The influence of immaturity on hypoxic-ischemic brain damage in the rat. The thermal probe test (MouseMet Thermal, Topcat Metrology) is a novel method recently described to quantify heat thresholds in mice (Deuis and Vetter, 2016). J. Gerontol. Sci. J. Because of its simplicity, systematic sampling is popular with researchers. The evaluation of the analgesic action of pethidine hydrocholoride (Demerol). The force is increased by rotation of the handheld device until paw withdrawal occurs. J. Pharmacol. The Practical Mouse Despite the advantages rats have over mice as human analogs, mice have dominated the modern genetic and biomedical research landscape. Typically, noxious stimuli activate nociceptors, a subset of peripheral sensory neurons, which have a range of specialized ion channels and receptors that transduce noxious stimuli into electrical signals. This book provides detailed information on a number of methodologies that can be used in The Rat: A Model Used in Biomedical Research 107, 497503. Exceptionally adaptable, these rodents now inhabit almost all environments on Earth, especially near human settlements where they are often seen as pests. Animals 6:47. doi: 10.3390/ani6080047. In addition, care should be taken to design experiments that minimize distress and suffering. Mice are cost effective because they are cheap and easy to look after. J. Invest. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. If there is no response, the next filament with a higher force is tested; if there is a response, the next lower force filament is tested. Methods 25, 241250. Rats as Pets Pros and Cons - HRF (A) Manual Von Frey. The mouse genome is very similar to our own, making mouse genetic research particularly useful for the study of human diseases. Am. When rodents are unwell, the amount of material removed from the burrow is decreased. Nonetheless, consistent measurements are possible in acclimatized animals, although guarding or altered weight distribution may lead to errors. 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). 24, 19281939. 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. Given the variability in cold pain thresholds, it may be difficult to differentiate between cold allodynia and cold hyperalgesia in the clinic. Unlike the hot plate test, the cold plate test is particularly useful for models where only one paw is affected or sensitized by the experimental compound (unilateral pain) as guarding of the affected limb can be easily achieved, and thus can be easily quantified. ILAR J. Quantitative somatosensory testing of warm and heat-pain thresholds: the effect of body region and testing method. Therefore, the results of the survey will be skewed to reflect the opinions of those who visit the website. doi: 10.1213/01.ane.0000158471.41575.f0, Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., et al. The increasing-temperature hot-plate test: an improved test of nociception in mice and rats. Sampling errors can significantly affect the precision and interpretation of the results, which can in turn lead to high costs for businesses or government agencies, or harm to populations of people or living organisms being studied. 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 test begins by assessing the response to a filament of the lowest force (in this case 0.4 grams-force) for a set number of applications (in this case five times). doi: 10.1097/BCR.0b013e3182033359. (C) Weight bearing (incapacitance test). J. J. doi: 10.1016/j.ejpain.2011.07.012, Ankier, S. I. Evaluation of dynamic weight bearing for measuring nonevoked inflammatory hyperalgesia in mice. Behav. A small sample size also affects the reliability of a survey's results because it leads to a higher variability, which may lead to bias. A monofilament is applied perpendicularly to the plantar surface of the hind paw until it buckles, delivering a constant pre-determined force (typically 0.213.7 mN for mice and 5.998 mN for rats) for 25 s (Figure 1A). Pharmacological interrogation of a rodent forced ambulation model: leveraging gait impairment as a measure of pain behavior pre-clinically. doi: 10.1016/0304-3959(94)90023-x, Colburn, R. W., Lubin, M. L., Stone, D. J. Jr., Wang, Y., Lawrence, D., DAndrea, M. R., et al. 16, 13241332. Pharmacol. The distinction between nociception and pain thus underlines a key difference in terminology when referring to communicating and non-communicating subjects. In the conventional hot plate test the rodent is placed on a metal surface maintained at a constant temperature (in this case 54C) and the time taken to elicit a nocifensive behavior (e.g., hind paw withdrawal or licking) is recorded. Efficient analysis of experimental observations. Gait analysis of C57BL/6 mice with complete Freunds adjuvant-induced arthritis using the CatWalk system. However, this requires the animals to be acclimatized to the apparatus to minimize ambulation so that withdrawal latencies can be accurately determined. A response is considered positive if the animal exhibits any nocifensive behaviors, including brisk paw withdrawal, licking, or shaking of the paw, either during application of the stimulus or immediately after the filament is removed. It is plausible that differences in behavior may relate to the type of sensory fiber activated. A radiant or infrared heat source is focused on the plantar surface of the hind paw and the time taken to withdraw from the heat stimulus is recorded. Researchers are often advised to begin their studies using rat models in these areas, not only because they are a suitable model, but also due to the fact that rats have already helped scientists reach a few significant breakthroughs in these areas. Click the button below to get a quote! 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. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. A small sample size can also lead to cases of bias, such as non-response, which occurs when some subjects do not have the opportunity to participate in the survey. 738, 111117. Methods 113, 9197. (2010). This includes minimizing the duration of models, replacing nocifensive model compounds for ones that cause shorter lasting nociception, or reducing the administered doses of compounds. 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. | All rights reserved. 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. Oxaliplatin administration increases expression of the voltage-dependent calcium channel 2-1 subunit in the rat spinal cord. (2007). 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 latency to paw withdrawal is recorded and used to quantify cold allodynia and hyperalgesia. | 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. Scientists recovered most of the Christmas Island rat's genome. However, as the animal is required to explore, habituation, time of day, and light levels may significantly affect results and diminish reproducibility (Millecamps et al., 2005; Balayssac et al., 2014). A disadvantage of systems that only use video recordings (e.g., DigiGait, GaitScan/TreadScan) is that they cannot measure paw print intensity or pressure (weight bearing parameters), which is relevant for pain models. 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. (2015). Rats have since been used to answer a wide range of basic science questions related to common human diseases in the fields of physiology, immunology, pharmacology, toxicology, nutrition, behavior and learning. As pain cannot be directly measured in rodents, many methods that quantify pain-like behaviors or nociception have been developed. (2014). 4:165. doi: 10.3389/fnbeh.2010.00165, Kayser, V., and Christensen, D. (2000). J. 1981. Front Neurol 7: 57. Neuron 54, 379386. The U.S. Department of Agriculture (USDA) does compile annual statistics on some animals used in . doi: 10.1016/0165-0270(94)90144-9, Chapman, C. R., Casey, K. L., Dubner, R., Foley, K. M., Gracely, R. H., and Reading, A. E. (1985). Rats were the first mammalian species specifically domesticated to be used in the laboratory. LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. 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 force ramp and paw withdrawal force are displayed by the software post-test. 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. Mol. J. Pharmacol. Anim. Pain 9, 445452. Eur. These decades of work will enable the integration of new techniques and technologies for cerebral palsy research and maximize the utility of the hypoxia-ischemia model. Animal Model Limitations | National Anti-Vivisection Society 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. Matsumiya, L. C., Sorge, R. E., Sotocinal, S. G., Tabaka, J. M., Wieskopf, J. S., Zaloum, A., et al. 9, 8998. Assoc. Osteoarthr. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. It's a little like tossing a rat into a vat of gasoline and then concluding that gasoline causes drowning. When animals such as mice or rats are selected as models for genetic experimentation, the main reason is the similarity of their genetic makeup to human DNA. FACTS and MYTHS - Animal Research at Stanford J. Neurosci. While this is generally not an issue when testing the anti-nociceptive effects of compounds delivered systematically or when phenotyping transgenic mice, this may confound the results for unilateral models of pain or for compounds administered by intraplantar injection. Researchers choose rats over other species for a number of reasons: Ethical Considerations in Mouse Experiments - PubMed This shift was primarily instigated by the availability of a much . For example, in C57BL/6 mice, the 50% withdrawal threshold determined using manual Von Frey is ~0.61 g, while using electronic Von Frey, the paw withdrawal thresholds are generally higher, with values of ~4 g obtained using MouseMet and ~6 g using Dynamic Plantar Aesthesiometer (Petrus et al., 2007; Minett et al., 2014; Deuis and Vetter, 2016; Gritsch et al., 2016). The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. 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. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. JRD, LSD and IV contributed to the preparation, revision and approval of the final manuscript. The laboratory rat, Rattus norvegicus, has been used in biomedical research for more than 150 years, and in many cases remains the model of choice for studies of physiology, behavior, and complex human disease. 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). A modified version of the thermal probe test suitable for quantifying heat thresholds in rats is still to be developed. doi: 10.1016/j.neuron.2011.02.051, Wallace, V. C., Norbury, T. A., and Rice, A. S. (2005). Lett. Some of these behaviors can be sensitive to analgesics, although differences are observed depending on the type of behavior quantified. 13, 587599. Eur. This assay is based on the hypothesis that a rodent with spontaneous pain will guard the painful paw, leading to changes in its gait (exhibiting a limp or changes in stride size, for instance) in addition to changes in weight bearing (Jacobs et al., 2014). Pain 154, 17491757. 104, 495502. To conduct a survey properly, you need to determine your sample group. Quantification of more subtle behaviors, such as walking backwards or grooming of the front paws has thus been proposed as alternatives to quantify cold pain behaviors, although the validity of this approach has not been systematically assessed. A cold stimulus is applied to the hind paw using a cut off syringe filled with dry ice or wet ice and the time to paw withdrawal is recorded. Mol. - 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). Key Takeaways. Joint Bone Spine 72, 359371. Pain 10, 767773. The first (1880-1950) was when mice and rats became common research animals. 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). Woolf, C. J., and Mannion, R. J. doi: 10.1016/j.pain.2006.01.041, Roughan, J. V., Bertrand, H. G., and Isles, H. M. (2016). Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. (C) Randall-Selitto test (handheld device). 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. (2012). Pain Headache Rep. 18:456. doi: 10.1007/s11916-014-0456-x, Jensen, T. S., and Finnerup, N. B. Rodents are allowed to freely move between a reference plate (neutral temperature) and test plate. Neurosci. Nociceptors: the sensors of the pain pathway. Pain 68, 141150. 43, 1726. Br. The Natural History of Model Organisms: The Norway rat, from an - eLife If the response rate is 40% or more (i.e., withdrawal response is elicited in two or more out of five applications) testing stops and the force of the last von Frey filament is designated as the mechanical withdrawal threshold (in this case 2 grams-force). While the Randall-Selitto test often results in similar types of outcomes to the Von Frey filament tests (Santos-Nogueira et al., 2012), the mechanical stimulation differs fundamentally from Von Frey filaments, which may also activate low-threshold mechanoreceptors in addition to nociceptors. When pain continues beyond the expected time of wound healing or without a clear reason, it is termed chronic pain. Little Albert Experiment (Watson & Rayner) - Simply Psychology doi: 10.1016/s0304-3959(96)03176-4, Yeomans, D. C., and Proudfit, H. K. (1994). Nurs. B., and Hole, K. (1985). It is a low-cost, single-use product made from sterilized quarry sand and treated with a hydrophobic coating. Is it Right or Not to Use Rats for Experiments? (B) Burrowing assay. Copyright 2017 Deuis, Dvorakova and Vetter. To obtain reliable data, animals need to be habituated to the restraint method and experimental apparatus, which can become very time-intensive. In nave C57BL/6 mice, the paw withdrawal temperature occurs at ~50C, and in unilateral models of inflammation the paw withdrawal temperature reduces to 4344C, providing a sufficient window to detect heat allodynia as well as hypoalgesia (Deuis and Vetter, 2016; Deuis et al., 2017a). There are protections in place for the animals. In the percent response method, several Von Frey filaments of varying forces are applied in ascending order an equal number of times (usually 510 applications) regardless of response, and the number of positive responses to each filament is converted to a percent response (Kim and Chung, 1992; Chaplan et al., 1994; Figure 2C). Pain 96, 129140. The temperature at which this occurs is designated as the response temperature (Ogren and Berge, 1984; Tjolsen et al., 1991). Pain 32, 7788. Cybersex and pornography addiction. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain. Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target. Evaluation of the usefulness of two established pain assessment tools in a burn population. Phenotypic changes in diabetic neuropathy induced by a high-fat diet in diabetic C57BL/6 mice. doi: 10.1016/S0014-2999(01)01302-4, Jensen, T. S., and Yaksh, T. L. (1986). (2007). (1989). Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. (2012). 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. 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. 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. Guidelines for the design and statistical analysis of experiments using laboratory animals. This research has almost exclusively used a single procedure to induce the condition in animal models. This work was supported by an Australian Research Council Future Fellowship (IV). doi: 10.1038/nmeth.1455, Leith, J. L., Koutsikou, S., Lumb, B. M., and Apps, R. (2010). Non-response occurs when some subjects do not have the opportunity to participate in the survey. 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. BMC Musculoskelet. Cartil. Advantages and Disadvantages of Using Small and Large Animals in Burn Sci. Physiol. The MouseMet or RatMet electronic Von Frey systems deliver a mechanical stimulus via a hand-held probe (Figure 1B). Pain 59, 369376. doi: 10.1111/j.1749-6632.1983.tb53494.x, Espejo, E. F., and Mir, D. (1993). (2017b). doi: 10.1016/s0140-6736(99)01307-0. doi: 10.1016/j.jneumeth.2015.08.010, Brenner, D. S., Golden, J. P., and Gereau, R. W. IV (2012). Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. Although animal research may have ethical concerns, the US has regulated its practice since 1966. 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. doi: 10.1016/s0304-3959(00)00307-9, Kim, S. H., and Chung, J. M. (1992). J. Sci. Braz. doi: 10.1016/j.joca.2015.05.001, Buys, M. J., and Alphonso, C. (2014). doi: 10.1016/s1474-4422(14)70102-4, Jensen, T. S., Gottrup, H., Sindrup, S. H., and Bach, F. W. (2001). An overview of animal models of pain: disease models and outcome measures. (1974). An SCN9A channelopathy causes congenital inability to experience pain. All we can possibly learn from high-dose experiments is what might happen in overdose situations. Data quality is usually improved if the time to occurrence of any behavior, rather than specific behavior types, is recorded, and if lower temperatures are used (Carter, 1991; Plone et al., 1996). Any long-term research involves mice and rats because of this unique aspect to the research. 524, 107110. The History of the Lab Rat Is Full of Scientific Triumphs and Ethical While the plantar surface of the hind paw is the most commonly used area for testing, other areas of the body, including the dorsal surface of the hind paw or the abdomen can also be used (Minett et al., 2014). Similarly, it overcomes some of the experimental difficulties of static weight bearing analysis, albeit no information on gait can be obtained. Pain 50, 355363. According to the replacement principle, the use of live animals should be replaced with in vitro or computational methods where possible, and if unavoidable, the use of non-sentient or less sentient animals is preferred. (2010). J. Neurosci. Mol. Also, since rats are easier to feed and smaller in size than other complex mammals, such as primates, they are a more convenient option for many researchers. doi: 10.1016/j.jbspin.2004.01.010, Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., et al. The up-down Von Frey method is used to determine the mechanical force required to elicit a paw withdrawal response in 50% of animals, based on the statistical formula used to determine LD50s (Dixon, 1980; Chaplan et al., 1994). Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration. 10:284. doi: 10.3389/fnmol.2017.00284. Interested in using rats for your next research project? 95% of animals used in experiments are not protected by the federal Animal Welfare Act (AWA), which excludes birds, rats and mice bred for research, and cold-blooded animals such as reptiles and most fish. J. Neurosci. Assessing hoarding in mice. Winter, C. A., and Flataker, L. (1965). It should be noted that behavioral assessment of animals in groups (even if blinded) is typically not sufficient, with a preferred method being measurements performed on animals in random order by an investigator blinded to the treatment group each animal has been allocated to. It is the premier source of information on the laboratory rat. Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation. The menthol receptor TRPM8 is the principal detector of environmental cold.
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