Hostname: page-component-848d4c4894-pjpqr Total loading time: 0 Render date: 2024-07-06T20:41:23.297Z Has data issue: false hasContentIssue false
  • English
  • Français

Painful dilemmas: the ethics of animal-based pain research

Published online by Cambridge University Press:  01 January 2023

M Magalhães-Sant’Ana ,
P Sandøe  and
IAS Olsson
M Magalhães-Sant’Ana*
Affiliation:
Laboratory Animal Science, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal Department of Veterinary Sciences, University Vasco da Gama, Quinta de S Jorge, Estrada da Conraria, 3040-714 Coimbra, Portugal
P Sandøe
Affiliation:
Danish Centre for Bioethics and Risk Assessment, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 25, 1958 Frederiksberg C, Denmark
IAS Olsson
Affiliation:
Laboratory Animal Science, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal Danish Centre for Bioethics and Risk Assessment, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 25, 1958 Frederiksberg C, Denmark
*
* Contact for correspondence and requests for reprints: mdsantana@euvg.net
Get access Rights & Permissions [Opens in a new window]

Abstract

While it has the potential to deliver important human benefits, animal-based pain research raises ethical questions, because it involves inducing pain in sentient beings. Ethical decision-making, connected with this variety of research, requires informed harm-benefit analysis, and the aim of this paper is to provide information for such an analysis. We present an overview of the different models and their consequences for animal welfare, showing that, of the many animal models available, most have a considerable welfare impact on the animal. While the usual approach to pain control through administration of analgesic substances is usually unsuitable in pain research, refinement remains an option, both within the experimental protocol and in general husbandry and handling. Drawing on the overview, we develop a discussion of the ethical acceptability of animal-based pain research against the background of the kinds of harm done to the animals involved, the potential for refinement, and the expected benefits of the research.

Keywords

animal modelsanimal welfareethicslaboratory animalspainThree Rs
Type
Research Article
Information
Animal Welfare , Volume 18 , Issue 1 , February 2009 , pp. 49 - 63
Copyright
© 2009 Universities Federation for Animal Welfare

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aley, KO, Reichling, DB and Levine, JD 1996 Vincristine hyperalgesia in the rat: a model of painful vincristine neuropathy in humans. Neuroscience 73: 259–265CrossRefGoogle Scholar
Allen, AR 1911 Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column. Journal of the American Medical Association 57: 878–880CrossRefGoogle Scholar
Allen, JW and Yaksh, T 2004 Assessment of acute thermal nociception in laboratory animals. In: Luo, ZD (ed) Pain Research: Methods and Protocols pp 11–23. Humana Press: Totowa, NJ, USACrossRefGoogle Scholar
Anand, KJS and Craig, KD 1996 Editorial: New perspectives on the definition of pain. Pain 67: 3–6Google Scholar
Animal Procedures Committee 2003 Review of Cost-Benefit Assessment in the Use of Animals in Research. Home Office: London, UKGoogle Scholar
Authier, N, Fialip, J, Eschalier, A and Coudore, F 2000 Assessment of allodynia and hyperalgesia after cisplatin administration to rats. Neuroscience Letters 291: 73–76CrossRefGoogle ScholarPubMed
AVMA 2003 Principles of Veterinary Medical Ethics. American Veterinary Medical Association: Schaumburg, IL, USA. http://www.avma.org/issues/policy/ethics.asp (accessed 25 July 2008)Google Scholar
Ben-Bassat, J, Peretz, E and Sulman, FG 1959 Analgesimetry and ranking of analgesic drugs by the receptacle method. Archives of International Pharmacodynamics and Therapeutics 122: 434–447Google ScholarPubMed
Bennett, GJ and Xie, Y-K 1988 A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33: 87–107CrossRefGoogle ScholarPubMed
Besson, JM 1999 The neurobiology of pain. The Lancet 353: 1610–1615CrossRefGoogle ScholarPubMed
Beynen, AC, Baumans, V, Bertens, APMG, Havenaar, R, Hesp, APM and van Zutphen, LFM 1987 Assessment of discomfort in gallstone-bearing mice: a practical example of the problems encountered in an attempt to recognize discomfort in laboratory animals. Laboratory Animals 21: 35–42CrossRefGoogle Scholar
Bove, G 2006 Mechanical sensory threshold testing using nylon monofilaments: the pain field's ‘tin standard’. Pain 124: 13–17CrossRefGoogle Scholar
Burman, OHP, Ilyat, A, Jones, G and Mendl, M 2007 Ultrasonic vocalizations as indicators of welfare for laboratory rats (Rattus norvegicus). Applied Animal Behaviour Science 104(1-2): 116–129CrossRefGoogle Scholar
Cavaletti, G, Tredici, G, Braga, M and Tazzari, S 1995 Experimental peripheral neuropathy induced in adult rats by repeated intraperitoneal administration of taxol. Experimental Neurology 133: 64–72CrossRefGoogle ScholarPubMed
Crabbe, JC, Wahlsten, D and Dudek, BC 1999 Genetics of mouse behavior: Interactions with laboratory environment. Science 284: 1670–1672CrossRefGoogle ScholarPubMed
Crawley, JN, Gerfen, CR, Rogawski, MA, Sibley, DR, Skolnick, P and Wray, S 2007 Short Protocols in Neuroscience - Systems and Behavioural Methods. John Wiley & Sons: Hoboken, NJ, USAGoogle Scholar
Crossley, NA, Sena, E, Goehler, J, Horn, J, van der Worp, B, Bath, PMW, Macleod, M and Dirnagl, U 2008 Empirical evidence of bias in the design of experimental stroke studies - A metaepidemiologic approach. Stroke 39: 929–934CrossRefGoogle ScholarPubMed
D’Amour, FE and Smith, DL 1941 A method for determining the loss of pain sensation. Journal of Pharmacology and Experimental Therapeutics 72: 74–79Google Scholar
de Boo, MJ, Rennie, AE, Buchanan-Smith, HM and Hendriksen, CFM 2005 The interplay between replacement, reduction and refinement: considerations where the Three Rs interact. Animal Welfare 14: 327–332Google Scholar
De Groot, AS and Martin, W 2003 From immunome to vaccine: epitope mapping and vaccine design tools. Novartis Foundation Symposium 254: 57–252Google ScholarPubMed
De Koning, P, Neijt, JP, Jennekens, FG and Gispen, WH 1987 Evaluation of cisdiamminedichloroplatinum (II) (cisplatin) neurotoxicity in rats. Toxicology and Applied Pharmacology 89: 81–87CrossRefGoogle Scholar
Decosterd, I and Woolf, CJ 2000 Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87: 149–158CrossRefGoogle ScholarPubMed
Dogrul, A, Gülmez, SE, Deveci, MS, Gul, H, Ossipov, MH, Porreca, F and Tulunay, FC 2007 The local antinociceptive actions of nonsteroidal antiinflammatory drugs in the mouse radiant heat tail-flick test. Anesthesia and Analgesia 104: 927–935CrossRefGoogle ScholarPubMed
Dubuisson, D and 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: 161–174CrossRefGoogle Scholar
Eaton, M 2003 Common animal models for sapasticity and pain. Journal of Rehabilitation Research and Development 40(4): S41–S54CrossRefGoogle ScholarPubMed
Eliav, E, Herzberg, U, Ruda, MA and Bennett, GJ 1999 Neuropathic pain from an experimental neuritis of the rat sciatic nerve. Pain 83: 169–182CrossRefGoogle ScholarPubMed
European Community 1986 Council Directive 86/609 on the Approximation of Laws, Regulations and Administrative Provisions of the Member States Regarding the Protection of Animals used for Experimental and Other Scientific Purposes. OJL 358. Official Journal of the European Communities, LuxembourgGoogle Scholar
Farazifard, R, Safarpour, F, Sheibani, V and Javan, M 2005 Eye-wiping test: A sensitive animal model for acute trigeminal pain studies. Brain Research Protocols 16: 44–49CrossRefGoogle ScholarPubMed
Flecknell, PA and Roughan, JV 2004 Assessing pain in animals - putting research into practice. Animal Welfare 13: S71–75Google Scholar
Ford, GK, Moriarty, O, McGuire, BE and Finn, DP 2008 Investigating the effects of distracting stimuli on nociceptive behaviour and associated alterations in brain monoamines in rats. European Journal of Pain 12(8): 970–979CrossRefGoogle ScholarPubMed
Gebhart, GF 1999 Animal Models of Pain. ILAR Journal 40(3). http://dels.nas.edu/ilar_n/ilarjournal/40_3/40_3Introduction.htmlGoogle Scholar
Gentle, MJ 2002 Attentional shifts alter pain perception in the chicken. Animal Welfare 10: S187–S194Google Scholar
Giamberardino, MA, Vecchiet, L and Albe-Fessard, D 1990 Comparison of the effects of ureteral calculosis and occlusion on muscular sensitivity to painful stimulation in rats. Pain 43(2): 227–234CrossRefGoogle ScholarPubMed
Grigg, P, Robichaud II, DR and Bove, GM 2007 A feedback-controlled dynamic linear actuator to test foot withdrawal thresholds in rat. Journal of Neuroscience Methods 163: 44–51CrossRefGoogle ScholarPubMed
Goetzl, FR, Burril, DY and Ivy, AC 1943 A critical analysis of algesiometric methods with suggestions for a useful procedure. Quarterly Bulletin Northwestern University Medical School 17: 280–291Google Scholar
Haffner, F 1929 Experimentelle Prüfung schmerzstillender Mittel. Deutsche Medizinische Wochenschrift 55: 731–733. [Title translation: Experimental test of analgesic means]CrossRefGoogle Scholar
Han, JS, Bird, GC, Li, WD, Jones, J and Neugebauer, V 2005 Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior. Journal of Neuroscience Methods 141: 261–269CrossRefGoogle ScholarPubMed
Hansen, AK, Sandøe, P, Svendsen, O, Forsmann, B and Thomsen, P 1999 The need to refine the notion of reduction. In: Hendriksen, CFM and Morton, DB (eds) Humane Endpoints in Animal Experiments for Biomedical Research pp 139–144. Proceedings of the International Conference, 22-25 November 1998, Zeist, The Netherlands. RSM Press: London, UKGoogle Scholar
Hargreaves, K, Dubner, R, Brown, F, Flores, C and Joris, J 1988 A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32: 77–88CrossRefGoogle ScholarPubMed
Houghton, AK, Hewitt, E and Westlund, KN 1997 Enhanced withdrawal responses to mechanical and thermal stimuli after bone injury. Pain 73: 325–337CrossRefGoogle ScholarPubMed
IASP 1994 Part III: Pain terms: A current list with definitions and notes on usage. In: Merskey, H and Bogduk, N (eds) Classification of Chronic Pain, Second Edition pp 209–214. IASP Press: Seattle, USAGoogle Scholar
Kim, SH and Chung, JM 1992 An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50: 355–363CrossRefGoogle Scholar
Kimble, GA 1955 Shock intensity and avoidance learning. Journal of Comparative and Physiological Psychology 48: 281–284CrossRefGoogle ScholarPubMed
Kruger, L 1991 The idiosyncratic problems associated with pain research. In: Kruger, L (ed) Methods in Pain Research pp 1–10. CRC Press: Boca Raton, Florida, USAGoogle Scholar
Lai, Y-Y and Chan, SHH 1982 Shortened pain response time following repeated algesiometric tests in rats. Physiology & Behavior 28: 1111–1113CrossRefGoogle ScholarPubMed
Langley, CK, Aziz, Q, Bountra, C, Gordon, G, Hawkins, P, Jones, A, Langley, G, Nurmikko, T and 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: 467–473CrossRefGoogle ScholarPubMed
Larson, AA and Wilcox, GL 1984 Synergistic behavioral effects of serotonin and tryptamine injected intrathecally in mice. Neuropharmacology 23: 1415–1418CrossRefGoogle ScholarPubMed
Le Bars, D, Gozariu, M and Cadden, SW 2001 Animal models of nociception. Pharmacological Reviews 53: 597–652Google ScholarPubMed
Leo, S, Straetemans, R, D’Hooge, R and Meert, T 2008 Differences in nociceptive behavioral performance between C57BL/6J, 129S6/SvEv, B6 129 F1 and NMRI mice. Behavioural Brain Research 190: 233–242CrossRefGoogle ScholarPubMed
Lindsay, TH, Jonas, BM, Sevcik, MA, Kubota, K, Halvorson, KG, Ghilardi, JR, Kuskowski, MA, Stelow, EB, Mukherjee, P, Gendler, SJ, Wong, GY and Mantyh, PW 2005 Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight, and disease progression. Pain 119: 233–246CrossRefGoogle ScholarPubMed
Luo, ZD 2004 Pain Research: Methods and Protocols. Humana Press: Totowa, NJ, USACrossRefGoogle Scholar
Ma, C 2007 Animal models of pain. International Anesthesiology Clinics 45: 121–131CrossRefGoogle ScholarPubMed
Macleod, MM, Fisher, M, O’Collins, V, Sena, ES, Dirnagl, U, Bath, PMW, Alastair, M, Buchan, AM, van der Worp, B, Traystman, R, Minematsu, K, Donnan, GA and Howells, DW Good laboratory practice: Preventing introduction of bias at the bench. Stroke, in press; doi:10.1161/STROKEAHA.108.525386CrossRefGoogle Scholar
Mao, J 2002 Translational pain research: Bridging the gap between basic and clinical research. Pain 97: 183–187CrossRefGoogle ScholarPubMed
Mauderli, AP, Acosta-Rua, A and Vierck, CJ 2000 An operant assay of thermal pain in conscious, unrestrained rats. Journal of Neuroscience Methods 97: 19–29CrossRefGoogle ScholarPubMed
Miranda, HF, Lopez, J, Sierralta, F, Correa, A and Pinardi, G 2001 NSAID antinociception measured in a chemical and a thermal assay in mice. Pain Research and Management 6: 190–196CrossRefGoogle Scholar
Mogil, JS and Crager, SE 2004 What should we be measuring in behavioral studies of chronic pain in animals? Pain 112: 12–15CrossRefGoogle ScholarPubMed
Molony, V 1997 Comments on Anand and Craig (Letters to the Editor) Pain 70: 293CrossRefGoogle Scholar
Monga, M and Sausville, EA 2002 Developmental therapeutics program at the NCI: molecular target and drug discovery process. Leukemia 16(4): 520–526CrossRefGoogle ScholarPubMed
Morton, DB 1992 A fair press for animals. New Scientist 1816: 28Google Scholar
Morton, DB 1998 The importance of non-statistical design in refining animal experimentation. ANZCCART Facts Sheet. ANZC-CART News 11(2). http://www.adelaide.edu.au/ANZCCART/publications/fs17.pdfGoogle Scholar
Morton, DB 2002 The importance of non-statistical experimental design in refining animal experiments for scientists, IACUCs, and other ethical review panels. In: Gluck, JP, DiPasquale, T and Barbara Orlans, F (eds) Applied Ethics in Animal Research. Philosophy, Regulation, and Laboratory Applications pp 149–178. Purdue University Press: West Layfayette, Indiana, USAGoogle Scholar
Morton, DB and Griffiths, PH 1985 Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Veterinary Record 116: 431–436CrossRefGoogle Scholar
Na, HS, Han, JS, Ko, KH and Hong, SK 1994 A behavioral model for peripheral neuropathy produced in rat's tail by inferior caudal trunk injury. Neuroscience Letters 177: 50–52CrossRefGoogle ScholarPubMed
Nagamine, K, Ozaki, N, Shinoda, M, Asai, H, Nishiguchi, H, Mitsudo, K, Tohnai, I, Ueda, M and Sugiura, Y 2006 Mechanical allodynia and thermal hyperalgesia induced by experimental squamous cell carcinoma of the lower gingiva in rats. Journal of Pain 7: 659–670CrossRefGoogle ScholarPubMed
Ness, TJ 1999 Models of visceral nociception. ILAR Journal 40(3): 119–128CrossRefGoogle ScholarPubMed
Oliveira, AR and Barros, HMT 2006 Ultrasonic rat vocalizations during the formalin test: A measure of the affective dimension of pain? Anesthesia and Analgesia 102: 832–839CrossRefGoogle ScholarPubMed
Olsson, IAS, Hansen, AK and Sandøe, P 2007 Ethics and refinement in animal research. Science 317: 1680CrossRefGoogle ScholarPubMed
Olsson, IAS, Hansen, AK and Sandøe, P 2008 Animal welfare and the refinement of neuroscience research methods - a case study of Huntington's disease models. Laboratory Animals 42(3): 277–283CrossRefGoogle ScholarPubMed
Pacharinsak, C and Beitz, A 2008 Animal models of cancer pain. Comparative Medicine 58: 220–233Google ScholarPubMed
Pelissier, T, Pajot, T and Dallel, R 2002 The orofacial capsaicin test in rats: effects of different capsaicin concentrations and morphine. Pain 96: 81–87CrossRefGoogle Scholar
Portfors, CV 2007 Types and functions of ultrasonic vocalizations in laboratory rats and mice. Journal of the American Association for Laboratory Animal Science 46: 28–34Google ScholarPubMed
Randall, LO and Selitto, JJ 1957 A method for measurement of analgesic activity on inflamed tissue. Archives of International Pharmacodynamics and Therapeutics 111(4): 409–419Google ScholarPubMed
RCVS 2008 Guide to Professional Conduct. Royal College of Veterinary Surgeons: London, UK. http://www.rcvs.org.uk/Templates/Internal.asp?NodeID=89642 (accessed on 25 July 2008)Google Scholar
Ren, K and Dubner, R 1996 An inflammation/hyperalgesia model for the study of orofacial pain. Journal of Dental Research 75: 217Google Scholar
Ren, K and Dubner, R 1999 Inflammatory models of pain and hyperalgesia. ILAR Journal 40(3): 111–118CrossRefGoogle ScholarPubMed
Riopelle, JM 1992 The ethics of using animal models to study treatment of phantom pain. Anesthesiology 76: 1069CrossRefGoogle ScholarPubMed
Rollin, B 1998 The Unheeded Cry: Animal Consciousness, Animal Pain, and Science. Iowa State University Press: Iowa, USAGoogle Scholar
Rollin, B 2003 Oncology and ethics. Reproduction in Domestic Animals 38: 50–53CrossRefGoogle ScholarPubMed
Roughan, JV and Flecknell, PA 2000 Effects of surgery and analgesic administration on spontaneous behaviour in singly-housed rats. Research in Veterinary Science 69: 283–288CrossRefGoogle ScholarPubMed
Roughan, JV and Flecknell, PA 2001 Behavioural effects of laparotomy and analgesic effects of ketoprofen and carprofen in rats. Pain 90: 65–74CrossRefGoogle ScholarPubMed
Roughan, JV and Flecknell, PA 2003 Evaluation of a short duration behaviour-based post-operative pain scoring in rats. European Journal of Pain 7: 397–406CrossRefGoogle Scholar
Roughan, JV, Flecknell, PA and Davies, BR 2004 Behavioural assessment of the effects of tumor growth in rats and the influence of the analgesics carprofen and meloxicam. Laboratory Animals 38: 286–296CrossRefGoogle ScholarPubMed
Sadzot-Delvaux, C, Merville-Louis, MP, Delree, P, Marc, P, Piette, J, Moonen, G and Rentier, B 1990 An in vivo model of varicella-zoster virus latent infection of dorsal root ganglia. Journal of Neuroscience Research 26: 83–89CrossRefGoogle Scholar
Schwei, MJ, Honore, P, Rogers, SD, Salak-Johnson, JL, Finke, MP, Ramnaraine, ML, Clohisy, DR and Mantyh, PW 1999 Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. Journal of Neuroscience 19: 10886–10897CrossRefGoogle Scholar
Sedcole, JR 2006 Experimental design: minimizing the number of subjects that suffer may not mean minimizing total suffering. Animal Behaviour 71: 735–738CrossRefGoogle Scholar
Seltzer, Z, Dubner, R and Shir, Y 1990 A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43: 205–218CrossRefGoogle ScholarPubMed
Shimoyama, M, Tanaka, K, Hasue, F and Shimoyama, N 2002 A mouse model of neuropathic cancer pain. Pain 99: 167–174CrossRefGoogle ScholarPubMed
Short, CE 2003 The management of animal pain. Where have we been, where are we now, and where are we going? The Veterinary Journal 165: 101–103CrossRefGoogle ScholarPubMed
Sima, AA 1980 Peripheral neuropathy in the spontaneously diabetic BB-Wistar-rat. An ultrastructural study. Acta Neuropathologica 51: 223–227CrossRefGoogle ScholarPubMed
Slart, R, Yu, AL, Yaksh, TL and Sorkin, LS 1997 An animal model of pain produced by systemic administration of an immunotherapeutic anti-ganglioside antibody. Pain 69: 119–125CrossRefGoogle ScholarPubMed
Smith, BH, Elliott, AM, Chambers, WA, Smith, WC, Hannaford, PC and Penny, K 2001 The impact of chronic pain in the community. Family Practice 18: 292–298CrossRefGoogle Scholar
Smith, JA, van den Broek, FAR, Cantó Martorell, J, Hackbarth, H, Ruksenas, O and Zeller, W 2007 Principles and practice in ethical review of animal experiments across Europe: summary of the report of a FELASA working group on ethical evaluation of animal experiments. Laboratory Animals 41: 143–160CrossRefGoogle Scholar
Sutton, DC and Lueth, HC 1930 Pain: Experimental production of pain on excitation of the heart and great vessels. Archives of Internal Medicine 45: 827–867CrossRefGoogle Scholar
Tannenbaum, J 1999 Ethics and pain research in animals. ILAR Journal 40(3): 97–110CrossRefGoogle Scholar
Tanner, KD, Reichling, DB and Levine, JD 1998 Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat. The Journal of Neuroscience 18(16): 6480–6491CrossRefGoogle ScholarPubMed
Taylor, AA and Weary, DM 2000 Vocal responses of piglets to castration: identifying procedural sources of pain. Applied Animal Behaviour Science 70: 17–26CrossRefGoogle ScholarPubMed
Taylor, AA, Weary, DM, Lessard, M and Braithwaite, LA 2001 Behavioural responses of piglets to castration: the effect of pig age. Applied Animal Behaviour Science 73: 35–45CrossRefGoogle Scholar
van der Staay, FJ 2006 Animal models of behavioral dysfunctions: Basic concepts and classifications, and an evaluation strategy. Brain Research Reviews 52: 131–159CrossRefGoogle Scholar
van der Warp, HB, de Haan, P, Morrema, E and Kalkman, CJ 2005 Methodological quality of animal studies on neuroprotection in focal cerebral ischaemia. Journal of Neurology 252: 1108–1114Google Scholar
Vander Wende, C and Margolin, S 1956 Analgesic tests based upon experimentally induced acute abdominal pain in rats. Federation Proceedings 15: 494Google Scholar
Vierck, CJ, Hansson, PT and Yezierski, RP 2008 Clinical and pre-clinical pain assessment: Are we measuring the same thing? Pain 135: 7–10CrossRefGoogle ScholarPubMed
Villanueva, L 2000 Is there a gap between preclinical and clinical studies of analgesia? Trends in Pharmacological Sciences 21: 461–462CrossRefGoogle Scholar
Viñuela-Fernández, I, Jones, E, Welsh, EM and Fleetwood-Walker, SM 2007 Pain mechanisms and their implication for the management of pain in farm and companion animals. The Veterinary Journal 174: 227–239CrossRefGoogle ScholarPubMed
von Frey, M 1922 Zur Physiologie der Juckempfindung. Archives Néerlandaises de Physiologie de l’Homme et des Animaux 7: 142–145. [Title translation : On the physiology of skin perception]Google Scholar
von Korff, M, Ormel, J, Keefe, FJ and Dworkin, SF 1992 Grading the severity of chronic pain. Pain 50: 133–149CrossRefGoogle ScholarPubMed
Vorstenbosch, JMG 2005 The ethics of the Three Rs principle: a reconsideration. Animal Welfare 14: 339–345Google Scholar
Vos, BP, Strassman, AM and Maciewicz, RJ 1994 Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve. Journal of Neuroscience 14: 2708–2723CrossRefGoogle Scholar
Wagner, R, DeLeo, JA, Coombs, DW, Willenbring, S and Fromm, C 1993 Spinal dynorphin immunoreactivity increases bilaterally in a neuropathic pain model. Brain Research 629: 323–326CrossRefGoogle Scholar
Walker, K, Alyson, JF and Urban, LA 1999 Animal models for pain research. Molecular Medicine Today 5: 319–321CrossRefGoogle ScholarPubMed
Wall, PD, Devor, M, Inbal, R, Scadding, JW, Schonfeld, D, Seltzer, Z and Tomkiewicz, MM 1979 Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 7: 103–111Google ScholarPubMed
Wang, LX and Wang, ZJ 2003 Animal and cellular models of chronic pain. Advanced Drug Delivery Reviews 55: 949–965CrossRefGoogle ScholarPubMed
Watson, BD, Prado, R, Dietrich, WD, Ginsberg, MD and Green, BA 1986 Photochemically induced spinal cord injury in the rat. Brain Research 367: 296–300CrossRefGoogle ScholarPubMed
Wenig, CM, Schmidt, CO, Kohlmann, T and Schweikert, B 2008 Costs of back pain in Germany. European Journal of Pain, in pressGoogle Scholar
Wiech, K, Seymour, B, Kalisch, R, Stephan, KE, Koltzenburg, M, Driver, J and Dolan, RJ 2005 Modulation of pain processing in hyperalgesia by cognitive demand. NeuroImage 27(1): 59–69CrossRefGoogle ScholarPubMed
Williams, WO, Riskin, DK and Mott, KM 2008 Ultrasonic sound as an indicator of acute pain in laboratory mice. Journal of the American Association for Laboratory Animal Science 47(1): 8–10Google ScholarPubMed
Wilson, SG and Mogil, JS 2001 Measuring pain in the (knockout) mouse: big challenges in a small mammal. Behavioural Brain Research 125: 65–73CrossRefGoogle Scholar
Woolfe, G and MacDonald, AD 1944 The evaluation of the analgesic action of pethidine hydrochloride. Journal of Pharmacology and Experimental Therapeutics 80: 300–307Google Scholar
Würbel, H 2000 Behavior and the standardization fallacy. Nature Genetics 26: 263CrossRefGoogle ScholarPubMed
Würbel, H 2002 Behavioural phenotyping enhanced: beyond (environmental) standardization. Genes Brain and Behavior 1: 3–8Google Scholar
Würbel, H 2007 Publications should include an animal welfare section. Nature 446: 257CrossRefGoogle ScholarPubMed
Würbel, H and Garner, JP 2007 Refinement of rodent research though environmental enrichment and systematic randomization. NC3Rs 9: 1–9Google Scholar