Gait analysis methods for rodent models of osteoarthritis. Ther. In terms of the diseases that they are used to study, rats are usually not the model of choice when it comes to disorders related to neoplasms, blood and immune function. doi: 10.1093/brain/awf055, Defrin, R., Shachal-Shiffer, M., Hadgadg, M., and Peretz, C. (2006). Although expensive to produce and not always precise, this became the preferred method to target rats in a specific manner. engagement in scientific research and . These values are not absolute, as heat thresholds are influenced by the ambient temperature, rate of heating (110C/s), the type (hairy or glabrous) and location of test skin, method of heat transfer, experimental design and skin temperature (for radiant heat only; Pertovaara et al., 1996; Defrin et al., 2006; Rolke et al., 2006). Pain 56, 155166. Pain 3:40. doi: 10.1186/1744-8069-3-40, Pitcher, G. M., Ritchie, J., and Henry, J. L. (1999). The mouse has many similarities to humans in terms of anatomy, physiology and genetics. Curr. One area where rats have contributed to major insights is the field of cerebral palsy research. A modified version of the thermal probe test suitable for quantifying heat thresholds in rats is still to be developed. Pain 123, 231243. doi: 10.1007/978-1-62703-459-3_14. doi: 10.1016/j.burns.2016.09.001, Deuis, J. R., Lim, Y. L., Rodrigues de Sousa, S., Lewis, R. J., Alewood, P. F., Cabot, P. J., et al. The historic struggle against pathogens of laboratory rodents is often divided into three periods. The severity of these expressions varies with the severity of perceived pain, and is graded on a scale with 0 being normal, 1 being moderately, and 2 being severely changed features. It's a little like tossing a rat into a vat of gasoline and then concluding that gasoline causes drowning. The Facts For decades, scientists have routinely used rats as a main model for brain research. 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. Its characterized primarily by motor impairment, but there are also a range of accompanying conditions such as seizure disorders and cognitive defects. PLoS One 7:e39765. 20, 441462. 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. 6, 17511758. Finally, whisker change refers to change in whisker position (may be backward, forward, or clumped together). Mice are placed individually in small cages with a barred floor. Rat models are therefore still widely used. 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. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Temperature 3, 199207. Life Sci. Second, the number of flinches over a set period of time can be recorded at a specific temperature (Deuis et al., 2013; Zimmermann et al., 2013). Exp. Pain 68, 133140. The Little Albert Experiment demonstrated that classical conditioning could be used to create a phobia. doi: 10.1080/23328940.2016.1157668, Deuis, J. R., Whately, E., Brust, A., Inserra, M. C., Asvadi, N. H., Lewis, R. J., et al. The temperature preference is used as a surrogate measure of thermal aversion and aims to assess temperature preference in rodents. In the case of researchers conducting surveys, for example, sample size is essential. 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. The same is likely to be true of other rodent species, many of . Neurosci. Quantitative sensory testing in the german research network on neuropathic pain (DFNS): standardized protocol and reference values. doi: 10.1038/nmeth.1455, Leith, J. L., Koutsikou, S., Lumb, B. M., and Apps, R. (2010). Alternatively, the number of flinches over a set period of time can be recorded at a specific temperature (Yalcin et al., 2009; Deuis et al., 2013; Zimmermann et al., 2013), although care must be taken that the chosen temperature and duration do not induce tissue damage or nocifensive behavior in nave animals. This review article provides an overview, as well as discussion of the advantages and disadvantages of the most commonly used behavioral methods of stimulus-evoked and non-stimulus-evoked nociception used in rodents. Nose bulge refers to the bulge noticeable on the bridge of the nose, whereas cheek bulge refers to the rounded projection of the cheek muscle compared to its typical appearance. Rodents are placed individually in small enclosures with a glass floor. Pain Med. Typically, the experimental setup consists of a test plate at a fixed temperature (usually between 5C and 55C) that is placed adjacent to a reference plate at neutral temperature (usually between 25C and 30C; Figure 5A). doi: 10.1111/j.1476-5381.2010.00873.x, Medhurst, S. J., Walker, K., Bowes, M., Kidd, B. L., Glatt, M., Muller, M., et al. Pain 68, 141150. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. J. Neurosci. Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation. Typically, the sensation of warm is elicited at temperatures of 3437C, while the sensation of pain is elicited at temperatures of 4248C (Pertovaara et al., 1996; Defrin et al., 2006; Rolke et al., 2006). Comparison of the antinociceptive action of and opioid receptor ligands in the periaqueductal gray matter, medial and paramedial ventral medulla in the rat as studied by the microinjection technique. The LabSand Option. The principles that apply to mice generally apply to rats and other laboratory rodents, but species-specific differences in behaviour and size alter the specifics of handling procedures that work well in each species. Exposure of the hind paw to acetone does not evoke paw withdrawal in lightly anesthetized animals (unlike the tail flick assay), while ethyl chloride application achieves skin temperatures approaching 5C or less, and is generally considered a noxious cold stimulus (Leith et al., 2010). However, it is proving useful as a tool to monitor animal welfare, not only in rodents, but also in other species, with grimace scales being developed for pigs, sheep and horses (Matsumiya et al., 2012; Miller and Leach, 2015; Dalla Costa et al., 2016; Hager et al., 2017; Viscardi et al., 2017). Differentiating thermal allodynia and hyperalgesia using dynamic hot and cold plate in rodents. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. (C) Hargreaves test. Facial expression is subjectively scored for severity of pain based on five facial features (ear position, eye closing, cheek bulging, whisker position, and nose bulging). 72, 7479. When rodents are unwell, the amount of material removed from the burrow is decreased. Rodent models of cerebral palsy have been studied for almost forty years to fill the gaps in our knowledge, hopefully pointing the way to future treatments. Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice. They have distinctive personality, which is a manifestation of their friendliness to people. A disadvantage of this method is that the number of measurements per animal is variable and that it requires repeated, time-intensive measurements, which may lead to sensitization or learnt responses. Oxaliplatin administration increases expression of the voltage-dependent calcium channel 2-1 subunit in the rat spinal cord. Cartil. It is now possible to more easily manipulate the rat genome to produce specific gene knockouts and knockins and apply results to our understanding of human genetic disorders. 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). While validated using an incisional model of pain in rats, this method takes longer to perform than the normal Hargreaves test and is not available to purchase commercially. doi: 10.1016/s0304-3959(00)00276-1, Defrin, R., Ohry, A., Blumen, N., and Urca, G. (2002). Gait analysis in freely walking rodents is used to study changes in limb movement and positioning in models with sensori-motor dysfunction, including Parkinsons disease, spinal cord injury and stroke. Rodents are placed individually in small cages with a mesh or barred floor. (2014). The main advantage of electronic Von Frey compared to manual Von Frey is that an increasing force is applied by a single filament. Pain Symptom Manage. (2005). 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. 16, 13241332. Exp. 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. However, concerns over the clinical translatability of stimulus-evoked nociception in recent years has led to the development and increasing implementation of non-stimulus evoked methods, such as grimace scales, burrowing, weight bearing and gait analysis. The U.S. Department of Agriculture (USDA) does compile annual statistics on some animals used in . While weight bearing is typically considered to be a measure of non-stimulus evoked nociception, it can be argued that ambulation itself applies a nociceptive mechanical stimulus to the affected limb(s), and it may therefore be a measure of stimulus-evoked nociceptive behavior, especially in the dynamic weight bearing test or gait analysis tests. Methods 53, 5563. Methods 25, 241250. However, in practice it is difficult to distinguish between allodynia and hyperalgesia in animals, and the terms allodynia and hyperalgesia are often used incorrectly or interchangeably in the literature. (2011). These techniques provide an insight into how sensitive to cold temperatures the animal is, and thus provides an indirect measure of cold-induced hyperalgesia and allodynia. A cold stimulus is delivered by applying a cut off syringe filled with dry ice (for temperature ranges of 512C) or wet ice (temperature of 17C) to the glass underneath the paw (Brenner et al., 2012, 2015; Figure 4B). This suggests that the tail flick response may be impacted by changes in motor processing (Chapman et al., 1985). Behavioral and physiological methods for early quantitative assessment of spinal cord injury and prognosis in rats. Anesth. (2009). The heat stimulus applied can be radiant heat, where a focused beam of light is applied to the tail, or hot water, where the distal end of the tail is immersed into a water bath set at a constant temperature between 46C and 52C, with the latter requiring no specialized equipment. The most common case of bias is a result of non-response. Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. 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. Matsumiya, L. C., Sorge, R. E., Sotocinal, S. G., Tabaka, J. M., Wieskopf, J. S., Zaloum, A., et al. 51, 4249. 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). Veterinarians are required to inspect the living conditions of the animals. Non-response occurs when some subjects do not have the opportunity to participate in the survey. A disadvantage of this method is that the number of measurements per animal is variable and that it requires repeated, time-intensive measurements, which may lead to sensitization or learnt responses. 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. Eng. Differentiating analgesic and non-analgesic drug activities on rat hot plate: effect of behavioral endpoint. Genetically engineered mouse models recapitulate aspects of the corresponding human diseases and are instrumental in studying disease mechanisms and testing therapeutic strategies. 39, 16131623. 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. 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. Pain cannot be directly measured in animals; instead pain is inferred from pain-like behaviors, such as withdrawal from a nociceptive stimulus, which is the most commonly used method to quantify nociception in animal studies. Figure 5.Temperature preference assays. 25, 73177323. Clin. However mice are less likely to survive the hypoxia-ischemia procedure, display a wider variety of brain damage, and have dramatic strain-to-strain differences. The device automatically records the force at which paw withdrawal occurs and the rate at which the force is applied can be changed. The Hargreaves test permits measurement of ipsilateral and contralateral heat thresholds, allowing each animal to serve as its own internal control in unilateral pain models. At least six responses around the estimated threshold are required for optimal calculation of the 50% threshold (Dixon, 1980). Osteoarthr. As each researcher cultivates a slightly different cut off point in their minds as to what constitutes a behavior on this spectrum, results can vary significantly between laboratories. (2005). Cartil. However, it is unclear to what degree changes in gait in rodent models reflect altered pain or nociception, or conversely, anti-nociception or analgesia. An overview of animal models of pain: disease models and outcome measures. Then there is the Sprague Dawley, an outbred albino preferred for behavioral studies. The sequenced genome will also unveil new targets for drug intervention. Adult mice multiply quickly. A rat model of bone cancer pain. Mol. (2006). Development of a piglet grimace scale to evaluate piglet pain using facial expressions following castration and tail docking: a pilot study. Interested in using rats for your next research project? Why use anyone else!, Murray Clarke, PhDUniversity of Cambridge. (2012). Curr. Rev. This test can be carried out using the same mouse enclosures as the electronic von Frey test (MouseMet) and is based on the application of a 2 mm thermal probe to the hind paw. Methods 219, 4151. Because of its simplicity, systematic sampling is popular with researchers. The sheep grimace scale as an indicator of post-operative distress and pain in laboratory sheep. 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. 52, 34703478. 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. doi: 10.1172/jci42843, Dubner, R. (1983). Life Sci. Animal models of pain: progress and challenges. LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. doi: 10.1371/journal.pone.0125822, Lu, R., and Schmidtko, A. Rep. 4:6370. doi: 10.1038/srep06370, Bove, S. E., Calcaterra, S. L., Brooker, R. M., Huber, C. M., Guzman, R. E., Juneau, P. L., et al. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. Am. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. doi: 10.1016/0304-3940(89)90397-2, Gaston-Johansson, F., Albert, M., Fagan, E., and Zimmerman, L. (1990). Woolf, C. J., and Mannion, R. J. Efficacy of drugs with different mechanisms of action in relieving spontaneous pain at rest and during movement in a rat model of osteoarthritis. Rodents are placed individually in small enclosures with a glass floor. Neurosci. To obtain reliable data, animals need to be habituated to the restraint method and experimental apparatus, which can become very time-intensive. (C) Randall-Selitto test (handheld device). J. The same methods that allow this to be so in mice have failed in rats. 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. J. Pharmacol. Evaluation of dynamic weight bearing for measuring nonevoked inflammatory hyperalgesia in mice. The Mouse Grimace Scale is highly accurate, but generally requires significant amounts of nociception in order to elicit a visible response, which limits its use. Therefore grimace scales have the potential to monitor and improve the welfare of animals used not only in research, but also in farming and industry. Irwin, S., Houde, R. W., Bennett, D. R., Hendershot, L. C., and Seevers, M. H. (1951). Characterization of the foot withdrawal response to noxious radiant heat in the rat. Appreciation that the human pain experience encompasses multiple stimulus modalities, distinct molecular mechanisms and sensory, motor, vegetative, emotional, motivational components should highlight the need for carefully designed experiments that take this complexity into consideration. Weight bearing evaluation in inflammatory, neuropathic and cancer chronic pain in freely moving rats. | Terms | Privacy Policy, Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review, The influence of immaturity on hypoxic-ischemic brain damage in the rat. As altered weight bearing can be a major symptom of human pain conditions, these tests were developed to improve translation of rodent nociception models to the clinic. While the method carries the disadvantage that the rodent has to be restrained, the tail flick test is of very short duration so handling can be minimized easily. Brain Res. Sensitivity to cold is recorded either by quantifying the number or duration of nocifensive responses, or scoring of the severity of the response (e.g., 0, no response; 1, brisk withdrawal or flick of the paw; 2, repeated flicking of the paw; 3, repeated flicking of the hind paw and licking of the paw; Colburn et al., 2007; Xing et al., 2007). 64, 8187. doi: 10.1016/0014-2999(74)90195-2, Anseloni, V. C., Ennis, M., and Lidow, M. S. (2003). (2015). Randall, L. O., and Selitto, J. J. LinkedIn. doi: 10.3791/52640, Brodkin, J., Frank, D., Grippo, R., Hausfater, M., Gulinello, M., Achterholt, N., et al. doi: 10.1016/j.jneumeth.2013.06.005, Baron, R., Binder, A., and Wasner, G. (2010). Sci. Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate. Pain 10, 767773. The presence and extent of aversive behaviors in responses to mechanical stimuli is typically determined using manual or electronic Von Frey or the Randall Selitto test, as described below (Figures 1AC). Similarly, it overcomes some of the experimental difficulties of static weight bearing analysis, albeit no information on gait can be obtained. Third, aversive response to a cooling ramp can be used to determine the cold response threshold (Yalcin et al., 2009). This review article will provide an overview of the current behavioral methods that are used to assess pain behaviors in mice and rats. doi: 10.1177/0023677214559084, Minett, M. S., Eijkelkamp, N., and Wood, J. N. (2014). J. Pharmacol. J. Neurosci. PLoS One 9:e104458. doi: 10.1523/JNEUROSCI.1526-05.2005, Schtt, E., Berge, O. G., Angeby-Mller, K., Hammarstrm, G., Dalsgaard, C. J., and Brodin, E. (1994). 160, 15731576. Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: 23, 16051612. Am. 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. doi: 10.1371/journal.pone.0104458, Minett, M. S., Quick, K., and Wood, J. N. (2011). Eur. Physiol. Boehmerle, W., Huehnchen, P., Peruzzaro, S., Balkaya, M., and Endres, M. (2014). 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. (2016). Two centuries ago, the brown rat Rattus norvegicus was used by scientists to understand human physiology and medicine, concentrating on the effects of food and oxygen deprivation. Deacon, R. M. (2006a). The rat had historically been the preferred animal model for biomedical research due to genetic and physiological similarities to humans. FIGURE 2 Figure 2 .Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. (A) Tail flick test (radiant heat).
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