. 255, 85–107 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Avona, A. et al. Dural calcitonin gene-related peptide produces female-specific responses in rodent migraine models. J. Neurosci. 39, 4323–4331 (2019).

    PubMed  PubMed Central  Google Scholar 

  11. Dahlhamer, J. et al. Prevalence of chronic pain and high-impact chronic pain among adults — United States, 2016. MMWR 67, 1001–1006 (2018).

    PubMed  PubMed Central  Google Scholar 

  12. Klinck, M. P. et al. Translational pain assessment: could natural animal models be the missing link? Pain 158, 1633–1646 (2017).

    PubMed  Google Scholar 

  13. Lascelles, B. D. X., Brown, D. C., Maixner, W. & Mogil, J. S. Spontaneous painful disease in companion animals can facilitate the development of chronic pain therapies for humans. Osteoarthr. Cartil. 26, 175–183 (2018).

    CAS  Google Scholar 

  14. Middleton, S. J. et al. Studying human nociceptors: from fundamentals to clinic. Brain 144, 1312–1335 (2021).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Mogil, J. S. et al. Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 80, 67–82 (1999).

    CAS  PubMed  Google Scholar 

  17. Tuttle, A. H., Philip, V. M., Chesler, E. J. & Mogil, J. S. Comparing phenotypic variation between inbred and outbred mice. Nat. Methods 15, 994–996 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mogil, J. S. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat. Rev. Neurosci. 21, 353–365 (2020).

    CAS  PubMed  Google Scholar 

  19. Clayton, J. A. & Collins, F. S. NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. Boerner, K. E. et al. Conceptual complexity of gender and its relevance to pain. Pain 159, 2137–2141 (2018).

    PubMed  Google Scholar 

  21. Bigal, M. E., Liberman, J. N. & Lipton, R. B. Age-dependent prevalence and clinical features of migraine. Neurology 67, 246–251 (2006).

    PubMed  Google Scholar 

  22. Weyer, A. D. et al. Nociceptor sensitization depends on age and pain chronicity. eNeuro https://doi.org/10.1523/ENEURO.0115-15.2015 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Flurkey, K., et al) in The Mouse in Biomedical Research 2nd edn Ch 20 (eds Fox, J. G. et al.) 637–672 (Academic Press, 2007).

  24. Reichling, D. B. & Levine, J. D. Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 32, 611–618 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Moloney, R. D. et al. Early-life stress induces visceral hypersensitivity in mice. Neurosci. Lett. 512, 99–102 (2012).

    CAS  PubMed  Google Scholar 

  26. Coutinho, S. V. et al. Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G307–G316 (2002).

    CAS  PubMed  Google Scholar 

  27. Pierce, A. N. et al. Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress. Brain Res. 1639, 58–73 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Vilela, F. C., Vieira, J. S., Giusti-Paiva, A. & da Silva, M. L. Experiencing early life maternal separation increases pain sensitivity in adult offspring. Int. J. Dev. Neurosci. 62, 8–14 (2017).

    PubMed  Google Scholar 

  29. Mizoguchi, H. et al. Maternal separation as a risk factor for aggravation of neuropathic pain in later life in mice. Behav. Brain Res. 359, 942–949 (2019).

    PubMed  Google Scholar 

  30. Smith, B. H., Hébert, H. L. & Veluchamy, A. Neuropathic pain in the community: prevalence, impact, and risk factors. Pain 161, S127–S137 (2020).

    PubMed  Google Scholar 

  31. Van Hecke, O., Austin, S. K., Khan, R. A., Smith, B. H. & Torrance, N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155, 654–662 (2014).

    PubMed  Google Scholar 

  32. Ho Kim, S. & Mo Chung, J. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–363 (1992).

    PubMed  Google Scholar 

  33. Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).

    PubMed  Google Scholar 

  34. Bennett, G. J. & Xie, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107 (1988).

    PubMed  Google Scholar 

  35. Muralidharan, A., Sotocinal, S. G., Austin, J. -S. & Mogil, J. S. The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice. Pain Rep. 5, e824 (2020).

    PubMed  PubMed Central  Google Scholar 

  36. Gadgil, S. et al. A systematic summary and comparison of animal models for chemotherapy induced (peripheral) neuropathy (CIPN). PLoS ONE 14, e0221787 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Pineda-Farias, J. B., Saloman, J. L. & Scheff, N. N. Animal models of cancer-related pain: current perspectives in translation. Front. Pharmacol. 11, 1975 (2020).

    Google Scholar 

  38. Donaldson, L. F., Seckl, J. R. & McQueen, D. S. A discrete adjuvant-induced monoarthritis in the rat: effects of adjuvant dose. J. Neurosci. Methods 49, 5–10 (1993).

    CAS  PubMed  Google Scholar 

  39. Gould, H. J. Complete Freund’s adjuvant-induced hyperalgesia: a human perception. Pain 85, 301–303 (2000).

    PubMed  Google Scholar 

  40. Winter, C. A., Risley, E. A. & Nuss, G. W. Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc. Soc. Exp. Biol. Med. 111, 544–547 (1962).

    CAS  PubMed  Google Scholar 

  41. Brennan, T. J., Vandermeulen, E. P. & Gebhart, G. F. Characterization of a rat model of incisional pain. Pain 64, 493–502 (1996).

    PubMed  Google Scholar 

  42. Banik, R. K., Woo, Y. C., Park, S. S. & Brennan, T. J. Strain and sex influence on pain sensitivity after plantar incision in the mouse. Anesthesiology 105, 1246–1253 (2006).

    PubMed  Google Scholar 

  43. Xu, J. & Brennan, T. J. Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision. Anesthesiology 112, 153–164 (2010).

    PubMed  Google Scholar 

  44. Radhakrishnan, R., Moore, S. A. & Sluka, K. A. Unilateral carrageenan injection into muscle or joint induces chronic bilateral hyperalgesia in rats. Pain 104, 567–577 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Janusz, M. J. et al. Induction of osteoarthritis in the rat by surgical tear of the meniscus: inhibition of joint damage by a matrix metalloproteinase inhibitor. Osteoarthr. Cartil. 10, 785–791 (2002).

    CAS  Google Scholar 

  46. Kamekura, S. et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthr. Cartil. 13, 632–641 (2005).

    CAS  Google Scholar 

  47. Van der Kraan, P. M., Vitters, E. L., Van de Putte, L. B. A. & Van den Berg, W. B. Development of osteoarthritic lesions in mice by ‘metabolic’ and ‘mechanical’ alterations in the knee joints. Am. J. Pathol. 135, 1001–1014 (1989).

    PubMed  PubMed Central  Google Scholar 

  48. Courtenay, J. S., Dallman, M. J., Dayan, A. D., Martin, A. & Mosedale, B. Immunisation against heterologous type II collagen induces arthritis in mice. Nature 283, 666–668 (1980).

    CAS  PubMed  Google Scholar 

  49. Caplazi, P. et al. Mouse models of rheumatoid arthritis. Vet. Pathol. 52, 819–826 (2015).

    CAS  PubMed  Google Scholar 

  50. Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1211–1259 (2017).

    Google Scholar 

  51. Burgos-Vega, C. C. et al. Non-invasive dural stimulation in mice: a novel preclinical model of migraine. Cephalalgia 39, 123–134 (2018).

    PubMed  PubMed Central  Google Scholar 

  52. Oshinsky, M. L. & Gomonchareonsiri, S. Episodic dural stimulation in awake rats: a model for recurrent headache. Headache 47, 1026–1036 (2007).

    PubMed  PubMed Central  Google Scholar 

  53. Bates, E. A. et al. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 30, 170–178 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. De Felice, M. et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann. Neurol. 67, 325–337 (2010).

    PubMed  PubMed Central  Google Scholar 

  55. Shi, C. et al. Animal models for studying the etiology and treatment of low back pain. J. Orthop. Res. 36, 1305–1312 (2018).

    PubMed  PubMed Central  Google Scholar 

  56. Daly, C., Ghosh, P., Jenkin, G., Oehme, D. & Goldschlager, T. A review of animal models of intervertebral disc degeneration: pathophysiology, regeneration, and translation to the clinic. BioMed. Res. Int. 2016, 5952165 (2016).

    PubMed  PubMed Central  Google Scholar 

  57. Kosek, E. et al. Do we need a third mechanistic descriptor for chronic pain states? Pain 157, 1382–1386 (2016).

    PubMed  Google Scholar 

  58. Queiroz, L. P. Worldwide epidemiology of fibromyalgia. Curr. Pain Headache Rep. 17, 356 (2013).

    PubMed  Google Scholar 

  59. DeSantana, J. M., da Cruz, K. M. L. & Sluka, K. A. Animal models of fibromyalgia. Arthritis Res. Ther. 15, 222 (2013).

    PubMed  PubMed Central  Google Scholar 

  60. Sluka, K. A., Kalra, A. & Moore, S. A. Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve 24, 37–46 (2001).

    CAS  PubMed  Google Scholar 

  61. Dina, O. A., Levine, J. D. & Green, P. G. Muscle inflammation induces a protein kinase Cε-dependent chronic-latent muscle pain. J. Pain 9, 457–462 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gregory, N. S., Gibson-Corley, K., Frey-Law, L. & Sluka, K. A. Fatigue-enhanced hyperalgesia in response to muscle insult: induction and development occur in a sex-dependent manner. Pain 154, 2668–2676 (2013).

    PubMed  PubMed Central  Google Scholar 

  63. Nagakura, Y., Oe, T., Aoki, T. & Matsuoka, N. Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: a putative animal model of fibromyalgia. Pain 146, 26–33 (2009).

    CAS  PubMed  Google Scholar 

  64. Goebel, A. et al. Passive transfer of fibromyalgia symptoms from patients to mice. J. Clin. Invest. 131, e144201 (2021).

    CAS  PubMed Central  Google Scholar 

  65. Oka, P. et al. Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 5, 908–917 (2020).

    PubMed  Google Scholar 

  66. Berry, S. H. et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the united states. J. Urol. 186, 540–544 (2011).

    PubMed  PubMed Central  Google Scholar 

  67. Zhang, J., Liang, C. Z., Shang, X. & Li, H. Chronic prostatitis/chronic pelvic pain syndrome: a disease or symptom? Current perspectives on diagnosis, treatment, and prognosis. Am. J. Men’s Health 14, 155798832090320 (2020).

    Google Scholar 

  68. Ness, T. J., Richter, H. E., Varner, R. E. & Fillingim, R. B. A psychophysical study of discomfort produced by repeated filling of the urinary bladder. Pain 76, 61–69 (1998).

    CAS  PubMed  Google Scholar 

  69. Ness, T. J., Metcalf, A. M. & Gebhart, G. F. A psychophysiological study in humans using phasic colonic distension as a noxious visceral stimulus. Pain 43, 377–386 (1990).

    CAS  PubMed  Google Scholar 

  70. Ness, T. J. & Elhefni, H. Reliable visceromotor responses are evoked by noxious bladder distention in mice. J. Urol. 171, 1704–1708 (2004).

    PubMed  Google Scholar 

  71. Ness, T. J., Lewis-Sides, A. & Castroman, P. Characterization of pressor and visceromotor reflex responses to bladder distention in rats: sources of variability and effect of analgesics. J. Urol. 165, 968–974 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  73. Morris, G. P. et al. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96, 795–803 (1989).

    CAS  PubMed  Google Scholar 

  74. Okayasu, I. et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694–702 (1990).

    CAS  PubMed  Google Scholar 

  75. 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).

    PubMed  Google Scholar 

  76. Coutinho, S. V., Meller, S. T. & Gebhart, G. F. Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors. Brain Res. 736, 7–15 (1996).

    CAS  PubMed  Google Scholar 

  77. Schwartzman, R. J., Erwin, K. L. & Alexander, G. M. The natural history of complex regional pain syndrome. Clin. J. Pain 25, 273–280 (2009).

    PubMed  Google Scholar 

  78. Guo, T. Z., Offley, S. C., Boyd, E. A., Jacobs, C. R. & Kingery, W. S. Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I. Pain 108, 95–107 (2004).

    CAS  PubMed  Google Scholar 

  79. Tajerian, M. et al. Sex differences in a murine model of complex regional pain syndrome. Neurobiol. Learn. Mem. 123, 100–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 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. Pain 112, 94–105 (2004).

    PubMed  Google Scholar 

  81. 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).

    PubMed  Google Scholar 

  82. Treede, R.-D. et al. Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the International Classification of Diseases (ICD-11). Pain 160, 19–27 (2019).

    PubMed  Google Scholar 

  83. Simone, D. A., Baumann, T. K. & LaMotte, R. H. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38, 99–107 (1989).

    CAS  PubMed  Google Scholar 

  84. Sakurada, T., Katsumata, K., Tan-No, K., Sakurada, S. & Kisara, K. The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord. Neuropharmacology 31, 1279–1285 (1992).

    CAS  PubMed  Google Scholar 

  85. Bonica, J. The Management of Pain (Lea & Febiger, 1953).

  86. Butler, R. K. & Finn, D. P. Stress-induced analgesia. Prog. Neurobiol. 88, 184–202 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  88. Gamaro, G. D. et al. The effects of acute and repeated restraint stress on the nociceptive response in rats. Physiol. Behav. 63, 693–697 (1998).

    CAS  PubMed  Google Scholar 

  89. Gameiro, G. H. et al. Nociception- and anxiety-like behavior in rats submitted to different periods of restraint stress. Physiol. Behav. 87, 643–649 (2006).

    CAS  PubMed  Google Scholar 

  90. Obernier, J. A. & Baldwin, R. L. Establishing an appropriate period of acclimatization following transportation of laboratory animals. ILAR J. 47, 364–369 (2006).

    CAS  PubMed  Google Scholar 

  91. Moehring, F., O’Hara, C. L. & Stucky, C. L. Bedding material affects mechanical thresholds, heat thresholds, and texture preference. J. Pain 17, 50–64 (2016).

    PubMed  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. Gabriel, A. F. et al. Enriched environment and the recovery from inflammatory pain: social versus physical aspects and their interaction. Behav. Brain Res. 208, 90–95 (2010).

    PubMed  Google Scholar 

  94. Vachon, P. et al. Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain. Behav. Brain Funct. 9, 1–9 (2013).

    Google Scholar 

  95. Tall, J. M. Housing supplementation decreases the magnitude of inflammation-induced nociception in rats. Behav. Brain Res. 197, 230–233 (2009).

    PubMed  Google Scholar 

  96. Shir, Y., Ratner, A. & Seltzer, Z. Diet can modify autotomy behavior in rats following peripheral neurectomy. Neurosci. Lett. 236, 71–74 (1997).

    CAS  PubMed  Google Scholar 

  97. Puglisi-Allegra, S. & Oliverio, A. Social isolation: effects on pain threshold and stress-induced analgesia. Pharmacol. Biochem. Behav. 19, 679–681 (1983).

    CAS  PubMed  Google Scholar 

  98. Tuboly, G., Benedek, G. & Horvath, G. Selective disturbance of pain sensitivity after social isolation. Physiol. Behav. 96, 18–22 (2009).

    CAS  PubMed  Google Scholar 

  99. Meng, Q., Li, N., Han, X., Shao, F. & Wang, W. Peri-adolescence isolation rearing alters social behavior and nociception in rats. Neurosci. Lett. 480, 25–29 (2010).

    CAS  PubMed  Google Scholar 

  100. Lu, Y. F. et al. Social interaction with a cagemate in pain increases allogrooming and induces pain hypersensitivity in the observer rats. Neurosci. Lett. 662, 385–388 (2018).

    CAS  PubMed  Google Scholar 

  101. Baptista-De-Souza, D. et al. Mice undergoing neuropathic pain induce anxiogenic-like effects and hypernociception in cagemates. Behav. Pharmacol. 26, 664–672 (2015).

    CAS  PubMed  Google Scholar 

  102. Smith, M. L., Asada, N. & Malenka, R. C. Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia. Science 371, 153–159 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, Z. et al. Social interaction with a cagemate in pain facilitates subsequent spinal nociception via activation of the medial prefrontal cortex in rats. Pain 155, 1253–1261 (2014).

    PubMed  Google Scholar 

  104. Langford, D. J. et al. Social modulation of pain as evidence for empathy in mice. Science 312, 1967–1970 (2006).

    CAS  PubMed  Google Scholar 

  105. Martin, L. J. et al. Reducing social stress elicits emotional contagion of pain in mouse and human strangers. Curr. Biol. 25, 326–332 (2015).

    CAS  PubMed  Google Scholar 

  106. Langford, D. J. et al. Varying perceived social threat modulates pain behavior in male mice. J. Pain 12, 125–132 (2011).

    PubMed  Google Scholar 

  107. Smith, M. L., Hostetler, C. M., Heinricher, M. M. & Ryabinin, A. E. Social transfer of pain in mice. Sci. Adv. 2, e1600855 (2016).

    PubMed  PubMed Central  Google Scholar 

  108. Raber, P. & Devor, M. Social variables affect phenotype in the neuroma model of neuropathic pain. Pain 97, 139–150 (2002).

    PubMed  Google Scholar 

  109. 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).

    PubMed  Google Scholar 

  110. Sharp, J., Zammit, T., Azar, T. & Lawson, D. Are ‘by-stander’ female Sprague-Dawley rats affected by experimental procedures? Contemp. Top. Lab. Anim. Sci. 42, 19–27 (2003).

    CAS  PubMed  Google Scholar 

  111. Kugler, J., Lange, K. W. & Kalveram, K. T. Influence of bleeding order on plasma corticosterone concentration in the mouse. Exp. Clin. Endocrinol. Diabetes 91, 241–243 (1988).

    CAS  Google Scholar 

  112. Drozdowicz, C. K., Bowman, T. A., Webb, M. L. & Lang, C. M. Effect of in-house transport on murine plasma corticosterone concentration and blood lymphocyte populations. Am. J. Vet. Res. 51, 1841–1846 (1990).

    CAS  PubMed  Google Scholar 

  113. Tuli, J. S., Smith, J. A. & Morton, D. B. Stress measurements in mice after transportation. Lab. Anim. 29, 132–138 (1995).

    CAS  PubMed  Google Scholar 

  114. Brown, G. M. & Martin, J. B. Corticosterone, prolactin, and growth hormone responses to handling and new environment in the rat. Psychosom. Med. 36, 241–247 (1974).

    CAS  PubMed  Google Scholar 

  115. 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. Methods 87, 185–193 (1999).

    CAS  PubMed  Google Scholar 

  116. 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. Pain 9, 174–184 (2008).

    PubMed  Google Scholar 

  117. Sorge, R. E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11, 629–632 (2014).

    CAS  PubMed  Google Scholar 

  118. Konecka, A. M. & Sroczynska, I. Circadian rhythm of pain in male mice. Gen. Pharmacol. 31, 809–810 (1998).

    CAS  PubMed  Google Scholar 

  119. Minett, M. S., Eijkelkamp, N. & Wood, J. N. Significant determinants of mouse pain behaviour. PLoS ONE 9, e104458 (2014).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  121. 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 

  122. Martin, L. J., Acland, E. L., Carlson, E. N., Schweinhardt, P. & Mogil Correspondence, J. S. Male-specific conditioned pain hypersensitivity in mice and humans. Curr. Biol. 29, 192–201 (2019).

    CAS  PubMed  Google Scholar 

  123. Fanselow, M. S. Odors released by stressed rats produce opioid analgesia in unstressed rats. Behav. Neurosci. 99, 589–600 (1985).

    CAS  PubMed  Google Scholar 

  124. Backonja, M. M. & Stacey, B. Neuropathic pain symptoms relative to overall pain rating. J. Pain 5, 491–497 (2004).

    PubMed  Google Scholar 

  125. Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63 (1994).

    CAS  PubMed  Google Scholar 

  126. Dixon, W. J. Efficient analysis of experimental observations. Annu. Rev. Pharmacol. Toxicol. 20, 441–462 (1980).

    CAS  PubMed  Google Scholar 

  127. Fried, N. T., Chamessian, A., Zylka, M. J. & Abdus-Saboor, I. Improving pain assessment in mice and rats with advanced videography and computational approaches. Pain 161, 1420–1424 (2020).

    PubMed  PubMed Central  Google Scholar 

  128. Abdus-Saboor, I. et al. Development of a mouse pain scale using sub-second behavioral mapping and statistical modeling. CellReports 28, 1623–1634 (2019).

    CAS  Google Scholar 

  129. Jones, J. M. et al. A machine-vision approach for automated pain measurement at millisecond timescales. Elife 9, e57258 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Burdge, J., Fried, N. T. & Abdus-Saboor, I. Using high-speed videography for objective and reproducible pain measurement on a mouse pain scale. Star. Protoc. 2, 100322 (2021).

    PubMed  PubMed Central  Google Scholar 

  131. La, J. H. & Chung, J. M. Peripheral afferents and spinal inhibitory system in dynamic and static mechanical allodynia. Pain 158, 2285–2289 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. Randall, L. O. & Selitto, J. J. A method for measurement of analgesic activity on inflamed tissue. Arch. Int. Pharmacodyn. Ther. 111, 409–419 (1957).

    CAS  PubMed  Google Scholar 

  133. Skyba, D. A., Radhakrishnan, R. & Sluka, K. A. Characterization of a method for measuring primary hyperalgesia of deep somatic tissue. J. Pain 6, 41–47 (2005).

    PubMed  Google Scholar 

  134. Woolfe, G. & Macdonald, A. D. The evaluation of the analgesic action of pethidine hydrochloride (Demerol). J. Pharmacol. Exp. Ther. 80, 300–307 (1944).

    CAS  Google Scholar 

  135. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception. Pain 32, 77–88 (1988).

    CAS  PubMed  Google Scholar 

  136. Yoon, C., Young Wook, Y., Heung Sik, N., Sun Ho, K. & Jin Mo, C. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59, 369–376 (1994).

    PubMed  Google Scholar 

  137. Allchorne, A. J., Broom, D. C. & Woolf, C. J. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats. Mol. Pain 1, 36 (2005).

    PubMed  PubMed Central  Google Scholar 

  138. Brenner, D. S., Golden, J. P. & Gereau IV, R. W. A novel behavioral assay for measuring cold sensation in mice. PLoS ONE 7, e39765 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Schmelz, M. What can we learn from the failure of quantitative sensory testing? Pain 162, 663–664 (2021).

    PubMed  Google Scholar 

  140. Forstenpointner, J. et al. No pain, still gain (of function): the relation between sensory profiles and the presence or absence of self-reported pain in a large multicenter cohort of patients with neuropathy. Pain 162, 718–727 (2021).

    CAS  PubMed  Google Scholar 

  141. Bennett, G. J. What is spontaneous pain and who has it? J. Pain 13, 921–929 (2012).

    PubMed  Google Scholar 

  142. Hunskaar, S. & Hole, K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30, 103–114 (1987).

    CAS  PubMed  Google Scholar 

  143. Matthies, B. K. & Franklin, K. B. J. Formalin pain is expressed in decerebrate rats but not attenuated by morphine. Pain 51, 199–206 (1992).

    CAS  PubMed  Google Scholar 

  144. Woolf, C. J. Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain 18, 325–343 (1984).

    PubMed  Google Scholar 

  145. Dolensek, N., Gehrlach, D. A., Klein, A. S. & Gogolla, N. Facial expressions of emotion states and their neuronal correlates in mice. Science 368, 89–94 (2020).

    CAS  PubMed  Google Scholar 

  146. Langford, D. J. et al. Coding of facial expressions of pain in the laboratory mouse. Nat. Methods 7, 447–449 (2010).

    CAS  PubMed  Google Scholar 

  147. Sotocinal, S. G. et al. The Rat Grimace Scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. Mol. Pain 7, 1744–8069-7–55 (2011).

    Google Scholar 

  148. Tuttle, A. H. et al. A deep neural network to assess spontaneous pain from mouse facial expressions. Mol. Pain 14, 1744806918763658 (2018).

    PubMed  PubMed Central  Google Scholar 

  149. Coulthard, P., Pleuvry, B. J., Brewster, M., Wilson, K. L. & Macfarlane, T. V. Gait analysis as an objective measure in a chronic pain model. J. Neurosci. Methods 116, 197–213 (2002).

    PubMed  Google Scholar 

  150. Mogil, J. S. et al. Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking) and dynamic weight bearing (gait) changes are not measures of neuropathic pain in mice. Mol. Pain 6, 1744–8069-6–34 (2010).

    Google Scholar 

  151. 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. Pain 9, 445 (2005).

    PubMed  Google Scholar 

  152. 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. Methods 141, 261–269 (2005).

    PubMed  Google Scholar 

  153. Negus, S. S., Bilsky, E. J., Do Carmo, G. P. & Stevenson, G. W. Rationale and methods for assessment of pain-depressed behavior in preclinical assays of pain and analgesia. Methods Mol. Biol. 617, 79–91 (2010).

    PubMed  PubMed Central  Google Scholar 

  154. Jirkof, P. et al. Burrowing behavior as an indicator of post-laparotomy pain in mice. Front. Behav. Neurosci. 4, 165 (2010).

    PubMed  PubMed Central  Google Scholar 

  155. Andrews, N. et al. Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. Eur. J. Pain 16, 485–495 (2012).

    CAS  PubMed  Google Scholar 

  156. Kandasamy, R., Calsbeek, J. J. & Morgan, M. M. Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats. J. Neurosci. Methods 263, 115–122 (2016).

    PubMed  PubMed Central  Google Scholar 

  157. Cobos, E. J. et al. Inflammation-induced decrease in voluntary wheel running in mice: a nonreflexive test for evaluating inflammatory pain and analgesia. Pain 153, 876–884 (2012).

    PubMed  PubMed Central  Google Scholar 

  158. Grace, P. M., Strand, K. A., Maier, S. F. & Watkins, L. R. Suppression of voluntary wheel running in rats is dependent on the site of inflammation: evidence for voluntary running as a measure of hind paw-evoked pain. J. Pain 15, 121–128 (2014).

    PubMed  Google Scholar 

  159. Stevenson, G. W. et al. Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: implications for preclinical behavioral assessment of chronic pain. Pharmacol. Biochem. Behav. 98, 35–42 (2011).

    CAS  PubMed  Google Scholar 

  160. Zhang, H. et al. Cage-lid hanging behavior as a translationally relevant measure of pain in mice. Pain 162, 1416–1425 (2021).

    CAS  PubMed  Google Scholar 

  161. Sheahan, T. D. et al. Inflammation and nerve injury minimally affect mouse voluntary behaviors proposed as indicators of pain. Neurobiol. Pain 2, 1–12 (2017).

    PubMed  PubMed Central  Google Scholar 

  162. Shepherd, A. J., Cloud, M. E., Cao, Y. Q. & Mohapatra, D. P. Deficits in burrowing behaviors are associated with mouse models of neuropathic but not inflammatory pain or migraine. Front. Behav. Neurosci. 12, 124 (2018).

    PubMed  PubMed Central  Google Scholar 

  163. Jirkof, P. et al. Assessment of postsurgical distress and pain in laboratory mice by nest complexity scoring. Lab. Anim. 47, 153–161 (2013).

    CAS  PubMed  Google Scholar 

  164. Urban, R., Scherrer, G., Goulding, E. H., Tecott, L. H. & Basbaum, A. I. Behavioral indices of ongoing pain are largely unchanged in male mice with tissue or nerve injury-induced mechanical hypersensitivity. Pain 152, 990–1000 (2011).

    PubMed  PubMed Central  Google Scholar 

  165. Brodkin, J. et al. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. J. Neurosci. Methods 224, 48–57 (2014).

    PubMed  Google Scholar 

  166. 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).

    CAS  PubMed  Google Scholar 

  167. Mathis, A. et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat. Neurosci. 21, 1281–1289 (2018).

    CAS  PubMed  Google Scholar 

  168. Chen, Z. et al. AlphaTracker: a multi-animal tracking and behavioral analysis tool. bioRxiv https://doi.org/10.1101/2020.12.04.405159 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Pereira, T. D. et al. SLEAP: multi-animal pose tracking. bioRxiv. https://doi.org/10.1101/2020.08.31.276246 (2020).

    Article  Google Scholar 

  170. Wiltschko, A. B. et al. Mapping sub-second structure in mouse behavior. Neuron 88, 1121–1135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Nilsson, S. R. O. et al. Simple Behavioral Analysis (SimBA) – an open source toolkit for computer classification of complex social behaviors in experimental animals. bioRxiv https://doi.org/10.1101/2020.04.19.049452 (2020).

    Article  Google Scholar 

  172. Bohnslav, J. P. et al. DeepEthogram: a machine learning pipeline for supervised behavior classification from raw pixels. bioRxiv https://doi.org/10.1101/2020.09.24.312504 (2020).

    Article  Google Scholar 

  173. Wiltschko, A. B. et al. Revealing the structure of pharmacobehavioral space through motion sequencing. Nat. Neurosci. 23, 1433–1443 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. King, T. et al. Unmasking the tonic-aversive state in neuropathic pain. Nat. Neurosci. 12, 1364–1366 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Sufka, K. J. Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. Pain 58, 355–366 (1994).

    PubMed  Google Scholar 

  176. 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. USA 98, 8077–8082 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Daou, I. et al. Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J. Neurosci. 33, 18631–18640 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Samineni, V. K., Grajales-Reyes, J. G., Sundaram, S. S., Yoo, J. J. & Gereau, R. W. Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray. Nat. Commun. 10, 1–15 (2019).

    CAS  Google Scholar 

  179. Lax, N. C., George, D. C., Ignatz, C. & Kolber, B. J. The mGluR5 antagonist fenobam induces analgesic conditioned place preference in mice with spared nerve injury. PLoS ONE 9, e103524 (2014).

    PubMed  PubMed Central  Google Scholar 

  180. Massaly, N. et al. Pain-induced negative affect is mediated via recruitment of the nucleus accumbens kappa opioid system. Neuron 102, 564–573 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Cowie, A. M., Moehring, F., O’Hara, C. & Stucky, C. L. Optogenetic inhibition of CGRPα sensory neurons reveals their distinct roles in neuropathic and incisional pain. J. Neurosci. 38, 5807–5825 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhang, Y. et al. Battery-free, fully implantable optofluidic cuff system for wireless optogenetic and pharmacological neuromodulation of peripheral nerves. Sci. Adv. 5, eaaw5296 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Samineni, V. K. et al. Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain. Sci. Rep. 7, 15865 (2017).

    PubMed  PubMed Central  Google Scholar 

  184. 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).

    CAS  PubMed  Google Scholar 

  185. Wu, H. E., Gemes, G., Zoga, V., Kawano, T. & Hogan, Q. H. Learned avoidance from noxious mechanical simulation but not threshold Semmes Weinstein filament stimulation after nerve injury in rats. J. Pain 11, 280–286 (2010).

    PubMed  Google Scholar 

  186. Moqrich, A. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468–1472 (2005).

    CAS  PubMed  Google Scholar 

  187. Lee, H., Iida, T., Mizuno, A., Suzuki, M. & Caterina, M. J. Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J. Neurosci. 25, 1304–1310 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Harte, S. E., Meyers, J. B., Donahue, R. R., Taylor, B. K. & Morrow, T. J. Mechanical Conflict System: a novel operant method for the assessment of nociceptive behavior. PLoS ONE 11, e0150164 (2016).

    PubMed  PubMed Central  Google Scholar 

  189. Reker, A. N. et al. The operant plantar thermal assay: a novel device for assessing thermal pain tolerance in mice. eNeuro https://doi.org/10.1523/ENEURO.0210-19.2020 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Neubert, J. K. et al. Use of a novel thermal operant behavioral assay for characterization of orofacial pain sensitivity. Pain 116, 386–395 (2005).

    PubMed  Google Scholar 

  191. Shansky, R. M. & Murphy, A. Z. Considering sex as a biological variable will require a global shift in science culture. Nat. Neurosci. 24, 457–464 (2021).

    CAS  PubMed  Google Scholar 

  192. Rostock, C., Schrenk-Siemens, K., Pohle, J. & Siemens, J. Human vs. mouse nociceptors – similarities and differences. Neuroscience 387, 13–27 (2018).

    CAS  PubMed  Google Scholar 

  193. Davidson, S. et al. Human sensory neurons: membrane properties and sensitization by inflammatory mediators. Pain 155, 1861–1870 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Shiers, S., Klein, R. M. & Price, T. J. Quantitative differences in neuronal subpopulations between mouse and human dorsal root ganglia demonstrated with RNAscope in situ hybridization. Pain 161, 2410–2424 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Han, C. et al. Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J. Neurophysiol. 113, 3172–3185 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Zhang, X., Priest, B. T., Belfer, I. & Gold, M. S. Voltage-gated Na+ currents in human dorsal root ganglion neurons. eLife 6, e23235 (2017).

    PubMed  PubMed Central  Google Scholar 

  197. Sheahan, T. D. et al. Metabotropic glutamate receptor 2/3 (mGluR2/3) activation suppresses TRPV1 sensitization in mouse, but not human, sensory neurons. eNeuro https://doi.org/10.1523/ENEURO.0412-17.2018 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Zhang, X. L., Lee, K. Y., Priest, B. T., Belfer, I. & Gold, M. S. Inflammatory mediator-induced modulation of GABAA currents in human sensory neurons. Neuroscience 310, 401–409 (2015).

    CAS  PubMed  Google Scholar 

  199. Zhang, X. et al. Nicotine evoked currents in human primary sensory neurons. J. Pain 20, 810–818 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Davidson, S. et al. Group II mGluRs suppress hyperexcitability in mouse and human nociceptors. Pain 157, 2081–2088 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Moy, J. K. et al. Distribution of functional opioid receptors in human dorsal root ganglion neurons. Pain 161, 1636–1649 (2020).

    PubMed  PubMed Central  Google Scholar 

  202. Dedek, A. et al. Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing. Brain 142, 1535–1546 (2019).

    PubMed  PubMed Central  Google Scholar 

  203. Price, T. J. & Flores, C. M. Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J. Pain 8, 263–272 (2007).

    CAS  PubMed  Google Scholar 

  204. Rigaud, M. et al. Species and strain differences in rodent sciatic nerve anatomy: implications for studies of neuropathic pain. Pain 136, 188–201 (2008).

    PubMed  PubMed Central  Google Scholar 

  205. Sadler, K. E., Moehring, F. & Stucky, C. L. Keratinocytes contribute to normal cold and heat sensation. eLife 9, e58625 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Lacroix-Fralish, M. L., Austin, J. S., Zheng, F. Y., Levitin, D. J. & Mogil, J. S. Patterns of pain: meta-analysis of microarray studies of pain. Pain 152, 1888–1898 (2011).

    PubMed  Google Scholar 

  207. Kostowski, W., Członkowski, A., Rewerski, W. & Piechocki, T. Morphine action in grouped and isolated rats and mice. Psychopharmacology 53, 191–193 (1977).

    CAS  PubMed  Google Scholar 

  208. Macolino, C. M., Daiutolo, B. V., Albertson, B. K. & Elliott, M. B. Mechanical allodynia induced by traumatic brain injury is independent of restraint stress. J. Neurosci. Methods 226, 139–146 (2014).

    PubMed  Google Scholar 

  209. Kerstein, P. C., del Camino, D., Moran M. M. & Stucky C. L. Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol. Pain 5, 19 (2009).

    PubMed  PubMed Central  Google Scholar 

  210. W, R. et al. Human cells and networks of pain: transforming pain target identification and therapeutic development. Neuron 109, 1426–1429 (2021).

    Google Scholar 

  211. Wangzhou, A. et al. Pharmacological target-focused transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia. Pain 161, 1497–1517 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Schrenk-Siemens, K. et al. PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors. Nat. Neurosci. 18, 10–16 (2015).

    CAS  PubMed  Google Scholar 

  213. Wainger, B. J. et al. Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat. Neurosci. 18, 17–24 (2015).

    CAS  PubMed  Google Scholar 

  214. Schoepf, C. L. et al. Selected ionotropic receptors and voltage-gated ion channels: more functional competence for human induced pluripotent stem cell (IPSC)-derived nociceptors. Brain Sci. 10, 344 (2020).

    CAS  PubMed Central  Google Scholar 

  215. Chambers, S. M. et al. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat. Biotechnol. 30, 715–720 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. McDermott, L. A. et al. Defining the functional role of NaV1.7 in human nociception. Neuron 101, 905–919 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Xiong, C. et al. Human induced pluripotent stem cell derived sensory neurons are sensitive to the neurotoxic effects of paclitaxel. Clin. Transl. Sci. 14, 568–581 (2021).

    CAS  PubMed  Google Scholar 

  218. Gupta, S. et al. Deriving dorsal spinal sensory interneurons from human pluripotent stem cells. Stem Cell Rep. 10, 390–405 (2018).

    CAS  Google Scholar 

  219. Kim, T. G. et al. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cell 32, 1789–1804 (2014).

    CAS  Google Scholar 

  220. North, R. Y. et al. Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons. Brain 142, 1215–1226 (2019).

    PubMed  PubMed Central  Google Scholar 

  221. Nickolls, A. et al. Transcriptional programming of human mechanosensory neuron subtypes. SSRN Electron. J. 30, 932–946 (2020).

    CAS  Google Scholar 

Download references

Acknowledgements

K.E.S. and C.L.S. are supported by grants from the US National Institutes of Health. J.S.M. is supported by funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Louise and Alan Edwards Foundation.

Author information

Authors and Affiliations

  1. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA

    Katelyn E. Sadler & Cheryl L. Stucky

  2. Department of Psychology, McGill University, Montreal, QC, Canada

    Jeffrey S. Mogil

  3. Department of Anesthesia, McGill University, Montreal, QC, Canada

    Jeffrey S. Mogil

Authors
  1. Katelyn E. Sadler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey S. Mogil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cheryl L. Stucky
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S.M. researched data for the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. K.E.S wrote the article.

Corresponding author

Correspondence to Cheryl L. Stucky.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks I. Abdus-Saboor and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Habituation periods

Time spent in the testing room/apparatus before commencement of testing procedures.

Randall-Selitto deep pressure test

A behaviour test that measures deep tissue mechanical sensitivity via the application of calipers or a weight to a part of the animal’s body (generally the hind paw of a rat).

Outbred strains

Strains in which direct brother–sister mating is avoided to minimize inbreeding.

Neuropathic pain

Pain caused by a lesion or disease of the somatosensory nervous system.

Chemotherapy-induced peripheral neuropathy (CIPN) assays

Neuropathic pain assays in which nerve damage is caused by the administration of chemotherapeutic drugs.

Face validity

A subjective assessment of whether an assay replicates the patient population that it is attempting to model.

Musculosketal pain

Pain affecting bones, joints, ligaments, tendons or muscles.

Osteoarthritis

A form of arthritis involving the degeneration of joint cartilage and the underlying bone.

Rheumatoid arthritis

A form of arthritis featuring inflammation in the joints and resulting in painful deformity and immobility.

Nociplastic pain

Pain that arises form altered nociception despite no clear evidence of actual or threatened tissue damage.

Mechanical allodynia

Mechanical pain due to a stimulus that does not usually provoke pain.

Stress-induced hyperalgesia

Higher sensitivity to pain due to stress-induced activation of descending pain modulatory circuitry.

Stress-induced analgesia

(SIA). Reduced sensitivity to pain due to stress-induced activation of descending pain modulatory circuitry.

Von Frey monofilaments

A set of calibrated nylon filaments used for measuring mechanical sensitivity.

Machine learning

Computer systems that are able to learn without following explicit instructions, by using algorithms that analyse and draw inferences from patterns in data.

Hargreaves test

An assay of thermal pain, also known as the radiant-heat paw withdrawal test.

Writhing

A measure of visceral pain, characterized by stereotypical abdominal constrictions.

Formalin test

An assay of chemical/inflammatory pain in which dilute formaldehyde is injected into the hind paw; subsequent recuperative behaviours are directed towards the injected paw.

Grimace scales

Scales to quantify animal pain levels on the basis of facial expressions.

Conditioned place aversion

An indirect measure of pain based on an animal learning an association between an environment with distinct cues and pain; the animal will avoid the environment paired with pain.

Conditioned place preference

An indirect measure of pain based on an animal learning an association between an environment with distinct cues and pain relief via analgesic administration; the animal will spend more time in the environment paired with the analgesic.

Operant conditioning assays

Associative learning processes through which the strength of a behaviour is modified by reinforcement or punishment (for example, pain).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sadler, K.E., Mogil, J.S. & Stucky, C.L. Innovations and advances in modelling and measuring pain in animals. Nat Rev Neurosci 23, 70–85 (2022). https://doi.org/10.1038/s41583-021-00536-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-021-00536-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing