This test involved application of an increasing mechanical force to the surface of the paw or tail until withdrawal or vocalization occurs. 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. Pain, as defined by the International Association for the Study of Pain (IASP), is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. The same is likely to be true of other rodent species, many of . Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats. 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. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. 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. doi: 10.1089/neu.2010.1700, Scholz, J., Broom, D. C., Youn, D. H., Mills, C. D., Kohno, T., Suter, M. R., et al. Exp. Rodents are placed individually in small cages with a mesh or barred floor. First, the response to a specific temperature (typically 5C to 15C) can be recorded (Allchorne et al., 2005). As pain cannot be directly measured in rodents, many methods that quantify pain-like behaviors or nociception have been developed. doi: 10.1016/0304-3959(85)90145-9, Choi, Y., Yoon, Y. W., Na, H. S., Kim, S. H., and Chung, J. M. (1994). An SCN9A channelopathy causes congenital inability to experience pain. An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. 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. Water heated to 30C and applied the same way is usually used as a control (Carlton et al., 1994; Choi et al., 1994). Rodents are allowed to freely move along a liner or circular surface with a temperature gradient. Methods used to assess mechanically evoked pain like behaviors in rodents. 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. The force at which this response occurs is recorded automatically by the apparatus and is designated as the paw withdrawal threshold. An overview of animal models of pain: disease models and outcome measures. As the nocifensive response can be too fast for an investigator to quantify in real time, video recordings that are played back in slow motion may be required to accurately analyze the response to acetone. Lab. 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. TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Methods 113, 9197. Brain Res. Mol. TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. doi: 10.1523/JNEUROSCI.1526-05.2005, Schtt, E., Berge, O. G., Angeby-Mller, K., Hammarstrm, G., Dalsgaard, C. J., and Brodin, E. (1994). 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. J. Pharmacol. Exp. These behavioral methods can be divided into stimulus-evoked or non-stimulus evoked (spontaneous) nociception, based on whether or not application of an external stimulus is used to elicit a withdrawal response. Development of a piglet grimace scale to evaluate piglet pain using facial expressions following castration and tail docking: a pilot study. Animals are stressed - there are many reasons for stress in the animals: transportation, insufficient time for adapting, cages without enrichment (e.g. The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). Cybersex and pornography addiction. The protective role of pain is most evident in individuals who have congenital insensitivity to pain, a rare genetic condition that results in the inability to sense tissue damaging or nociceptive stimuli (Cox et al., 2006). Protoc. 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. Facial expressions of mice can be used to score the subjective intensity of pain. Sensory determinants of thermal pain. J. Neurosci. This normally protective response, which is absent in these individuals, leads to frequent injuries and often results in higher mortality rates early in life (Bennett and Woods, 2014). Rodents are allowed to freely move between a reference plate (neutral temperature) and test plate. 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). 1. Rodents are placed individually in small enclosures with a glass floor. J. Assoc. J. Neurosci. 1, 118121. 4:51. doi: 10.3389/fvets.2017.00051, Vissers, K., and Meert, T. (2005). Evaluation of dynamic weight bearing for measuring nonevoked inflammatory hyperalgesia in mice. Assoc. . Similarly, if a stimulus is applied that does normally evoke a withdrawal response, but the animal withdraws with an exaggerated response, the animal is considered to have hyperalgesia. 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. Mol. In this experiment, a previously unafraid baby was conditioned to become afraid of a rat. doi: 10.1002/ejp.871, Roughan, J. V., Wright-Williams, S. L., and Flecknell, P. A. Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice. doi: 10.1016/j.ejphar.2014.05.048, Jacobs, B. Y., Kloefkorn, H. E., and Allen, K. D. (2014). Nevertheless, the temperature preference test has been used extensively in the study of the role of thermosensitive transient receptor potential (TRP) channels in thermal nociception including TRPA1, TRPM8, TRPM3, TRPV3 and TRPV4 (Bautista et al., 2007; Knowlton et al., 2010; Huang et al., 2011; Vriens et al., 2011; Touska et al., 2016). Figure 2.Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. 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. Whether you need help solving quadratic equations, inspiration for the upcoming science fair or the latest update on a major storm, Sciencing is here to help. LinkedIn. Lancet Neurol. Pain 10, 767773. Painful and painless channelopathies. Effects of morphine on thermal sensitivity in adult and aged rats. J. Pharmacol. J. 13, 924935. doi: 10.1097/fbp.0000000000000026, Banik, R. K., and Kabadi, R. A. 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: 10.1016/j.pain.2010.05.021, Langford, D. J., Bailey, A. L., Chanda, M. L., Clarke, S. E., Drummond, T. E., Echols, S., et al. While relatively quick and easy to perform, an important consideration with the tail flick test is that a similar behavioral response can be observed in spinally transected rats, consistent with the notion that the tail withdrawal response is a spinal reflex, rather than an indication of pain behaviors involving higher brain centers (Irwin et al., 1951). (2007). 5, 94100. doi: 10.1080/23328940.2015.1135689, Vazquez, G., Alvarez, E., and Navaza, J. M. (1995). Most importantly, however, from the very beginning their knowledge and competence convinced me they would deliver on our project, so I trusted them and they fully met our expectations. The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. Figure 1. Unlike the tail flick test, the hot plate test and other tests that apply heat stimuli to the hind paws are considered to integrate supraspinal pathways, as rats with spinal transection do not withdraw the hind limbs in the hot plate test (Giglio et al., 2006). 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. 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. Interested in using rats for your next research project? The experiment begins by testing the response to a filament estimated to be close to the 50% withdrawal threshold. The purpose of pain in the above cases is to alert an individual to withdraw from immediate tissue damaging stimuli and to prevent further damage to the site of injury during the healing process. 10:284. doi: 10.3389/fnmol.2017.00284. J. Neurosci. (B) The ascending stimulus method. Simmons has worked as a freelance writer since 2009. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Berryman, E. R., Harris, R. L., Moalli, M., and Bagi, C. M. (2009). doi: 10.1021/je00019a016, Viscardi, A. V., Hunniford, M., Lawlis, P., Leach, M., and Turner, P. V. (2017). Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate. Dynamic mechanical allodynia and hyperalgesia can be assessed by brushing the skin with a cotton bud, paintbrush or cotton ball, and in the case of allodynia, can be evoked by the brushing of clothing, bed sheets or towels against the skin (Jensen and Finnerup, 2014). Irwin, S., Houde, R. W., Bennett, D. R., Hendershot, L. C., and Seevers, M. H. (1951). 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. Life Sci. 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. Methods 25, 241250. Third, aversive response to a cooling ramp can be used to determine the cold response threshold (Yalcin et al., 2009). 13, 587599. Rat models are therefore still widely used. 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. Lancet 353, 19591964. N Y Acad. Some examples of human disorders and diseases for which mice and rats are used as models include: Hypertension Diabetes Cataracts Obesity Seizures Respiratory problems Deafness Parkinson's. Individual differences in the hotplate test and effects of habituation on sensitivity to morphine. Researchers and scientists conducting surveys and performing experiments must adhere to certain procedural guidelines and rules in order to insure accuracy by avoiding sampling errors such as large variability, bias or undercoverage. Pain 14, 628637. Diabetes Res. A camera below records the paw prints, which are illuminated by internally reflected light in the glass. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. doi: 10.1016/j.pain.2013.05.032, Dixon, W. J. (2011). 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. 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. Int. Monofilaments of differing forces are applied perpendicularly to the hind paw. 27, 1368013690. Clin. 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. Rodents may also respond to initial contact with a filament with a touch-on response. 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. 7. Eur. J. Neurosci. In human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. Am. doi: 10.1016/j.joca.2015.05.001, Buys, M. J., and Alphonso, C. (2014). A soft transducer ensures minimal vibration and reduces touch-on responses. When pain continues beyond the expected time of wound healing or without a clear reason, it is termed chronic pain. 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. 738, 111117. Lett. The main advantage of the thermal probe test is that the mice are placed in individual runs standing on bars instead of glass enabling access to the plantar surface, which allows simultaneous assessment of mechanical thresholds by von Frey, removing the need for acclimation in two different enclosures. Rodents are placed individually in small enclosures with a glass floor. Sci. The assay is also capable of detecting side effects of analgesics, such as drowsiness, although it may be difficult to distinguish whether decreased burrowing arises from lack of efficacy or adverse effects unless additional behavioral tests or full dose-response curves are performed (Andrews et al., 2012). 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. 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. In humans, spontaneous or background pain is pain that occurs without an identifiable stimulus. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. While the underlying principle of the temperature gradient assay is similar to the two-temperature choice assay, the animal is free to explore along the gradient (usually between 4C and 65C over a length of 120 cm) until they settle within their preferred temperature or comfort zone. 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). (2015). doi: 10.1111/pme.12230, Dalla Costa, E., Stucke, D., Dai, F., Minero, M., Leach, M. C., and Lebelt, D. (2016). J. Pharmacol. A disadvantage of the Hargreaves test is that the paw withdrawal time is recorded rather than directly measuring the paw withdrawal temperature. Pharmacodyn. 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. (2014). The Behavioral Spectrometer has been validated in a mouse model of carrageenan-induced hind paw inflammation, where the frequency of grooming was increased and the number of ambulations were decreased (Brodkin et al., 2014). 27, 14. 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. doi: 10.1093/ilar.43.4.244, Gabriel, A. F., Marcus, M. A., Walenkamp, G. H., and Joosten, E. A. 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). Biol. In the case of researchers conducting surveys, for example, sample size is essential. Nonetheless, the thermal probe test remains to be validated in other pain models that cause more pronounced mechanical allodynia. Eur. Nonetheless, consistent measurements are possible in acclimatized animals, although guarding or altered weight distribution may lead to errors. 95% of all animals used in research are rats because their genetic, biological and behavioral characteristics are so similar to that of humans. Protoc. Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. Adams, B. L., Guo, W., Gors, R. T., and Knopp, K. L. (2016). In this model, the lateral plantar skin of the hind paw, which is the area of innervation of the sural nerve, has the greatest reduction in mechanical thresholds compared to other innervation areas of the plantar skin (Decosterd and Woolf, 2000). Behaviors tend to occur on a spectrum of intensity, but are usually scored in binary as either present or absent. 429, 111. 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. Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: Neuro Oncol. The sensation of pleasant or innocuous cooling is typically elicited at temperatures of ~2329C, while the sensation of cold pain is significantly variable, with multimodal distribution of the cold pain threshold recently reported, corresponding to modal threshold temperatures of 23.7C, 13.2C and 1.5C, respectively (Ltsch et al., 2015).
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