Abstract
Nociceptive reflexes are predominant in traditional “pain” tests using rodents. However, pain is not a nociceptive reflex, but an unpleasant personal experience associated with a complex sensory, emotional and cognitive phenomenology. Modern research methods in behavioral neuroscience have now enabled preclinical pain researchers to develop procedures which differentially combine reflex and non-reflex based measures, thus making various aspects of pain experience experimentally accessible in rodents. These aspects include the aversive component, anxiodepressive and cognitive consequences of pain as well as pain empathy. Rodents are also highly sensitive to their environmental context, and can accordingly attribute different contextual meaning to different experimental situations. This chapter summarizes classically used nociceptive tests, but mainly focuses on the recent developments highlighting the possibility to address the complex experience of pain in rodents.
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References
Andrews N, Legg E, Lisak D, Issop Y, Richardson D, Harper S, Pheby T, Huang W, Burgess G, Machin I, Rice AS (2012) Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. Eur J Pain 16(4):485–495. doi:10.1016/j.ejpain.2011.07.012
Barrot M (2012) Tests and models of nociception and pain in rodents. Neuroscience 211:39–50. doi:10.1016/j.neuroscience.2011.12.041
Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I (2015) The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry 77(3):236–245. doi:10.1016/j.biopsych.2014.08.004
Barton NJ, Strickland IT, Bond SM, Brash HM, Bate ST, Wilson AW, Chessell IP, Reeve AJ, McQueen DS (2007) Pressure application measurement (PAM): a novel behavioural technique for measuring hypersensitivity in a rat model of joint pain. J Neurosci Methods 163(1):67–75. doi:10.1016/j.jneumeth.2007.02.012
Benbouzid M, Pallage V, Rajalu M, Waltisperger E, Doridot S, Poisbeau P, Freund-Mercier MJ, Barrot M (2008) Sciatic nerve cuffing in mice: a model of sustained neuropathic pain. Eur J Pain 12(5):591–599. doi:10.1016/j.ejpain.2007.10.002
Bendele A (2001) Animal models of rheumatoid arthritis. J Musculoskelet Neuronal Interact 1(4):377–385
Benison AM, Chumachenko S, Harrison JA, Maier SF, Falci SP, Watkins LR, Barth DS (2011) Caudal granular insular cortex is sufficient and necessary for the long-term maintenance of allodynic behavior in the rat attributable to mononeuropathy. J Neurosci Off J Soc Neurosci 31(17):6317–6328. doi:10.1523/JNEUROSCI.0076-11.2011
Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33(1):87–107
Bevaart L, Vervoordeldonk MJ, Tak PP (2010) Evaluation of therapeutic targets in animal models of arthritis: how does it relate to rheumatoid arthritis? Arthritis Rheum 62(8):2192–2205. doi:10.1002/art.27503
Billiau A, Matthys P (2011) Collagen-induced arthritis and related animal models: how much of their pathogenesis is auto-immune, how much is auto-inflammatory? Cytokine Growth Factor Rev 22(5–6):339–344. doi:10.1016/j.cytogfr.2011.11.003
Bolon B, Stolina M, King C, Middleton S, Gasser J, Zack D, Feige U (2011) Rodent preclinical models for developing novel antiarthritic molecules: comparative biology and preferred methods for evaluating efficacy. J Biomed Biotechnol 2011:569068. doi:10.1155/2011/569068
Calvino B, Besson JM, Boehrer A, Depaulis A (1996) Ultrasonic vocalization (22–28 kHz) in a model of chronic pain, the arthritic rat: effects of analgesic drugs. NeuroReport 7(2):581–584
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63
Chapman CR, Tuckett RP, Song CW (2008) Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions. J Pain Off J Am Pain Soc 9(2):122–145. doi:10.1016/j.jpain.2007.09.006
Choi Y, Yoon YW, Na HS, Kim SH, Chung JM (1994) Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59(3):369–376
Colleoni M, Sacerdote P (2010) Murine models of human neuropathic pain. Biochim Biophys Acta 10:924–933. doi:10.1016/j.bbadis.2009.10.012
Craig AD (2009) A rat is not a monkey is not a human: comment on Mogil (Nature Rev Neurosci 10:283–294 (2009)). Nat Rev Neurosci 10(6):466. doi:10.1038/nrn2606-c1
D’Amato FR, Pavone F (2012) Modulation of nociception by social factors in rodents: contribution of the opioid system. Psychopharmacology 224(1):189–200. doi:10.1007/s00213-012-2863-1
D’Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79
Delmas P (2008) SnapShot: ion channels and pain. Cell 134 (2):366 e361. doi:10.1016/j.cell.2008.07.006
Dubuisson D, Dennis SG (1977) The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4(2):161–174
Fone KC, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32(6):1087–1102. doi:10.1016/j.neubiorev.2008.03.003
Han JS, Bird GC, Li W, Jones J, Neugebauer V (2005) Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior. J Neurosci Methods 141(2):261–269. doi:10.1016/j.jneumeth.2004.07.005
Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32(1):77–88
Holmdahl R, Lorentzen JC, Lu S, Olofsson P, Wester L, Holmberg J, Pettersson U (2001) Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis. Immunol Rev 184:184–202
Hu JW (2006) Calibrated forceps: a useful tool to study mechanical nociception. J Pain Off J Am Pain Soc 7(1):40–42. doi:10.1016/j.jpain.2005.10.008
Hunskaar S, Fasmer OB, Hole K (1985) Formalin test in mice, a useful technique for evaluating mild analgesics. J Neurosci Methods 14(1):69–76
Jaggi AS, Jain V, Singh N (2011) Animal models of neuropathic pain. Fundam Clin Pharmacol 25(1):1–28. doi:10.1111/j.1472-8206.2009.00801.x
Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S (2015) Evaluation of models of parkinson’s disease. Front Neurosci 9:503. doi:10.3389/fnins.2015.00503
Johansen JP, Fields HL, Manning BH (2001) The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc Natl Acad Sci U S A 98(14):8077–8082. doi:10.1073/pnas.141218998
Jourdan D, Ardid D, Eschalier A (2002) Analysis of ultrasonic vocalisation does not allow chronic pain to be evaluated in rats. Pain 95(1–2):165–173
Kavaliers M, Choleris E, Colwell DD (2001) Learning from others to cope with biting flies: social learning of fear-induced conditioned analgesia and active avoidance. Behav Neurosci 115(3):661–674
Kayser V, Basbaum AI, Guilbaud G (1990) Deafferentation in the rat increases mechanical nociceptive threshold in the innervated limbs. Brain Res 508(2):329–332
Khan N, Smith MT (2014) Multiple sclerosis-induced neuropathic pain: pharmacological management and pathophysiological insights from rodent EAE models. Inflammopharmacology 22(1):1–22. doi:10.1007/s10787-013-0195-3
King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F (2009) Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci 12(11):1364–1366. doi:10.1038/nn.2407
Kurejova M, Nattenmuller U, Hildebrandt U, Selvaraj D, Stosser S, Kuner R (2010) An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain. Mol Pain 6:18. doi:10.1186/1744-8069-6-18
LaBuda CJ, Fuchs PN (2000) A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats. Exp Neurol 163(2):490–494. doi:10.1006/exnr.2000.7395
Langford DJ, de Williams AC (2014) The caring, sharing rat? Pain 155(7):1183–1184. doi:10.1016/j.pain.2014.03.026
Langford DJ, Bailey AL, Chanda ML, Clarke SE, Drummond TE, Echols S, Glick S, Ingrao J, Klassen-Ross T, Lacroix-Fralish ML, Matsumiya L, Sorge RE, Sotocinal SG, Tabaka JM, Wong D, van den Maagdenberg AM, Ferrari MD, Craig KD, Mogil JS (2010) Coding of facial expressions of pain in the laboratory mouse. Nat Methods 7(6):447–449. doi:10.1038/nmeth.1455
Langford DJ, Tuttle AH, Briscoe C, Harvey-Lewis C, Baran I, Gleeson P, Fischer DB, Buonora M, Sternberg WF, Mogil JS (2011) Varying perceived social threat modulates pain behavior in male mice. J Pain Off J Am Pain Soc 12(1):125–132. doi:10.1016/j.jpain.2010.06.003
Langley CK, Aziz Q, Bountra C, Gordon N, Hawkins P, Jones A, Langley G, Nurmikko T, Tracey I (2008) Volunteer studies in pain research–opportunities and challenges to replace animal experiments: the report and recommendations of a Focus on Alternatives workshop. Neuroimage 42(2):467–473. doi:10.1016/j.neuroimage.2008.05.030
Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53(4):597–652
Li Z, Lu YF, Li CL, Wang Y, Sun W, He T, Chen XF, Wang XL, Chen J (2014) Social interaction with a cagemate in pain facilitates subsequent spinal nociception via activation of the medial prefrontal cortex in rats. Pain 155(7):1253–1261. doi:10.1016/j.pain.2014.03.019
Luis-Delgado OE, Barrot M, Rodeau JL, Schott G, Benbouzid M, Poisbeau P, Freund-Mercier MJ, Lasbennes F (2006) Calibrated forceps: a sensitive and reliable tool for pain and analgesia studies. J Pain Off J Am Pain Soc 7(1):32–39. doi:10.1016/j.jpain.2005.07.011
Mao J (2009) Translational pain research: achievements and challenges. J Pain Off J Am Pain Soc 10(10):1001–1011. doi:10.1016/j.jpain.2009.06.002
Mao J (2012) Current challenges in translational pain research. Trends Pharmacol Sci 33(11):568–573. doi:10.1016/j.tips.2012.08.001
Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6(7):521–532. doi:10.1038/nrn1700
Martin LJ, Tuttle AH, Mogil JS (2014) The interaction between pain and social behavior in humans and rodents. Curr Top Behav Neurosci 20:233–250. doi:10.1007/7854_2014_287
Melchior M, Poisbeau P, Gaumond I, Marchand S (2016) Insights into the mechanisms and the emergence of sex-differences in pain. Neuroscience (in press). doi:10.1016/j.neuroscience.2016.05.007
Miczek KA, Thompson ML, Shuster L (1982) Opioid-like analgesia in defeated mice. Science 215(4539):1520–1522
Mogil JS, Davis KD, Derbyshire SW (2010) The necessity of animal models in pain research. Pain 151(1):12–17. doi:10.1016/j.pain.2010.07.015
Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KS, Andahazy M, Story GM, Patapoutian A (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307(5714):1468–1472. doi:10.1126/science.1108609
Negus SS, Vanderah TW, Brandt MR, Bilsky EJ, Becerra L, Borsook D (2006) Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. J Pharmacol Exp Ther 319(2):507–514. doi:10.1124/jpet.106.106377
Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13(10):1161–1169. doi:10.1038/nn.2647
Neugebauer V, Han JS, Adwanikar H, Fu Y, Ji G (2007) Techniques for assessing knee joint pain in arthritis. Mol Pain 3:8. doi:10.1186/1744-8069-3-8
O’Callaghan JP, Holtzman SG (1975) Quantification of the analgesic activity of narcotic antagonists by a modified hot-plate procedure. J Pharmacol Exp Ther 192(3):497–505
Pachner AR (2011) Experimental models of multiple sclerosis. Curr Opin Neurol 24(3):291–299. doi:10.1097/WCO.0b013e328346c226
Park J, Lim CS, Seo H, Park CA, Zhuo M, Kaang BK, Lee K (2015) Pain perception in acute model mice of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mol Pain 11:28. doi:10.1186/s12990-015-0026-1
Poewe W (2008) Non-motor symptoms in Parkinson’s disease. Eur J Neurol 15(Suppl 1):14–20. doi:10.1111/j.1468-1331.2008.02056.x
Qu C, King T, Okun A, Lai J, Fields HL, Porreca F (2011) Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain 152(7):1641–1648. doi:10.1016/j.pain.2011.03.002
Randall LO, Selitto JJ (1957) A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther 111(4):409–419
Rosemann M, Ivashkevich A, Favor J, Dalke C, Holter SM, Becker L, Racz I, Bolle I, Klempt M, Rathkolb B, Kalaydjiev S, Adler T, Aguilar A, Hans W, Horsch M, Rozman J, Calzada-Wack J, Kunder S, Naton B, Gailus-Durner V, Fuchs H, Schulz H, Beckers J, Busch DH, Burbach JP, Smidt MP, Quintanilla-Martinez L, Esposito I, Klopstock T, Klingenspor M, Ollert M, Wolf E, Wurst W, Zimmer A, de Angelis MH, Atkinson M, Heinzmann U, Graw J (2010) Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 (416insG) mice. Mamm Genome 21(1–2):13–27. doi:10.1007/s00335-009-9235-0
Sasaki A, Serizawa K, Andoh T, Shiraki K, Takahata H, Kuraishi Y (2008) Pharmacological differences between static and dynamic allodynia in mice with herpetic or postherpetic pain. J Pharmacol Sci 108(3):266–273. PMID 18987431
Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, O’Donnell D, Kieffer BL, Basbaum AI (2009) Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137(6):1148–1159. doi:10.1016/j.cell.2009.04.019
Sluka KA, Clauw DJ (2016) Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience. doi:10.1016/j.neuroscience.2016.06.006
Smith SB, Crager SE, Mogil JS (2004) Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred mouse strains. Life Sci 74(21):2593–2604. doi:10.1016/j.lfs.2004.01.002
Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Salter MW, Mogil JS (2015) Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 18(8):1081–1083. doi:10.1038/nn.4053
Sorkin LS, Yaksh TL (2009) Behavioral models of pain states evoked by physical injury to the peripheral nerve. Neurotherapeutics 6(4):609–619. doi:10.1016/j.nurt.2009.07.007
Sotocinal SG, Sorge RE, Zaloum A, Tuttle AH, Martin LJ, Wieskopf JS, Mapplebeck JC, Wei P, Zhan S, Zhang S, McDougall JJ, King OD, Mogil JS (2011) The Rat Grimace Scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. Mol Pain 7:55. doi:10.1186/1744-8069-7-55
Sufka KJ (1994) Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. Pain 58(3):355–366
Suzuki T, Amata M, Sakaue G, Nishimura S, Inoue T, Shibata M, Mashimo T (2007) Experimental neuropathy in mice is associated with delayed behavioral changes related to anxiety and depression. Anesth Analg 104 (6):1570–1577 (table of contents). doi:10.1213/01.ane.0000261514.19946.66
Tassorelli C, Armentero MT, Greco R, Fancellu R, Sandrini G, Nappi G, Blandini F (2007) Behavioral responses and Fos activation following painful stimuli in a rodent model of Parkinson’s disease. Brain Res 1176:53–61. doi:10.1016/j.brainres.2007.08.012
Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K (1992) The formalin test: an evaluation of the method. Pain 51(1):5–17
Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11(12):823–836. doi:10.1038/nrn2947
Wallace VC, Norbury TA, Rice AS (2005) Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain. Eur J Pain 9(4):445–452. doi:10.1016/j.ejpain.2004.10.006
Wallace DL, Han MH, Graham DL, Green TA, Vialou V, Iniguez SD, Cao JL, Kirk A, Chakravarty S, Kumar A, Krishnan V, Neve RL, Cooper DC, Bolanos CA, Barrot M, McClung CA, Nestler EJ (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12(2):200–209. doi:10.1038/nn.2257
Wang J, Goffer Y, Xu D, Tukey DS, Shamir DB, Eberle SE, Zou AH, Blanck TJ, Ziff EB (2011) A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology 115(4):812–821. doi:10.1097/ALN.0b013e31822f16ae
Woolfe G, MacDonald AL (1944) The evaluation of the analgesic action of pethidine hydrochloride (Demerol). J Pharmacol Exp Ther 80:300–307
Yalcin I, Barrot M (2014) The anxiodepressive comorbidity in chronic pain. Curr Opin Anaesthesiol 27(5):520–527. doi:10.1097/ACO.0000000000000116
Yalcin I, Charlet A, Freund-Mercier MJ, Barrot M, Poisbeau P (2009) Differentiating thermal allodynia and hyperalgesia using dynamic hot and cold plate in rodents. J Pain Off J Am Pain Soc 10(7):767–773. doi:10.1016/j.jpain.2009.01.325
Yalcin I, Bohren Y, Waltisperger E, Sage-Ciocca D, Yin JC, Freund-Mercier MJ, Barrot M (2011a) A time-dependent history of mood disorders in a murine model of neuropathic pain. Biol Psychiatry 70(10):946–953. doi:10.1016/j.biopsych.2011.07.017
Yalcin I, Charlet A, Cordero-Erausquin M, Tessier LH, Picciotto MR, Schlichter R, Poisbeau P, Freund-Mercier MJ, Barrot M (2011b) Nociceptive thresholds are controlled through spinal beta2-subunit-containing nicotinic acetylcholine receptors. Pain 152(9):2131–2137. doi:10.1016/j.pain.2011.05.022
Yalcin I, Barthas F, Barrot M (2014) Emotional consequences of neuropathic pain: insight from preclinical studies. Neurosci Biobehav Rev 47:154–164. doi:10.1016/j.neubiorev.2014.08.002
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Barrot, M., Salvat, E., Yalcin, I. (2016). Tests and Models to Study Pain in Animal-Based Translational Research. In: van Rysewyk, S. (eds) Meanings of Pain. Springer, Cham. https://doi.org/10.1007/978-3-319-49022-9_22
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