13840110d2d515487e83b87 disadvantages of using rats in research
Burrowing, a spontaneous and self-motivated behavior, can be used as a measure of spontaneous or non-stimulus evoked nociception in mice and rats. The effects of morphine methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation. doi: 10.1093/gerona/glr210, OBrien, D. E., Brenner, D. S., Gutmann, D. H., and Gereau, R. W. IV (2013). 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. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. 13, 924935. The experiment begins by testing the response to a filament estimated to be close to the 50% withdrawal threshold. Robinson, I., Sargent, B., and Hatcher, J. P. (2012). (2013). 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. 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). ILAR J. Repeated exposure to sham testing procedures reduces reflex withdrawal and hot-plate latencies: attenuation of tonic descending inhibition? The MouseMet or RatMet electronic Von Frey systems deliver a mechanical stimulus via a hand-held probe (Figure 1B). doi: 10.1111/j.1749-6632.1983.tb53494.x, Espejo, E. F., and Mir, D. (1993). Phenotypic changes in diabetic neuropathy induced by a high-fat diet in diabetic C57BL/6 mice. Rock, M. L., Karas, A. 27, 14. Science 307, 14681472. doi: 10.1002/9780470942390.mo110116, Mogil, J. S. (2009). Sensory determinants of thermal pain. In fact, over 90% of test subjects are mice, birds and rats. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The advantage of this approach is that each animal receives the same number and type of stimuli, although the number of tests per hind paw could exceed 50 (e.g., five different von Frey filaments each applied 10 times), which is not only time consuming, but potentially exposes animals with mechanical hind paw sensitivity to a disproportionate number of more aversive stimuli. 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). 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. Some animals, however, are more preferred by laboratories. Pain 50, 355363. (2014). Influence of skin temperature on heat pain threshold in humans. 89, 707758. 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. Osteoarthr. doi: 10.1007/978-1-62703-459-3_14. 111, 409419. So far, no single behavioral assay can capture the full spectrum of nociception in non-communicating subjects. One way to evaluate nociception in non-communicating subjects is through observation of behavior. Diabetes Res. 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. Adult mice multiply quickly. (B) The ascending stimulus method. 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. Methods 25, 241250. Facebook 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. Mechanical pressure is applied focally to the dorsal or plantar surface of the hind paw or tail, which is placed between a pointed probe tip and a flat surface. 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). 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. It's a little like tossing a rat into a vat of gasoline and then concluding that gasoline causes drowning. doi: 10.1016/0014-2999(74)90195-2, Anseloni, V. C., Ennis, M., and Lidow, M. S. (2003). It is descended from wild Norway rats, Rattus norvegicus, which despite their name likely originated in Asia. 372, 301312. Analg. 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. J. Neurosci. Res. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Characterization of the foot withdrawal response to noxious radiant heat in the rat. doi: 10.1016/s1474-4422(14)70102-4, Jensen, T. S., Gottrup, H., Sindrup, S. H., and Bach, F. W. (2001). Prior to the development of automated digitized platforms, this test was performed by coloring the animals paws with ink; the animal was then allowed to walk freely on a paper, which could be scanned for analysis (Ishikawa et al., 2014). Clin. (2011). For example, if you call 100 people between 2 and 5 p.m. and ask whether they feel that they have enough free time in their daily schedule, most of the respondents might say "yes." 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. As for heat pain, these values are likely influenced by a number of factors including ambient temperature, rate of cooling and anatomical location. doi: 10.1016/0304-3959(85)90145-9, Choi, Y., Yoon, Y. W., Na, H. S., Kim, S. H., and Chung, J. M. (1994). Analgesic treatment of ciguatoxin-induced cold allodynia. Coding of facial expressions of pain in the laboratory mouse. doi: 10.1080/23328940.2016.1157668, Deuis, J. R., Whately, E., Brust, A., Inserra, M. C., Asvadi, N. H., Lewis, R. J., et al. Mechanical hyperalgesia and allodynia can be further subdivided into dynamic (triggered by brushing), punctate (triggered by touch) and static (triggered by pressure). Of acute wounds, burns are one of the most devastating injuries known to mankind. Biol. Lett. 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. Lab. Both versions of the test require the animal to be loosely restrained. 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. doi: 10.1016/s0304-3959(96)03176-4, Yeomans, D. C., and Proudfit, H. K. (1994). In this test, animals are placed individually in small cages with a mesh or otherwise penetrable bottom. (2016). 101, 132143. For example, in the case of application of a stimulus to the hind paw, the investigator must determine if the animal withdrew the hind paw due to its aversive nature, or whether the animal withdrew the hind paw for another reason (e.g., tickle, grooming, ambulation). 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. Pain 10, 767773. doi: 10.1016/S0304-3959(01)00437-7, Menndez, L., Lastra, A., Hidalgo, A., and Baamonde, A. In addition, the experimental time is dramatically reduced, as few applications (usually 34) are needed to determine the paw withdrawal threshold (Deuis et al., 2014, 2015). Pain is a multifaceted and diverse experience that can be categorized into a number of types and modalities, depending on the presentation and triggering stimulus of the pain event. Woolf, C. J., and Mannion, R. J. PLoS One 10:e0125822. The software records the duration of different behavior types, including movement, grooming and rearing behaviors. However, this requires the animals to be acclimatized to the apparatus to minimize ambulation so that withdrawal latencies can be accurately determined. In a 1926 letter to Nature, Selye described the findings of a series of experiments on rats, in which the animals were subjected to numerous stressors, which he referred to as "nocuous agents . Pain 66, 265270. 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. J. Neurotrauma 29, 898904. The Kantian view denies moral value to animals because they lack reason. The force is increased by rotation of the handheld device until paw withdrawal occurs. 34, 17551762. Pain measurement: an overview. J. Pharmacol. The same methods that allow this to be so in mice have failed in rats. Anim. For people who choose to own rats at home, here are some of the benefits that they can receive: Rats are very intelligent animals. Optimization of the mechanical nociceptive threshold testing with the Randall-Selitto assay. It should be noted that the paw withdrawal threshold can be considered a measure of spinal reflex, with some researchers favoring vocalization as an end-point (Winter and Flataker, 1965; Kayser and Christensen, 2000; Santos-Nogueira et al., 2012). doi: 10.1016/s0140-6736(99)01307-0. J. Sci. The three Rs are: Reduction, Refinement, Replacement.. Toxicol. Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain. Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate. 64, 8187. Rumajogee P, Bregman T, Miller SP, Yager JY, Fehlings MG. 2016. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. doi: 10.1016/j.jpain.2013.06.008, Griffioen, M. A., Dernetz, V. H., Yang, G. S., Griffith, K. A., Dorsey, S. G., and Renn, C. L. (2015). Figure 4.Methods used to assess cold-evoked pain like behaviors and temperature preference in rodents. A method for determining loss of pain sensation. 1, 28282830. Disord. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. The temperature at which this occurs is designated as the response temperature (Ogren and Berge, 1984; Tjolsen et al., 1991). If the response rate is less than 40% (i.e., a withdrawal response is elicited in none or one out of five applications) the next filament is tested. 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). In human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. The latency to paw withdrawal is recorded and used to quantify cold allodynia and hyperalgesia. engagement in scientific research and . However the distinction between stimulus-evoked and non-stimulus evoked pain may be difficult to make clinically, as arguable it could be allodynia occurring from an unidentified stimulus. Eng. Mice are placed individually in small cages with a barred floor. 89% of scientists surveyed by the Pew Research Center were in favor of animal testing for scientific research. The burrows are placed in the rodents cage for a pre-determined duration and the amount of material displaced is weighed and recorded (Deacon, 2006b; Jirkof et al., 2010). 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. An advantage of this method is that it avoids excessive application of Von Frey filaments that elicit aversive behaviors. 104, 495502. Behavioral measures of pain thresholds. Almost all disease-linked human genes have counterparts in the rat. 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. Facial expressions of mice can be used to score the subjective intensity of pain. Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. doi: 10.1016/0304-3959(94)90090-6, Carter, R. B. doi: 10.1016/j.jbspin.2004.01.010, Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., et al. In addition, the Hargreaves test enables quantification of heat thresholds in unrestrained animals, reducing the likelihood of stress-induced responses. 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). The framework for these standards and guidelines are based on the principles of the 3Rs (replacement, reduction, refinement). 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). The rodent is placed in an inclined holder with the hind paws resting on two separate pressure sensors. 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. 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. Rodents are placed individually in small enclosures with a glass floor. Pain 14, 12551269. A behavioral and pharmacological validation of the acetone spray test in gerbils with a chronic constriction injury. Burns 43, 304309. Testing should also be avoided while the animal is engaged in grooming behaviors, as this can produce false negative responses. doi: 10.1523/JNEUROSCI.1526-05.2005, Schtt, E., Berge, O. G., Angeby-Mller, K., Hammarstrm, G., Dalsgaard, C. J., and Brodin, E. (1994). Reaction thresholds to pressure in edematous hindpaws of rats and responses to analgesic drugs. 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. Gait analysis methods for rodent models of osteoarthritis. 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). This alleviates the mosaicism common with targeting embryos, allowing for the production of specifically targeted germline rats in as little as 3 months. opportunities for species-specific behaviour), handling, procedures at daytime in nocturnal species, changes in groups for randomization, and too many male animals caged together. Anim. 1, 383412. 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. Any long-term research involves mice and rats because of this unique aspect to the research. With the sequencing of the Brown Norway rat in 2004 by the Rat Genome Sequencing Project Consortium, led by the Baylor College of Medicine, it is now known that almost all disease-linked human genes have counterparts in the rat. doi: 10.1213/01.ane.0000158471.41575.f0, Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., et al. FIGURE 2 Figure 2 .Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. Exp. The most common case of bias is a result of non-response. Their premise is based on the presumption that because we share similar biological processes, and because animals are whole, complex organisms, data obtained from an animal model can be extrapolated and . 51, 4249. Technology Addiction. (D) Thermal probe test. Figure 6.Methods used to assess non-stimulus evoked pain behaviors in rodents. As pain cannot be directly measured in rodents, many methods that quantify pain-like behaviors or nociception have been developed. Researchers choose rats over other species for a number of reasons: In contrast to other Von Frey setups, animals are housed in individual enclosures with bars, rather than mesh, to help maximize the surface area of the hind paw available for application of the filament. 47, 810. 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. PLoS One 9:e104458. This sample - and the results - are biased, as most workers are at their jobs during these hours. While forepaw withdrawal often occurs first, hind paw withdrawal or licking is considered to be a more reliable indicator of nociception, as the forepaws are frequently used in grooming and exploration and are not consistently in contact with the metal surface (Woolfe and Macdonald, 1944; Minett et al., 2011). Animals are stressed - there are many reasons for stress in the animals: transportation, insufficient time for adapting, cages without enrichment (e.g. Behaviors tend to occur on a spectrum of intensity, but are usually scored in binary as either present or absent. 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). 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. 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. Other advantages of this methodology include eliminating the phenomenon of clustered selection and a low . 738, 111117. 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. Water heated to 30C and applied the same way is usually used as a control (Carlton et al., 1994; Choi et al., 1994). Mol. B., and Hole, K. (1985). The thermal probe test: a novel behavioral assay to quantify thermal paw withdrawal thresholds in mice. The method is based on the application of monofilaments with increasing force until a withdrawal response is elicited, and the force of the von Frey filament that elicits this positive response is designated as the mechanical withdrawal threshold (Figure 2B). Then in 2012, CRISPR/Cas9 changed genome manipulation as we know it. Institute of Neurosciences, Spanish National Research Council (CSIC), Spain, Livestock Behavior Research Unit, Agricultural Research Service (USDA), United States. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats. In the case of researchers conducting surveys, for example, sample size is essential. The U.S. Department of Agriculture (USDA) does compile annual statistics on some animals used in . Cerebral palsy. 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. Veterinarians are required to inspect the living conditions of the animals. The evaluation of the analgesic action of pethidine hydrocholoride (Demerol). An SCN9A channelopathy causes congenital inability to experience pain. Pain 32, 7788. Pain Med. 9, 807819. The Rat Grimace Scale is able to detect spontaneous pain induced by intraarticular kaolin-carrageenan, intraplantar Complete Freunds Adjuvant (CFA), and post-surgical pain. Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands. Rolke, R., Baron, R., Maier, C., Tlle, T. R., Treede, R. D., Beyer, A., et al. Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration. Sci. Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. Stimulus-evoked pain is described as either hyperalgesia or allodynia, and is further subdivided on the basis of the evoked stimulus modality (e.g., mechanical, heat, cold, chemical; Woolf and Mannion, 1999). Research scientists worldwide agree that the use of rat models for disease research and experimentation has become more relevant in the past few years. J. Neurosci. Similarly, the terms nociception and pain are often used interchangeably, although the term pain is rarely appropriate to use in reference to animal studies. doi: 10.1016/S0014-2999(01)01302-4, Jensen, T. S., and Yaksh, T. L. (1986). J. Pharmacol. 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. 30, 49334942. Pain 12:1744806916629049. doi: 10.1177/1744806916629049, Guilford, B. L., Ryals, J. M., and Wright, D. E. (2011). 3. Practical mechanical threshold estimation in rodents using von Frey hairs/Semmes-Weinstein monofilaments: towards a rational method. Pain 154, 17491757. 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. Some results suggest that the rat more accurately reflects human physiology than other species, mimicking human disease more accurately in many cases. publix hot soup schedule, install mame 2003 plus on retropie, fitbit hourly activity reminder not working charge 5,
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