An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Ther. 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. It was around this time that gene editing came into being, specifically Zn Finger nucleases and TALENS. Methods 87, 185193. 1981. (2014). (2006). 67, 705713. Rep. 5:14648. doi: 10.1038/srep14648. A modified Hargreaves method for assessing threshold temperatures for heat nociception. (2007). Thus, the hot plate test can produce greatly variable data, even within laboratories. However, theyre more widely used in studying cardiovascular and metabolic disorders, as well as the onset of conditions that relate to the brain, digestive system, and various health problems related to behavior. (2015). 25, 73177323. The exception is use of the test on the tail of mice (Minett et al., 2014), although this may not be useful to assess nociceptive behaviors in commonly used models that are localized to the hind paw. Lett. Optimization of the mechanical nociceptive threshold testing with the Randall-Selitto assay. However, this also requires animals to be acclimatized to the cages, to ensure ambulation and exploratory behaviors, which could be misinterpreted as a positive response, are kept to a minimum. 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. Am. Pharmacol. 2014. (1957). Weight distribution between the hind paws is recorded. Toxicol. Res. doi: 10.1097/fbp.0000000000000026, Banik, R. K., and Kabadi, R. A. DAmour, F. E., and Smith, D. L. (1941). Behavioral and physiological methods for early quantitative assessment of spinal cord injury and prognosis in rats. (2015). 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. Pain 16, 485495. Digigait quantitation of gait dynamics in rat rheumatoid arthritis model. doi: 10.3791/52640, Brodkin, J., Frank, D., Grippo, R., Hausfater, M., Gulinello, M., Achterholt, N., et al. Development of a piglet grimace scale to evaluate piglet pain using facial expressions following castration and tail docking: a pilot study. 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. Rev. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. LinkedIn. They know how to use their own litter tray at home. Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice. If you've taken an introductory psychology class, then you have probably read about seminal psychological research that was done with animals: Skinner's rats, Pavlov's dogs, Harlow's monkeys. 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). Nocifensive behaviors include forepaw withdrawal or licking, hind paw withdrawal or licking, stamping, leaning posture and jumping (Espejo and Mir, 1993). Disadvantage 2: Uncoverage Bias 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. J. Neurosci. ingenious was very competitively priced compared to other reputable transgenic companies. Depending on the species and strain of rodent used, at least 12 different behaviors have been noted in the hot plate test, including sniffing, grooming, stamping of the legs, freezing, licking, leaning and jumping (Espejo and Mir, 1993). In humans, acute pain is defined as short-lasting (36 months) and is directly related to injury or tissue damage, such as a cut, burn or broken bone. For people who choose to own rats at home, here are some of the benefits that they can receive: Rats are very intelligent animals. The 50% threshold is then calculated using the formula: 50% threshold (g) = 10(X+kd)/104, where X = the value (in log units) of the final von Frey filament, k = tabular value for the response pattern (see Appendix 1 in Chaplan et al., 1994) and d = the average increment (in log units) between von Frey filaments. Some animals, however, are more preferred by laboratories. Characterization of the foot withdrawal response to noxious radiant heat in the rat. 56, 171176. Ther. doi: 10.1093/ilar.43.4.244, Gabriel, A. F., Marcus, M. A., Walenkamp, G. H., and Joosten, E. A. Osteoarthr. The most common case of bias is a result of non-response. The cold plate test is one of the simplest assays to determine behavioral responses to both noxious and innocuous cold temperatures in both mice and rats. In addition, welfare benefits in form of testing of unrestrained mice and exposure of only a single hind paw to a noxious heat stimulus are favorable. 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. 1020, 215221. 2 The human, social, and economic burden of burns is considerable with an estimated annual expenditure of >$2 billion . A radiant or infrared heat source is positioned underneath the animal and aimed at the plantar surface of the hind paw (Figure 3C). Adams, B. L., Guo, W., Gors, R. T., and Knopp, K. L. (2016). (C) Randall-Selitto test (handheld device). Pain 12:1744806916665366. doi: 10.1177/1744806916665366, Yoburn, B. C., Morales, R., Kelly, D. D., and Inturrisi, C. E. (1984). Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence. Nat. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. doi: 10.1016/s1474-4422(14)70024-9, Berge, O. G., Garcia-Cabrera, I., and Hole, K. (1988). This raises a moral issue in animal experimentation. Both the mouse and rat grimace scale are limited by the need for extensive training of the observer and a degree of subjectivity, which could lead to variability. J. Neurotrauma 29, 898904. Chronic pain serves no protective purpose, and depending on the severity, can be a debilitating condition that is difficult to treat, with the currently available analgesics often lacking efficacy and suffering dose-limiting adverse effects. doi: 10.1016/j.ejphar.2014.05.048, Jacobs, B. Y., Kloefkorn, H. E., and Allen, K. D. (2014). Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Thus, the term nociception is used to describe the peripheral neuronal response to noxious stimuli, which encompasses any stimuli, being mechanical, thermal, electrical or chemical, that have the potential to damage are damaging to tissue (Dubin and Patapoutian, 2010). Pain 150, 340350. 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). 9, 807819. Sci. 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. Key Takeaways. The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. February 8, 2018| Kristen Coughlin | CRISPR, Rat Models, Last Updated on January 23, 2023 by ingenious. doi: 10.1177/0023677214559084, Minett, M. S., Eijkelkamp, N., and Wood, J. N. (2014). The Advanced Dynamic Weight Bearing apparatus (Bioseb) was developed as a modification from static weight bearing or incapacitance tests and computes weight bearing for each of the front and rear paws, weight ratio and paw surface area in freely moving animals (Griffioen et al., 2015). The thermal probe test (MouseMet Thermal, Topcat Metrology) is a novel method recently described to quantify heat thresholds in mice (Deuis and Vetter, 2016). The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). 15, 6172. While paw withdrawal temperature can be derived from the time to withdrawal (Hargreaves et al., 1988), the actual temperature applied to the skin would need to be experimentally determined by attaching a thermocouple probe to the skin. doi: 10.1016/0160-5402(91)90014-v, Touska, F., Winter, Z., Mueller, A., Vlachova, V., Larsen, J., and Zimmermann, K. (2016). Almost all disease-linked human genes have counterparts in the rat. (2013). Sci. Pain 154, 19992006. J. Pharmacol. 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). The test begins by assessing the response to a filament estimated to be close to the 50% withdrawal threshold (in this case 1 grams-force). Hyperalgesia is defined as an increased or exaggerated pain response to a normally noxious stimulus, while allodynia is defined as a painful response to a normally non-noxious or innocuous stimulus. Quantitative sensory testing in the german research network on neuropathic pain (DFNS): standardized protocol and reference values. (B) Electronic von Frey (MouseMet, TopCat Metrology). And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. White, V.M.D., M.S., DACLAM, Dipl. Animal models of pain: progress and challenges. An additional disadvantage of the hot plate test is that all four paws and the tail are exposed to the heat stimulus. 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). Oxaliplatin administration increases expression of the voltage-dependent calcium channel 2-1 subunit in the rat spinal cord. 47, 810. 5, 94100. Lancet 383(9924): 1240-9. J. 1. 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). Nature 444, 894898. The force is increased by rotation of the handheld device until paw withdrawal occurs. Exp. Lett. 11, 821830. 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. Voluntary response bias is another disadvantage that comes with a small sample size. (1991). Influence of skin temperature on heat pain threshold in humans. Role of the NLRP3 inflammasome in a model of acute burn-induced pain. You want to survey as large a sample size as possible; the larger the standard deviation, the less accurate your results might be, since smaller sample sizes get decreasingly representative of the entire population. This continues until at least four readings are obtained after the first change of direction. Gene editing technologies allow scientists to use rats more often in their research. 95% of all animals used in research are rats because their genetic, biological and behavioral characteristics are so similar to that of humans. (1974). 37, 18351841. Neurosci. BMC Musculoskelet. Despite some degree of uncertainty about the validity of the anthropomorphization of pain in animals, the capacity to experience pain and distress, particularly resulting from procedures or conditions that would cause pain and distress in humans, must be assumed unless there is evidence to the contrary. Surface tension of alchol water + water from 20 to 50 degrees celcius. Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target. doi: 10.1016/j.joca.2015.05.001, Buys, M. J., and Alphonso, C. (2014). Neurosci. Anim. J. Neurosci. (C) The percent response method. Nat. Originally the method was used on rat pups seven days after birth, when their brains are most similar to those of newborn babies. Neurosci. 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). The need for randomization in animal trials: an overview of systematic reviews. Sci. Exp. 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. Assoc. Readership. 53, 2428. Neurosci. 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). In addition, rodents are intelligent and can learn that premature withdrawal will result in less human interaction and stimulation. Winter, C. A., and Flataker, L. (1965). 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). In the Mouse Grimace Scale (Figure 6A), five facial features are scored: orbital tightening, nose bulge, cheek bulge, ear position, and whisker position (Langford et al., 2010). (2011). JRD, LSD and IV contributed to the preparation, revision and approval of the final manuscript. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. 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. Cartil. Stimulus-independent or spontaneous pain may be paroxysmal (sudden and severe) or continuous, and can be described as aching, cramping, crushing, shooting and burning (Jensen et al., 2001). Well-established strains of rat are used to study a number of human diseases such as: obesity and diabetes cancer cardiovascular disease (including high blood pressure and heart failure). N Y Acad. Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. The latency to paw withdrawal is recorded and used to quantify cold allodynia and hyperalgesia. With a much less expensive and more precise method for targeting genomes via embryos, the potential for rats as a model system of human disease could be pursued even easier. Dogs, cats, and nonhuman primates together account for less than 1% of all animals necessary for medical research. Both versions of the test require the animal to be loosely restrained. Our goal is to make science relevant and fun for everyone. Rodents are placed individually in a small cage with a barred floor. Importantly, the pain appears to be spontaneous, with no identifiable stimulus. The Practical Mouse Despite the advantages rats have over mice as human analogs, mice have dominated the modern genetic and biomedical research landscape. 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). Protoc. 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.

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