Ishikawa, G., Nagakura, Y., Takeshita, N., and Shimizu, Y. 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). Eur. Anim. Mouse model: Pros & Cons - SlideShare 96, 312317. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. It is the premier source of information on the laboratory rat. Increasing temperatures are applied for 10 s from 35C to 70C in intervals of 2.5C until a paw withdrawal behavior is observed (Banik and Kabadi, 2013). doi: 10.1016/s0304-3959(00)00276-1, Defrin, R., Ohry, A., Blumen, N., and Urca, G. (2002). (2013). Rodents are placed individually in small enclosures with a glass floor. "Its brain is larger than that of a mouse, so it's easier to study the structures," said Joyce. 39, 18811890. Nature 444, 894898. doi: 10.1097/NNR.0000000000000082, Gritsch, S., Bali, K. K., Kuner, R., and Vardeh, D. (2016). Toxicol. A disadvantage of the Hargreaves test is that the paw withdrawal time is recorded rather than directly measuring the paw withdrawal temperature. In addition, rodents are intelligent and can learn that premature withdrawal will result in less human interaction and stimulation. Nevertheless, the acetone evaporation test has been validated in multiple models of inflammatory and neuropathic pain in both mice and rats (Choi et al., 1994; Colburn et al., 2007; Yamamoto et al., 2016). (2015). Anim. So far, no single behavioral assay can capture the full spectrum of nociception in non-communicating subjects. 429, 111. Rodents are allowed to freely move along a liner or circular surface with a temperature gradient. 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. Exceptionally adaptable, these rodents now inhabit almost all environments on Earth, especially near human settlements where they are often seen as pests. 25, 99111. 5, 94100. Toxicol. doi: 10.1038/nrn2606, Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., et al. For instance, improving data homogeneity and enhancing statistical power (Dell et al., 2002) will result in fewer animals being necessary to achieve the required confidence level (Festing and Altman, 2002). The rats ability to learn, remember, and interact gives them an advantage over other species, allowing for insights into the basic principles behind learning and behavior which can then be translated to human behavior and learning. (2010). Deacon, R. M. (2006a). Multimodal distribution of human cold pain thresholds. Brain Res. 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. Protoc. doi: 10.1016/j.jneumeth.2013.06.005, Baron, R., Binder, A., and Wasner, G. (2010). Analgesic treatment of ciguatoxin-induced cold allodynia. The Kantian view denies moral value to animals because they lack reason. Nonetheless, consistent measurements are possible in acclimatized animals, although guarding or altered weight distribution may lead to errors. Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. 80, 300307. Voluntary response bias is another disadvantage that comes with a small sample size. New hot plate tests to quantify antinociceptive and narcotic antagonist activities. The hypoxia-ischemia model, first published in 1981, has brain damage similar to that observed in cerebral palsy patients. Becoming overdependent and even addicted to our gadgets is another of the main disadvantages in technology. doi: 10.1371/journal.pone.0125822, Lu, R., and Schmidtko, A. Technology Addiction. Behaviors tend to occur on a spectrum of intensity, but are usually scored in binary as either present or absent. Neurosci. Nature 448, 204208. Finally, whisker change refers to change in whisker position (may be backward, forward, or clumped together). Cooling of the glass leads to unilateral exposure of the hind paws to a cooled surface, the temperature of which can be determined by attaching a thermocouple probe to the glass or skin. FACTS and MYTHS - Animal Research at Stanford The three Rs are: Reduction, Refinement, Replacement.. Arthritis Rheum. Sensory determinants of thermal pain. doi: 10.1016/j.neuron.2011.02.051, Wallace, V. C., Norbury, T. A., and Rice, A. S. (2005). While application of a contact heat stimulus achieves consistent and efficient thermal transfer, it also represents a mechanical stimulus that may lead to premature paw withdrawal in models with mechanical allodynia. Methods 113, 9197. Boehmerle, W., Huehnchen, P., Peruzzaro, S., Balkaya, M., and Endres, M. (2014). Rev. Pain 123, 231243. Anim. TRPM3 is a nociceptor channel involved in the detection of noxious heat. Lett. doi: 10.1523/JNEUROSCI.0122-10.2010, Ltsch, J., Dimova, V., Lieb, I., Zimmermann, M., Oertel, B. G., and Ultsch, A. A small metal probe is applied to the hind paw, and heating is triggered by rotation of the handheld device until the mouse withdraws the paw. doi: 10.1016/0024-3205(84)90575-7, Zimmermann, K., Deuis, J. R., Inserra, M. C., Collins, L. S., Namer, B., Cabot, P. J., et al. doi: 10.1097/fbp.0000000000000026, Banik, R. K., and Kabadi, R. A. Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine. Pain in rodents is associated with decreased burrowing behaviors. The Disadvantages of a Small Sample Size | Sciencing J. Neurosci. While the underlying protocols and principles are different, it remains to be determined if electronic Von Frey activates a different subset of sensory neurons compared to manual Von Frey (e.g., high-threshold vs. low threshold mechanoreceptors). Pain 56, 155166. Therefore, there is an urgent need to increase our understanding of the underlying mechanisms of pain and to develop new treatments. (2016). Pharmacodyn. 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. In line with this, the uptake of grimace scales to study pain in the scientific community has been low, with approximately 30 studies published using the method in rodents since its introduction by Langford et al. (2010). Dogs, cats, and nonhuman primates together account for less than 1% of all animals necessary for medical research. This review article will provide an overview of the current behavioral methods that are used to assess pain behaviors in mice and rats. 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. Cartil. doi: 10.1093/neuonc/nou048, Deuis, J. R., and Vetter, I. 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. Cold thresholds in humans can be determined in a similar manner to heat thresholds, where a metal probe is applied to skin that decreases in temperature (usually starting at 32C) until a cooling sensation or pain threshold is reached. DAmour, F. E., and Smith, D. L. (1941). These measures can have a profound effect on the apparent anti-nociceptive efficacy of test compounds and should thus be carefully considered during experimental design (Winter and Flataker, 1965). Animals 6:47. doi: 10.3390/ani6080047. It also demonstrates two additional concepts, originally outlined by Pavlov. Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: Twitter Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. 406, 128132. Because of its simplicity, systematic sampling is popular with researchers. Lab. 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. Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. Also, after advances in gene targeting and gene editing, it is possible to specifically modify the rat genome to produce knockouts and knockins, further enhancing our understanding of human disease through the development of powerful customized CRISPR rat models. This problem can be overcome by restraining the rodent and only placing the plantar surface of a one hind paw on the metal surface and recording the time to withdrawal, however this method requires significant handling and associated stress (Menndez et al., 2002). Pain 154, 17491757. Attenuated cold sensitivity in TRPM8 null mice. Methods 131, 9397. 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. In addition, as for manual Von Frey tests, animals still need to be habituated to the cages until exploratory behaviors have ceased. (2017b). Burn Care Res. 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. The rodent is placed in an inclined holder with the hind paws resting on two separate pressure sensors. The device automatically records the temperature that paw withdrawal occurred (in this case 50C). (2011). Role of the NLRP3 inflammasome in a model of acute burn-induced pain. 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. The intensity of the light source should be adjusted to produce withdrawal latencies of 1012 s in nave animals, providing a sufficient window to detect heat allodynia and hypoalgesia, with a pre-determined cut off time to prevent tissue damage. Ther. Almost all disease-linked human genes have counterparts in the rat. Exp. In 2001 however with the development of targeted genetic manipulation in mouse embryonic stem (ES) cells, rats took somewhat of a back seat as the rodent of choice for specific gene targeting because this technology was not yet available in the rat. Arch. Allowing rodents to have several trial runs prior to the actual experiment can increase burrowing behaviors and reduce variability (Deacon, 2006b). Using the horse grimace scale (HGS) to assess pain associated with acute laminitis in horses (Equus caballus). doi: 10.1016/j.jpain.2009.01.325, Yamamoto, K., Tsuboi, M., Kambe, T., Abe, K., Nakatani, Y., Kawakami, K., et al. What are some disadvantages of using Wistar rats in research and some disadvantages in using rats over mice in general? A novel behavioral assay for measuring cold sensation in mice. Static weight bearing or incapacitance assays measure the distribution of weight across the hind paws and typically involve placing the animal in an inclined holder forcing placement of the hind paws on two independent pressure sensors (Figure 6C). The Hargreaves test is usually carried out using a glass bottom enclosure, which can be heated to minimize errors arising from heat sink effects. Sci. Neurosci. Rotation of the handle of the hand-held device initiates heating from room temperature to 60C at a rate of 2.5C/s, which is terminated automatically by paw withdrawal, removal of the probe from the paw by the operator, or on reaching a predetermined cut-out (usually 60C; Figure 3D). An advantage of this method is that it avoids excessive application of Von Frey filaments that elicit aversive behaviors. Originally the method was used on rat pups seven days after birth, when their brains are most similar to those of newborn babies. PLoS One 10:e0125822. doi: 10.1093/ilar.43.4.207, Deuis, J. R., Dekan, Z., Wingerd, J. S., Smith, J. J., Munasinghe, N. R., Bhola, R. F., et al. Methods 25, 241250. Exp. 3. For people who choose to own rats at home, here are some of the benefits that they can receive: Rats are very intelligent animals. Accordingly, dynamic weight bearing or gait analysis may provide similar data without the need for extensive animal and experimenter training. Although the ability to target rat ES cells was then available, doing so was still difficult. The Practical Mouse Despite the advantages rats have over mice as human analogs, mice have dominated the modern genetic and biomedical research landscape. In anesthetized rats, steep temperature gradients and high skin temperatures are associated with activation of A fibers, while slower heating and lower temperatures lead to firing of C fibers (Yeomans and Proudfit, 1994, 1996; Yeomans et al., 1996). 43, 1726. Mol. Most of the animals needed for medical and scientific inquiry in the U.S. are rodents (for example, rats and mice), and they are specifically bred for this purpose. The software records the duration of different behavior types, including movement, grooming and rearing behaviors. Behavioral measures of pain thresholds. Their brains are larger than mice, and the animals are less timid and more intelligent. doi: 10.1523/JNEUROSCI.2203-07.2007, Yalcin, I., Charlet, A., Freund-Mercier, M. J., Barrot, M., and Poisbeau, P. (2009). 7. 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. Handling and restraint: General principles | NC3Rs Rats are often used to study behaviour in psychology experiments. (2011). Mechanical hyperalgesia and allodynia can be further subdivided into dynamic (triggered by brushing), punctate (triggered by touch) and static (triggered by pressure). An additional disadvantage of the hot plate test is that all four paws and the tail are exposed to the heat stimulus. Rock, M. L., Karas, A. The withdrawal response is detected visually by the researcher, resulting in subjective measurement of the threshold. Lett. doi: 10.1371/journal.pone.0175839, Han, J. S., Bird, G. C., Li, W., Jones, J., and Neugebauer, V. (2005). A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Efficient analysis of experimental observations. 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).

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