Its characterized primarily by motor impairment, but there are also a range of accompanying conditions such as seizure disorders and cognitive defects. (D) Gait analysis (Catwalk XT, Noldus). Eur. doi: 10.1016/j.jneumeth.2004.07.005, Hargreaves, K., Dubner, R., Brown, F., Flores, C., and Joris, J. Similarly, as it cannot be said that the animal feels pain, analgesia and analgesic intervention cannot take placeonly anti-nociception and anti-nociceptive interventions can. (A) Grimace scales. 120, 37603772. doi: 10.1016/0304-3959(88)90026-7, Harvey, V. L., and Dickenson, A. H. (2009). doi: 10.1016/0304-3940(88)90497-1. Oxaliplatin administration increases expression of the voltage-dependent calcium channel 2-1 subunit in the rat spinal cord. In fact, over 90% of test subjects are mice, birds and rats. It should be noted that the absolute values obtained using manual and electronic Von Frey can differ significantly. In cases of sensory loss, hypoalgesia may be present, which is defined as decreased sensitivity to a nociceptive stimulus. Williams, W. O., Riskin, D. K., and Mott, A. K. (2008). Efficacy of drugs with different mechanisms of action in relieving spontaneous pain at rest and during movement in a rat model of osteoarthritis. All we can possibly learn from high-dose experiments is what might happen in overdose situations. TRPM8 mechanism of cold allodynia after chronic nerve injury. The latency to paw withdrawal is recorded and used to quantify cold allodynia and hyperalgesia. doi: 10.1016/j.ejphar.2014.05.048, Jacobs, B. Y., Kloefkorn, H. E., and Allen, K. D. (2014). The second view, by Singer, considers animals as sentient creat Mice count morally because they can be harmed. In addition, a programmable hold step with constant force application can also be incorporated in the experimental setup to determine the time to withdrawal (Lu and Schmidtko, 2013). The behavioral methods used to measure nociception in rodents can be divided into stimulus-evoked (and further subdivided by the stimulus modalitymechanical, heat, cold) and non-stimulus evoked, with the most commonly used methods discussed in this review article. Lett. Protoc. Using the horse grimace scale (HGS) to assess pain associated with acute laminitis in horses (Equus caballus). Skinner's Box Experiment | Behaviorism | Practical Psychology Monofilaments of differing forces are applied perpendicularly to the hind paw. Eng. Methods used to assess mechanically evoked pain like behaviors in rodents. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. The acetone evaporation test, first described in 1994, is a technique used to measure aversive behaviors triggered by evaporative cooling and is typically considered as a measure of cold allodynia (Carlton et al., 1994; Choi et al., 1994; Vissers and Meert, 2005). In addition, care should be taken to design experiments that minimize distress and suffering. In its simplest form, the animal can choose between two adjacent areas maintained at different temperatures. February 8, 2018| Kristen Coughlin | CRISPR, Rat Models, Last Updated on January 23, 2023 by ingenious. Disord. Eur. An additional disadvantage of incapacitance or static weight bearing tests is that only models with unilateral hind paw nociception can be assessed in this manner. A Guide to Research Rodent Housing William J. Some of these parameters are altered in rodent models of pain, making gait analysis a method that is increasingly used to quantify non-stimulus evoked or spontaneous nociception in rodents. 150, 165171. 9, 807819. Analg. First, the response to a specific temperature (typically 5C to 15C) can be recorded (Allchorne et al., 2005). Is it Right or Not to Use Rats for Experiments? Curr. doi: 10.1016/j.pain.2013.06.015, Keywords: pain, rodent, hyperalgesia, allodynia, spontaneous pain, mechanical, heat, cold, Citation: Deuis JR, Dvorakova LS and Vetter I (2017) Methods Used to Evaluate Pain Behaviors in Rodents. A caveat is, however, that no pain-specific behaviors are captured, leading to potential interference from drug or phenotype effects that could mask nociception, or anti-nociception. However, the force required to trigger probe heating is low (~1 g), adjustable, and the surface of the heating probe is rather large compared to the punctate von Frey filaments. It should be noted that no test can therefore measure pain in animals directlythe presumably unpleasant emotional experience of pain is inferred from pain-like behaviors which can include the withdrawal of a body part from a stimulus, reduced ambulation, agitation, an increase in grooming of the affected area, and vocalizations upon sensory stimulation. In fact, it is a requirement for publication of in vivo data in high quality journals that relevant standards and guidelines are strictly adhered to (McGrath et al., 2010). Most studies focus on either testing how a specific genetic pathway responds to the brain injury, or how administering a drug affects the severity of damage after injury. Then there is the Sprague Dawley, an outbred albino preferred for behavioral studies. 119, 481488. doi: 10.1111/ejn.12643, Tetreault, P., Dansereau, M. A., Dor-Savard, L., Beaudet, N., and Sarret, P. (2011). 51, 4249. These neurons are pseudo-unipolar, with a peripheral branch that terminates in the skin or viscera and a central branch that terminates in the spinal cord. doi: 10.1016/j.jneumeth.2015.08.010, Brenner, D. S., Golden, J. P., and Gereau, R. W. IV (2012). Adult mice multiply quickly. Ther. Exp. Third, aversive response to a cooling ramp can be used to determine the cold response threshold (Yalcin et al., 2009). (2009). They have distinctive personality, which is a manifestation of their friendliness to people. Mechanical pressure is applied focally to the dorsal or plantar surface of the hind paw or tail, which is placed between a pointed probe tip and a flat surface. (2014). In addition, rodents are intelligent and can learn that premature withdrawal will result in less human interaction and stimulation. doi: 10.1007/bf00230429, Petrus, M., Peier, A. M., Bandell, M., Hwang, S. W., Huynh, T., Olney, N., et al. Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine. However, as the testing surface can influence the results of von Frey, it is possible that values obtained using MouseMet or RatMet are not directly comparable to other methods (Pitcher et al., 1999). Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence. 25, 99111. In human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. J. Neurosci. A modified version of the thermal probe test suitable for quantifying heat thresholds in rats is still to be developed. Ann Neurol 9(2): 131-41. Ishikawa, G., Nagakura, Y., Takeshita, N., and Shimizu, Y. doi: 10.1016/j.jpain.2009.01.325, Yamamoto, K., Tsuboi, M., Kambe, T., Abe, K., Nakatani, Y., Kawakami, K., et al. J. Neurosci. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Despite the development of electronic Von Frey tests, manual Von Frey remains the gold standard for determining mechanical thresholds in mice. doi: 10.1016/s0885-3924(05)80022-3, Giglio, C. A., Defino, H. L., da-Silva, C. A., de-Souza, A. S., and Del Bel, E. A. The sequence of outcomes ( for no response or + for response) is recorded and later used to calculate the 50% withdrawal threshold. Influence of skin temperature on heat pain threshold in humans. (2014). Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Although animal models of pain have undoubtedly provided key advances, the advantages and disadvantages of each model and behavioral test should be taken into account to obtain objective and meaningful results that will improve our understanding and management of pain. 738, 111117. Stimulus-evoked pain is described as either hyperalgesia or allodynia, and is further subdivided on the basis of the evoked stimulus modality (e.g., mechanical, heat, cold, chemical; Woolf and Mannion, 1999). Using animals in experiments | The Humane Society of the United States A number of parameters are automatically analyzed by the software, including paw intensity, print area, stance phase duration (time spent on paw) and swing phase duration (time spent off paw). doi: 10.3791/52640, Brodkin, J., Frank, D., Grippo, R., Hausfater, M., Gulinello, M., Achterholt, N., et al. Similarly, measures to improve data quality, including appropriate randomization and blinding procedures, are key to ensure validity of the obtained results. (A) Two-temperature choice assay. Many of these original stocks harbored a variety of natural, or indigenous, pathogens. Accordingly, the development of thermal allodynia was demonstrated to be independent to the development of mechanical allodynia in unilateral models of carrageen-induced inflammation and burn injury (Deuis and Vetter, 2016). Mol. Copyright 2017 Deuis, Dvorakova and Vetter. Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice. doi: 10.1016/j.jpain.2013.06.008, Griffioen, M. A., Dernetz, V. H., Yang, G. S., Griffith, K. A., Dorsey, S. G., and Renn, C. L. (2015). Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. In contrast to other Von Frey setups, animals are housed in individual enclosures with bars, rather than mesh, to help maximize the surface area of the hind paw available for application of the filament. It should be noted that rather than flinching or licking, some rat strains tend to simply avoid weight bearing on the affected paw or reposition their stance to minimize contact with the cool surface, so all observation should be adapted to the specific model animal. While species such as saccharomyces cerevisiae, fruit flies, and zebrafish have been used for the study of cancer, organ development, recombination or large scale mutations, the rat model offers insights into human disease that the study of other species will not allow. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. Protoc. The pressure is increased until withdrawal or vocalization occurs. doi: 10.1016/j.bbr.2008.12.018, Gamble, G. D., and Milne, R. J. 14 Articles, This article is part of the Research Topic, Creative Commons Attribution License (CC BY). Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. His experiments, conducted in what is known as "Skinner's box," are some of the most well-known experiments in psychology. As the animal is unaware of the researcher and neither needs to be restrained or trained, this technique eliminates operator subjectivity and reduces animal stress. Brain Res. (1989). Other advantages of this methodology include eliminating the phenomenon of clustered selection and a low . The burrowing assay has been validated for models of post-surgical pain in mice and in models of peripheral nerve injury, osteoarthritis and inflammation induced by CFA in rats (Jirkof et al., 2010; Andrews et al., 2012; Bryden et al., 2015). doi: 10.1590/s0100-879x2006001200013, Gregory, N. S., Harris, A. L., Robinson, C. R., Dougherty, P. M., Fuchs, P. N., and Sluka, K. A. The biggest challenge of temperature preference tests is choosing the optimal temperature pairs, so that preference for one side is either exaggerated or overcome in experimental animals compared with control animals. doi: 10.1038/nrn2606, Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., et al. Analgesic treatment of ciguatoxin-induced cold allodynia. Arthritis Rheum. Nociceptive signals are then sent to the spinal cord and brain for processing as the sensation of pain. Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. Ther. (C) Randall-Selitto test (handheld device). Sci. Pain Symptom Manage. Weight bearing evaluation in inflammatory, neuropathic and cancer chronic pain in freely moving rats. 101, 457464. Spinal processing of noxious and innocuous cold information: differential modulation by the periaqueductal gray. However, with the use of animal models come challenges relating to the appropriate quantification of behavioral responses that could be considered equivalent to pain in humans. A touch-on reaction is more likely to occur if the filament is not applied perpendicularly, if the filament is not applied smoothly, or if the filament moves horizontally during application, inducing scratching. Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice. - Ther. Hyperalgesia and allodynia: peripheral mechanisms. 5, 94100. J. Gerontol. Originally the method was used on rat pups seven days after birth, when their brains are most similar to those of newborn babies. FACTS and MYTHS - Animal Research at Stanford Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Development of the Rodent Face Finder, which captures stills of rodent faces that a researcher then scores according to the relevant scale, has automated some of the experimental process (Sotocinal et al., 2011) albeit development of automatic facial expression scoring will make this approach even more widely useful. Better rat models are likely to decrease drug failure in clinical trials currently standing at about 90% which will decrease development costs and time to market. This suggests that the tail flick response may be impacted by changes in motor processing (Chapman et al., 1985). J. Neurosci. (1957). Differentiating analgesic and non-analgesic drug activities on rat hot plate: effect of behavioral endpoint. In recent years mice have been used with increasing frequency, to take advantage of genetically modified lines as well as the relatively lower costs compared with rats. Animal Testing | Pros & Cons | ProCon.org Animal Model Limitations | National Anti-Vivisection Society Behav. doi: 10.1016/j.jneumeth.2013.06.005, Baron, R., Binder, A., and Wasner, G. (2010). A novel behavioral assay for measuring cold sensation in mice. A major advantage of the thermal probe test is the reduced time required for acclimatization to the testing environment, enabling characterization of models or compounds with short duration of action, as well as testing of mechanical and thermal thresholds in the same enclosure. Lett. Pain Med. The three Rs are: Reduction, Refinement, Replacement.. Rice JE 3rd, Vannucci RC, Brierley JB. Front Neurol 7: 57. J. Their brains are larger than mice, and the animals are less timid and more intelligent. Almost all disease-linked human genes have counterparts in the rat. doi: 10.1016/0160-5402(91)90014-v, Touska, F., Winter, Z., Mueller, A., Vlachova, V., Larsen, J., and Zimmermann, K. (2016). For example, in a rat model of carrageenan-induced inflammation, significantly altered plate preference was only observed for temperatures of 15C and 45C relative to the test plate maintained at 25C (Balayssac et al., 2014). Heat thresholds in humans can be determined by applying a metal probe to the skin that increases in temperature (starting at 32C) until a warm-sensation threshold and heat-pain threshold is reached. Neurosci. Efficient analysis of experimental observations. (2010). Methods 53, 5563. Thus, the focus is often on reduction of the number of animals necessary to obtain data, and refinement of the method with the aim to decrease the amount of nociception caused to the animal. Testing should also be avoided while the animal is engaged in grooming behaviors, as this can produce false negative responses. Assoc. Circadian pattern of spontaneous behavior in monarthritic rats: a novel global approach to evaluation of chronic pain and treatment effectiveness. Toxicol. Neurosci. J. Pharmacol. International standards and guidelines, as well as country-specific codes and legislation, have been developed to protect the welfare of animals used for research. A single, un-bending filament is applied perpendicularly to the hind paw. 524, 107110. As for the static hot plate test, cut off times should be carefully designed and strictly adhered to in order to avoid unnecessary nociceptive stimulation and tissue damage. Electronic Von Frey systems operate under similar principles as manual von Frey, except that a single, un-bending filament is applied with increasing force until a paw withdrawal response is elicited. Mouse model: Pros & Cons - SlideShare Address: 2200 Smithtown Avenue Pain studies in humans are difficult to perform, are subjective, and are limited by ethical considerations, leading to the widespread use of animals as models to study pain, with the most commonly used species being mice and rats (Mogil, 2009). LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. (E) Behavioral Spectrometer (Behavioral Instruments). It is a low-cost, single-use product made from sterilized quarry sand and treated with a hydrophobic coating. Particular mention should also go to timely publication of data, be it positive or negative results, in order to reduce experimental duplication and unnecessary use of animals. Mice are placed individually in small cages with a barred floor. Picking up rats by the tail is stressful and should be avoided . Pain 14, 628637. Spontaneous pain can be quantified in humans by asking them to describe their pain using a numeric pain scale (010), visual analog scale (transected line) or verbal scale (no pain to worst pain; Gaston-Johansson et al., 1990; Wibbenmeyer et al., 2011). The manual Von Frey tests enable quantification of mechanical thresholds in unrestrained animals, which removes the risk of handling-induced stress. doi: 10.1523/JNEUROSCI.1526-05.2005, Schtt, E., Berge, O. G., Angeby-Mller, K., Hammarstrm, G., Dalsgaard, C. J., and Brodin, E. (1994). Exp. If the response rate is less than 40% (i.e., a withdrawal response is elicited in none or one out of five applications) the next filament is tested. (2011). An additional disadvantage of the hot plate test is that all four paws and the tail are exposed to the heat stimulus. 10 Major Disadvantages of Technology [2022 Technology Disadvantages The mouse with a human ear on its back may have been one of the more bizarre and visually unsettling experiments carried out on a rodent, but mice have been used for scientific experiments since. doi: 10.1016/0304-3959(94)90090-6, Carter, R. B. Similar to the Hargreaves test, the thermal probe tests enables quantification of ipsilateral and contralateral heat thresholds in unrestrained mice, but with a shorter habituation time of 510 min. To obtain reliable data, animals need to be habituated to the restraint method and experimental apparatus, which can become very time-intensive. Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. Attenuated cold sensitivity in TRPM8 null mice. doi: 10.1016/s0304-3959(00)00276-1, Defrin, R., Ohry, A., Blumen, N., and Urca, G. (2002). Neuro Oncol. A phobia is an irrational fear, that is out of proportion to the danger. doi: 10.1152/physrev.00025.2008, Santos-Nogueira, E., Redondo Castro, E., Mancuso, R., and Navarro, X. The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. Irwin, S., Houde, R. W., Bennett, D. R., Hendershot, L. C., and Seevers, M. H. (1951). PDF A Guide to Research Rodent Housing - Charles River Laboratories J. Neurosci. The time spent on the test plate relative to the reference plate is measured over a set period of time. 64, 8187. Pain measurement: an overview. Meloxicam prevents COX-2-mediated post-surgical inflammation but not pain following laparotomy in mice. Age-related neurodegenerative diseases are largely limited to humans and rarely occur spontaneously in animals. Z., Rodriguez, K. B., Gallo, M. S., Pritchett-Corning, K., Karas, R. H., et al. Pain 88, 5360. Similarly, the terms nociception and pain are often used interchangeably, although the term pain is rarely appropriate to use in reference to animal studies. Pain 47, 211220. Mouse Model: Pros and Cons Ankita Das Chetana Tamadaddi Prashant Waiker Indian Institute of Science Education & Research Bhopal ; MOUSE : Mammalian model organism ; Genome Mammalian 20 chromosomes 2.6 Gb ~25000 genes 99% have human counterpart Strains Inbred Outbred Recombinant inbred Consomic Fluorescent Life Cycle 4-day oestrus 20-day gestation 4-8 pups per litter 2 . Rodents are allowed to freely move along a liner or circular surface with a temperature gradient. The Rat Grimace Scale is also scored 02 depending on observed changes in facial features, and evaluates the extent of orbital tightening, nose/cheek flattening, ear change and whisker change (Sotocinal et al., 2011). doi: 10.1371/journal.pone.0039765, Brenner, D. S., Golden, J. P., Vogt, S. K., and Gereau, R. W. (2015). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Rat ES cells are very unstable, with any disturbance leading them to activate, so that they could not be implanted in an embryo and brought to term. Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. Am. J. Neurosci. If no nocifensive behaviors are observed, the animal must be removed from the hot plate after pre-determined cut-off time to prevent tissue damage. A method for measurement of analgesic activity on inflamed tissue. Stimulus-evoked methods, which include manual and electronic von Frey, Randall-Selitto and the Hargreaves test, were the first to be developed and continue to be in widespread use. Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation. These people will not be included in the survey, and the survey's accuracy will suffer from non-response. 7 Unconscious Biases That Still Affect Black Women Today - Bustle It is estimated that more than 50 million animals are used in experiments each year in the United States. While rats tend the habituate quickly (<15 min), mice can take up to an hour or more to settle in the cage before testing can begin, which can be time consuming (Chaplan et al., 1994; Minett et al., 2011). Pain 12:1744806916629049. doi: 10.1177/1744806916629049, Guilford, B. L., Ryals, J. M., and Wright, D. E. (2011). (C) Hargreaves test. Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior. The first (1880-1950) was when mice and rats became common research animals. 16 Integral Pros and Cons of Animal Experimentation It is the premier source of information on the laboratory rat. Unfortunately, no accurate figures are available to determine precisely how many animals are used in experiments in the U.S. or worldwide. Some of the disadvantages of choosing a different animal model for these fields could be difficulty in collecting accurate data, comparing data from previous studies that used rat models, and drawing definitive conclusions that could apply to future studies. Rev. This continues until at least four readings are obtained after the first change of direction. Similarly, human scoring lends itself to bias, although this can be avoided with appropriate randomization, allocation concealment and blind outcome assessment (Hirst et al., 2014). 86, 284288. In addition to displaying force at which paw withdrawal occurs, the rate at which the force was applied is also displayed post-test by the software, to ensure the force ramp was applied consistently. Accordingly, dynamic weight bearing or gait analysis may provide similar data without the need for extensive animal and experimenter training. The same is likely to be true of other rodent species, many of . Readership. 39, 16131623. Consistent and precise placement of the filament is important to reduce intra-subject and inter-subject variability, with the specific placement dependent on the innervation territories of the test area and the model used.

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