Cited by 1,459Pain Mechanisms and TreatmentsAnimal testing and alternativesVeterinary Pharmacology and Anesthesia

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Animal Models of Nociception

Le Bars, Daniel, Gozariu, Manuela, Cadden, Samuel W.·2001·Pharmacological Reviews

DOI 10.1016/s0031-6997(24)01514-x

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Background
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Method
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Background
Tokishakuyakusan, a Kampo medicine, attenuates endometriosis‐like lesions and hyperalgesia in murine with endometriosis‐like symptoms
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Method
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Influential
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BackgroundMethod
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“) Injection Rats were anesthetized with 3% sevoflurane (HENGRUI, Jiangsu, China) followed by a single intrathecal injection described previously.(15) L5-6 clearance as a puncture point, left thumb, middle finger fixed to the rat sacrum bilaterally, and index finger pressed on the bilateral anterior sacral line midpoin…”
Method
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Background
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Influential
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Method
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Background
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Background
Pharmacological sensitivity of reflexive and nonreflexive outcomes as a correlate of the sensory and affective responses to visceral pain in mice
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“…response was due to a flexion reflex mediated at the spinal cord level, while the paw licking/ lifting response was a more complex reflex mediated by activity at supraspinal levels and was thus less sensitive to descending inhibition (Le Bars et al 2001; Okuda et al 2001; Watanabe et al 2003).”
Background
A preliminary investigation into the practicality of use and duration of action of slow-release preparations of morphine and hydromorphone in laboratory rats
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Morais, M. G., Saldanha, A. A., Mendes, I. C., Rodrigues, J. P. C., Azevedo, L. S., Ferreira, L. M., Amado, P. A., Zanuncio, V. S. S., Farias, K. D. S., Silva, D. B., et al. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117640 · Cited by 13
Effects of creatine supplementation on nociception in young male and female mice
Munoz, H. I., Gonzales, E. B., & Sumien, N. (2017) · Pharmacological Reports · doi:10.1016/j.pharep.2017.11.002 · Cited by 13
“The tail immersion test is designed to provoke a quick reflex reaction [30] which does not involve inflammatory mediators.”
Background
Epidural administration of liposome-encapsulated hydromorphone provides extended analgesia in a rodent model of stifle arthritis.
Schmidt, J. R., Krugner-Higby, L. A., Heath, T. D., Sullivan, R., & Smith, L. J. (2011) · Europe PMC (PubMed Central) · Cited by 13
Remote Controlled Nociceptive Threshold Testing Systems in Large Animals
Taylor, P. M. (2020) · Animals · doi:10.3390/ani10091556 · Cited by 13
“Other tests such as the tail flick [1] and the Randall-Sellito method [4] used in rodents may involve actual physical restraint with even greater impact on behaviour.”
BackgroundMethod
Antinociceptive activity of doliroside B
Bai, X., Li, Y., Li, Y., Li, M., Luo, M. J., Tian, K., Jiang, M., Xiong, Y., Lu, Y., Li, Y., et al. (2023) · Pharmaceutical Biology · doi:10.1080/13880209.2022.2163407 · Cited by 13
“Stimulation of hot plate generates a noninflammatory and acute nociceptive response appeared as paw licking and jumping behaviors occurring at the supraspinal level (Le Bars et al. 2001).”
Background
Leaf extract from Clusia nemorosa induces an antinociceptive effect in mice via a mechanism that is adrenergic systems dependent
Ferro, J. N. D. S., da Silva, J. P., Conserva, L. M., & Barreto, E. (2013) · Chinese Journal of Natural Medicines · doi:10.1016/s1875-5364(13)60056-4 · Cited by 13
“It was reported that substance P and bradykinin participate in the appearance of the first-phase responses, while histamine, serotonin, prostaglandin and bradykinin are involved in the second-phase responses ([15]).”
Background
Semi-mechanistic Pharmacokinetic/Pharmacodynamic Modelling of the Antinociceptive Response in the Presence of Competitive Antagonism: The Interaction Between Tramadol and its Active Metabolite on μ-Opioid Agonism and Monoamine Reuptake Inhibition, in the Rat
Beier, H., Garrido, M. J., Christoph, T., Kasel, D., & Trocóniz, I. F. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9489-8 · Cited by 13
“One of the disadvantages of tail-flick as antinociceptive model is due to its limitation to reflect nonopiod mediated effects such as the monoamine re-uptake inhibition (9).”
Quantitative assessment of the nociceptive withdrawal reflex in healthy, non-medicated experimental sheep
Rohrbach, H., Zeiter, S., Andersen, O. K., Wieling, R., & Spadavecchia, C. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.02.017 · Cited by 13
“Analgesic drugs might modify the steepness of the curve without changing the NWR 80 threshold [19].”
Background
Kavain analogues as potential analgesic agents
Kormann, E. C., Amaral, P. D. A., David, M., Eifler-Lima, V. L., Filho, V. C., & Buzzi, F. D. C. (2012) · Pharmacological Reports · doi:10.1016/s1734-1140(12)70939-8 · Cited by 13
“the spinal cord [20, 26].”
Enkephalin derivative, cyclo[Nε,Nβ-carbonyl-d-Lys2, Dap5] enkephalinamide (cUENK6), induces a highly potent antinociception in rats
Kotlinska, J. H., Bochenski, M., Łagowska-Lenard, M., Gibuła‐Tarłowska, E., Witkowska, E., & Izdebski, J. (2009) · Neuropeptides · doi:10.1016/j.npep.2009.03.003 · Cited by 13
Exploring Pharmacological Activities and Signaling of Morphinans Substituted in Position 6 as Potent Agonists Interacting with the μ Opioid Receptor
Haddou, T. B., Malfacini, D., Calò, G., Aceto, M. D. G., Harris, L. S., Traynor, J. R., Coop, A., Schmidhammer, H., & Spetea, M. (2014) · Molecular Pain · doi:10.1186/1744-8069-10-48 · Cited by 13
“Activity in the hot-plate test suggests that a drug acts at the supraspinal level, whereas the tail-flick may reflect spinal activity [32].”
Background
Antinociceptive and Smooth Muscle Relaxant Activity of Croton tiglium L Seed: An In-vitro and In-vivo Study.
Liu, Z., Gao, W., Zhang, J., & Hu, J. Y. (2012) · Europe PMC (PubMed Central) · Cited by 13
Natural Product Research: Formerly Natural Product Letters
Giampieri, F., Álvarez-Suárez, J. M., Mazzoni, L., Romandini, S., Bompadre, S., Diamanti, J., Capocasa, F., Mezzetti, B., Quiles, J. L., Ferreiro, M. S., et al. (2014) · Cited by 13
Antinociceptive activity of a polysaccharide from the roots of Sophora flavescens
Jia, R., Li, Q., Shen, W., Zhang, J., Zheng, L., & Wang, G. (2016) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2016.08.054 · Cited by 13
Anti-Inflammatory and Anti-Nociceptive Activities of Stem-Bark Extracts and Fractions of Carpolobia Lutea (Polygalaceae)
Nwidu, L. L., Airhihen, B., & Ahmadu, A. A. (2016) · Journal of Basic and Clinical Pharmacy · doi:10.4103/0976-0105.195097 · Cited by 13
“) irritates serous membranes and provokes a stereotypical behavior in mice characterized by abdominal contractions, movements of the whole body, twisting of dorso‐abdominal muscles, and a reduction in motor activity and coordination.[43] The administration of the stem extract reduces abdominal constriction dose depend…”
Background
Phytochemical screening and analgesic profile of the lyophilized aqueous extract obtained from Chrysobalanus icaco leaves in experimental protocols
Araújo-Filho, H. G., Dias, J. S., Quintans-Júnior, L., Santos, M. R. V., White, P. A. S., Barreto, R. S. S., Barreto, A., Estevam, C., Araujo, S., Almeida, J., et al. (2016) · Pharmaceutical Biology · doi:10.1080/13880209.2016.1204618 · Cited by 12
“This method shows good sensitivity but poor specificity because the abdominal writhing response may be suppressed by muscle relaxants and other drugs, leaving scope for the misinterpretation of results (Le Bars et al. 2001).”
BackgroundMethod
Validation of a thermal threshold nociceptive model in bearded dragons (Pogona vitticeps)
Couture, É. L., Monteiro, B. P., Aymen, J., Troncy, É., & Steagall, P. V. M. (2017) · Veterinary Anaesthesia and Analgesia · doi:10.1016/j.vaa.2016.07.005 · Cited by 13
Indole alkaloids and anti-nociceptive mechanisms of Tabernaemontana divaricata (L.) R. Br. flower methanolic extract
Khan, M. S. A., Misbah, Ahmed, N., Arifuddin, M., Rehman, A., & Ling, M. P. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.06.007 · Cited by 13
Changes in TRPV1-Mediated Physiological Function in Rats Systemically Treated With Capsaicin on the Neonate
Jeong, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093143 · Cited by 13
“The paw pressure test is a technique for the measurement of the pain response in animals and is used to test the effectiveness of analgesics by observing the reaction to gradually increasing pressure on an inflamed paw [32].”
Method
Antinociceptive Effects of Kappa-Opioid Receptor Agonists
Lazenka, M. F. (2021) · Handbook of experimental pharmacology · doi:10.1007/164_2020_430 · Cited by 13
Antinociceptive effect of 7-methoxyflavone isolated fromZornia brasiliensis
da Silva, A. D. S., Silva, L. H. A. C., da Matta, C. B. B., Silva, D. D. F., de Araújo, M. V., Tavares, J. F., da Silva, M. S., & Alexandre‐Moreira, M. S. (2013) · Natural Product Research · doi:10.1080/14786419.2013.768988 · Cited by 13
Involvement of cellular prion protein in the nociceptive response in mice
Meotti, F. C., Carqueja, C. L., Gadotti, V. M., Tasca, C. I., Walz, R., & Santos, A. R. S. (2007) · Brain Research · doi:10.1016/j.brainres.2007.03.024 · Cited by 13
Analgesic and anti-inflammatory properties of Oxyanthus unilocularis
Nkeh-Chungag, B. N., Bekwa, P. C. M., Ndebia, E. J., Kayo, M. T., Mbafor, T. J., & Iputo, E. J. (2010) · Journal of Medicinal Plants Research · doi:10.5897/jmpr10.112 · Cited by 13
Role of adenosine receptors in the anti-nociceptive effects of allopurinol in mice.
Essawy, S. S., & El-Baz, A. A. (2013) · PubMed · Cited by 13
Analgesic potential of standardized methanol stem bark extract of Ficus platyphylla in mice: Mechanisms of action
Chindo, B. A., Schröder, H., Koeberle, A., Werz, O., & Becker, A. (2016) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2016.03.003 · Cited by 13
Commonly Used Preclinical Models of Pain
Jeong, Y., & Holden, J. E. (2007) · Western Journal of Nursing Research · doi:10.1177/0193945907304439 · Cited by 13
“…as nociceptors and there are some technical difficulties in a freely moving animal, monofilament stimulation is commonly used to measure mechanical sensitivity both in animals and in humans (Gould et al., 2000; Le Bars et al., 2001; Milligan et al., 2003; Yashpal, Fisher, Chabot, & Coderre, 2001).”
Background
TailTimer: A device for automating data collection in the rodent tail immersion assay
Udell, M. E., Ni, J., Martinez, A. G., Mulligan, M. K., Redei, E. E., & Chen, H. (2021) · PLoS ONE · doi:10.1371/journal.pone.0256264 · Cited by 12
“Thermal stimulation, however, models a naturally-encountered stimulus, and its ability to induce pain with a relatively high degree of specificity contributes to its wide utilization throughout pain research [1].”
Background
Antinociceptive and Toxicological Effects ofDioclea grandifloraSeed Pod in Mice
Sá, R. D. C. D. S. E., Oliveira, L., Nóbrega, F. F. D. F., Bhattacharyya, J., & de Almeida, R. N. (2010) · BioMed Research International · doi:10.1155/2010/606748 · Cited by 12
Methods for Evaluating Sensory, Affective and Cognitive Disorders in Neuropathic Rodents
Palazzo, E., Marabese, I., Gargano, F., Guida, F., Belardo, C., & Maione, S. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200831153117 · Cited by 12
Intrinsic connections within the pedunculopontine tegmental nucleus are critical to the elaboration of post‐ictal antinociception
Mazzei‐Silva, E. C., de Oliveira, R. C., dos Anjos‐Garcia, T., Falconi‐Sobrinho, L. L., Almada, R. C., & Coimbra, N. C. (2014) · Synapse · doi:10.1002/syn.21749 · Cited by 12
“In fact, the tailflick test involves spinal cord sensory-motor reflexes (Dickenson et al., 1979; Le Bars et al., 2001) instead of supra-spinal ones, recruited by other nociceptive tests, like hot-plate and paw oedema model.”
Background
Neurotoxicity of intrathecal injections of dexmedetomidine into the rat spinal dorsal horn.
Hou, J., Xia, Z., Xiao, X., Wan, X., & Zhao, B. (2012) · PubMed Central · doi:10.3969/j.issn.1673-5374.2012.23.001 · Cited by 12
“TFL: The test was conducted in a quiet, dimly lit room with an ambient temperature of 20 ± 2°C.”
MethodInfluential
Challenges of thermal nociceptive threshold testing in the donkey
Grint, N. J., Whay, H. R., Beths, T., Yvorchuk, K., & Murrell, J. C. (2014) · Veterinary Anaesthesia and Analgesia · doi:10.1111/vaa.12182 · Cited by 12
Antinociceptive and anti-inflammatory activity of the siaresinolic acid, a triterpene isolated from the leaves of Sabicea grisea Cham. & Schltdl. var. grisea
de Oliveira, A. M., de Araújo, A. F., Lemos, R. P. L., Conserva, L. M., Ferro, J. N. D. S., & Barreto, E. (2015) · Journal of Natural Medicines · doi:10.1007/s11418-014-0883-3 · Cited by 12
“This test, however, is insensitive to NSAIDs such as cyclooxygenase inhibitors [28].”
Background
Anti hyperalgesic potentials of Laggera aurita in Swiss Albino mice.
Olurishe, T. O., & Mati, F. G. (2014) · PubMed · Cited by 12
Evaluation of the anti-nociceptive effects of morphine, tramadol, meloxicam and their combinations using the tail-flick test in rats.
Foroud, M., & Vesal, N. (2015) · Europe PMC (PubMed Central) · Cited by 12
Phytochemical andAntimicrobial Potentials Leaves Extract of Eucalyptus Globulus Oil from Maichew Tigray Ethiopia
Amabye, T. G. (2016) · International Journal of Complementary & Alternative Medicine · doi:10.15406/ijcam.2016.03.00056 · Cited by 12
“The hydro distillation lasted for 3 hours and the oil collected was dried with sodium sulphate and stored at 4°C in a refrigerator for further use [12].”
Method
Application of a handheld Pressure Application Measurement device for the characterisation of mechanical nociceptive thresholds in intact pig tails
Giminiani, P. D., Sandercock, D. A., Malcolm, E. M., Leach, M. C., Herskin, M. S., & Edwards, S. A. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.07.006 · Cited by 12
Phytochemical profile and mechanisms involved in the anti-nociception caused by the hydroethanolic extract obtained from Tocoyena formosa (Cham. & Schltdl.) K. Schum (Jenipapo-bravo) leaves in mice
Cesário, F. R. A. S., de Albuquerque, T. R., de Lacerda, G. M., de Oliveira, M. R. C., Rodrigues, L. B., Martins, A. O. B. P. B., Boligon, A. A., Quintans‐Júnior, L. J., Araújo, A. A. D. S., Vale, M. L., et al. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.10.054 · Cited by 12
Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury
Sun, M., Baker, T. L., Wilson, C. T., Brady, R. D., Mychasiuk, R., Yamakawa, G. R., Vo, A. N. Q., Wilson, T., McDonald, S. J., & Shultz, S. R. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.937350 · Cited by 12
Refinement of a thermal threshold probe to prevent burns
Dixon, M., Taylor, P. M., Slingsby, L., & Murrell, J. C. (2015) · Laboratory Animals · doi:10.1177/0023677215577313 · Cited by 12
“Thermal NTT has become a well accepted laboratory method of assessing the likely therapeutic efficacy of an analgesic.(1) Studies in cats have also demonstrated that increased TT appears to correlate with clinical perception of the efficacy and duration of opioid analgesics.”
Method
Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain
Taneja, A., Nyberg, J., de Lange, E. C. M., Danhof, M., & Pasqua, O. E. D. (2012) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-012-9278-9 · Cited by 12
The effect of social isolation, gender and familiarity with the experimental procedure on tests of porcine nociceptive thresholds
Giminiani, P. D., Stausholm, J. S., Viitasaari, E., Petersen, L. J., & Herskin, M. S. (2015) · Veterinary Anaesthesia and Analgesia · doi:10.1111/vaa.12254 · Cited by 12
Pain tests provoke modality-specific cardiovascular responses in awake, unrestrained rats
Rigaud, M., Gemes, G., Abram, S. E., Dean, C., Hopp, F. A., Stucky, C. L., Eastwood, D. C., Tarima, S. S., Seagard, J. L., & Hogan, Q. H. (2010) · Pain · doi:10.1016/j.pain.2010.09.010 · Cited by 12
“Although quantifying somatomotor behavior induced by cutaneous stimulation is the accepted standard for sensory testing in animals, this has been adopted largely out of convenience, and doubts have been raised regarding the validity of this approach [25,45].”
Background
Do mice have a pain face?
Flecknell, P. A. (2010) · Nature Methods · doi:10.1038/nmeth0610-437 · Cited by 12
In Vivo Electrophysiology of Dorsal-Horn Neurons
Stanfa, L. C., & Dickenson, A. H. (2004) · Methods in molecular medicine · doi:10.1007/978-1-59259-770-3_12 · Cited by 12
A prospective study of breed differences in the thermal pain sensitivity of dogs
Bowden, J., Beausoleil, N. J., Stafford, K. J., Gieseg, M. A., & Bridges, J. P. (2017) · Veterinary Anaesthesia and Analgesia · doi:10.1016/j.vaa.2017.07.003 · Cited by 12
Antinociceptive compounds and LC-DAD-ESIMSn profile from Dictyoloma vandellianum leaves
Abreu, L. S., Alves, I. M., Santo, R. F. D. E., do Nascimento, Y. M., Dantas, C. A. G., dos Santos, G. G. L., Hyaric, M. L., Guedes, M. L. S., da Silva, M. S., Villarreal, C. F., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224575 · Cited by 12
Differentiating hemodynamic responses in rat primary somatosensory cortex during non-noxious and noxious electrical stimulation by optical imaging.
Luo, W., Li, P.-C., Chen, S., Zeng, S.-Q., & Luo, Q. (2007) · Brain Research · doi:10.1016/j.brainres.2006.09.111 · Cited by 12
When Similar Is Not Alike
Petrenko, A. B., Ishii, H. H., Kohno, T., & Baba, H. (2012) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e318263ca5c · Cited by 12
“Third, the rat tail is a richly vascularized thermoregulatory organ and vasodilators can increase tail skin temperature.(2)”
Experimental behaviour testing: pain
Savage, S., & Ma, D. (2014) · British Journal of Anaesthesia · doi:10.1093/bja/aeu346 · Cited by 12
“(acute), up to a few months (chronic) depending on the stimulus used.(5) Formalin injection”
Background
Infusion of aerial parts of Salvia chudaei Batt. & Trab. from Algeria: Chemical, toxicological and bioactivities characterization
Semaoui, R., Ouafi, S., Machado, S., Barros, L., Ferreira, I. C. F. R., & Oliveira, M. B. P. P. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114455 · Cited by 11
Intravenous chloral hydrate anesthesia provides appropriate analgesia for surgical interventions in male Sprague-Dawley rats
Ward-Flanagan, R., & Dickson, C. T. (2023) · PLoS ONE · doi:10.1371/journal.pone.0286504 · Cited by 11
“While the assessment of nociception using reflexive responses can be a difficult task due to the many inter-related physiological factors that can influence behavioural outcomes [14], we endeavoured to mitigate these confounds by using a within-subjects design to compare the naïve unanesthetized baseline to the anesth…”
BackgroundMethodInfluential

Authors: Le Bars, D., Gozariu, M., & Cadden, S. W.
Venue: Pharmacological Reviews
Publisher: Elsevier BV
Published: 2001-12
Volume: 53
Issue: 4
Pages: 597-652
ISSN: 0031-6997 (ISSN-L)
DOI: 10.1016/s0031-6997(24)01514-x
OpenAlex: W4406058850
Cited by: 1,459
References: 621
Citations by year: 2026: 39 · 2025: 31 · 2024: 22 · 2023: 34 · 2022: 42 · 2021: 52 · 2020: 42 · 2019: 38 · 2018: 64 · 2017: 98 · 2016: 107 · 2015: 121 · 2014: 117 · 2013: 86 · 2012: 87
FWCI: 4.39
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Pharmacological Reviews (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Health Sciences › Veterinary › Small Animals › Veterinary Pharmacology and Anesthesia
Keywords: animal models of pain, nociception, animal pain assessment, nociceptive stimuli, thermal pain, mechanical pain, chemical pain, electrical pain, nociceptive threshold, spinal reflexes, inflammation, homeostatic mechanisms
MeSH terms: Analgesics, Animals, Disease Models, Animal, Humans, Nerve Fibers, Pain, Pain Measurement

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