4:51. doi: 10.3389/fvets.2017.00051, Vissers, K., and Meert, T. (2005). PLoS One 9:e98856. The mouse has many similarities to humans in terms of anatomy, physiology and genetics. 43, 1726. J. Brain Res. This raises a moral issue in animal experimentation. Sci. doi: 10.1016/s0304-3959(00)00276-1, Defrin, R., Ohry, A., Blumen, N., and Urca, G. (2002). Rats were the first mammalian species specifically domesticated to be used in the laboratory. Pain 22, 130136. (2015). Then in 2012, CRISPR/Cas9 changed genome manipulation as we know it. 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. In the case of researchers conducting surveys, for example, sample size is essential. 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). 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. Pain 66, 265270. (B) The ascending stimulus method. Anim. 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. Variability is determined by the standard deviation of the population; the standard deviation of a sample is how the far the true results of the survey might be from the results of the sample that you collected. 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. In addition, care should be taken to design experiments that minimize distress and suffering. Email: inquiry@genetargeting.com Because of its simplicity, systematic sampling is popular with researchers. 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). (2014). (2014). 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). As a result, mice became the more prominent model organism due to the availability of genetically modified lines where a gene of interest can be activated or inactivated in specific cells. doi: 10.1371/journal.pone.0175839, Han, J. S., Bird, G. C., Li, W., Jones, J., and Neugebauer, V. (2005). 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. 111, 409419. *Correspondence: Irina Vetter, i.vetter@uq.edu.au, View all 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). doi: 10.1016/s0304-3959(96)03177-6, Yin, K., Deuis, J. R., Lewis, R. J., and Vetter, I. doi: 10.1016/j.neuron.2007.04.017, Coutaux, A., Adam, F., Willer, J. C., and Le Bars, D. (2005). Rock, M. L., Karas, A. In addition to burrowing, other spontaneous behaviors can be assessed, including nesting construction and food hoarding (Deacon, 2006a; Rock et al., 2014). An SCN9A channelopathy causes congenital inability to experience pain. (2017a). (2010). Lab. Assoc. However, the force required to trigger probe heating is low (~1 g), adjustable, and the surface of the heating probe is rather large compared to the punctate von Frey filaments. 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). doi: 10.1016/j.pain.2006.01.041, Roughan, J. V., Bertrand, H. G., and Isles, H. M. (2016). Nevertheless, the acetone evaporation test has been validated in multiple models of inflammatory and neuropathic pain in both mice and rats (Choi et al., 1994; Colburn et al., 2007; Yamamoto et al., 2016). A Biol. (2015). In the past, housing of rodents used for research was designed primarily to prevent (B) Cold plantar assay. Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate. Figure 6.Methods used to assess non-stimulus evoked pain behaviors in rodents. Guidelines for the design and statistical analysis of experiments using laboratory animals. A Guide to Research Rodent Housing William J. To conduct a survey properly, you need to determine your sample group. 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. doi: 10.1089/neu.2010.1700, Scholz, J., Broom, D. C., Youn, D. H., Mills, C. D., Kohno, T., Suter, M. R., et al. Ann Neurol 9(2): 131-41. (2013). The clinical picture of neuropathic pain. Osteoarthr. Here, the rodent is placed on the plate after it has been cooled to the desired temperature and the time taken to evoke nociceptive behavior such as shaking, jumping or licking in the animal is recorded as the response time. Figure 4.Methods used to assess cold-evoked pain like behaviors and temperature preference in rodents. Rolke, R., Baron, R., Maier, C., Tlle, T. R., Treede, R. D., Beyer, A., et al. Heat thresholds in humans can be determined by applying a metal probe to the skin that increases in temperature (starting at 32C) until a warm-sensation threshold and heat-pain threshold is reached. 24, 19281939. Nurs. 89% of scientists surveyed by the Pew Research Center were in favor of animal testing for scientific research. PLoS One 12:e0175839. Rumajogee P, Bregman T, Miller SP, Yager JY, Fehlings MG. 2016. As many animal models of pain using stimulus-evoked measures of nociception have failed in the past to translate into the clinic, spontaneous pain as an efficacy endpoint may be more relevant to the human condition and increase the clinical validity of animal models of pain in the future (Mogil, 2009). In the case of rats specifically, their particular DNA and physiology has allowed scientists to explore a variety of physiological and pathophysiological mechanisms that would not be possible in a mouse model. J. Pharmacol. Pain 12:1744806916665366. doi: 10.1177/1744806916665366, Yoburn, B. C., Morales, R., Kelly, D. D., and Inturrisi, C. E. (1984). The RatMet or MouseMet von Frey filament (0.3 and 0.5 mm tip diameter, delivering forces of 180 g and 0.17 g, respectively) is placed against the plantar surface of the paw and the force is linearly increased via rotation of the device handle (Deuis and Vetter, 2016). (1974). Closely related to the last point is the subject of digital addiction. 150, 165171. The CatWalk method: assessment of mechanical allodynia in experimental chronic pain. Neurosci. Similarly, measures to improve data quality, including appropriate randomization and blinding procedures, are key to ensure validity of the obtained results. Eur. The Kantian view denies moral value to animals because they lack reason. engagement in scientific research and . Development of a piglet grimace scale to evaluate piglet pain using facial expressions following castration and tail docking: a pilot study. Multimodal distribution of human cold pain thresholds. Cartil. ILAR J. 120, 37603772. doi: 10.1126/science.1108609, Morgan, D., Mitzelfelt, J. D., Koerper, L. M., and Carter, C. S. (2012). Neurosci. Rev. In its simplest form, the animal can choose between two adjacent areas maintained at different temperatures. A method for determining loss of pain sensation. Pharmacol. Its characterized primarily by motor impairment, but there are also a range of accompanying conditions such as seizure disorders and cognitive defects. A large number of parameters can be analyzed, including paw intensity (a measure of paw pressure or weight bearing), paw print parameters (e.g., toe spread, print length, print width, print area), dynamic parameters (e.g., stance phase, swing phase, duty cycle, stride length, swing speed) and regularity index (a measure of interlimb coordination). 101, 457464. 9, 807819. doi: 10.1080/23328940.2016.1157668, Deuis, J. R., Whately, E., Brust, A., Inserra, M. C., Asvadi, N. H., Lewis, R. J., et al. 107, 497503. Also, after advances in gene targeting and gene editing, it is possible to specifically modify the rat genome to produce knockouts and knockins, further enhancing our understanding of human disease through the development of powerful customized CRISPR rat models. Importantly, the pain appears to be spontaneous, with no identifiable stimulus. Exp. Neuron 54, 379386. 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). Eur. The rodent is restrained and the hind paw (or tail) is placed between a pointed probe tip and flat surface. The thermal probe test: a novel behavioral assay to quantify thermal paw withdrawal thresholds in mice. Neurosci. 43, 244258. (2016). The most common case of bias is a result of non-response. Diabetes Res. The manual Von Frey tests enable quantification of mechanical thresholds in unrestrained animals, which removes the risk of handling-induced stress. doi: 10.1371/journal.pone.0039765, Brenner, D. S., Golden, J. P., Vogt, S. K., and Gereau, R. W. (2015). doi: 10.1021/je00019a016, Viscardi, A. V., Hunniford, M., Lawlis, P., Leach, M., and Turner, P. V. (2017). doi: 10.1016/j.joca.2016.05.022, PubMed Abstract | CrossRef Full Text | Google Scholar, Allchorne, A. J., Broom, D. C., and Woolf, C. J. Methods 219, 4151. doi: 10.1152/physrev.00025.2008, Santos-Nogueira, E., Redondo Castro, E., Mancuso, R., and Navarro, X. An additional advantage of the acetone drop test is the unilateral application of the thermal stimulus, enabling comparison to the contralateral side in unilateral models, and a perhaps more ethical stimulus in bilateral models. Curr. Spinal processing of noxious and innocuous cold information: differential modulation by the periaqueductal gray. Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review. An estimated 71% of all NIH grant applications from 2008 to 2015 mentioned the keywords mus musculus, mouse, or mice. To obtain reliable data, animals need to be habituated to the restraint method and experimental apparatus, which can become very time-intensive. 37, 18351841. This sample group should include individuals who are relevant to the survey's topic. Pain 47, 211220. The software records the duration of different behavior types, including movement, grooming and rearing behaviors. Anim. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats. 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. (2011). At least six responses around the estimated threshold are required for optimal calculation of the 50% threshold (Dixon, 1980). (2016). Scientists recovered most of the Christmas Island rat's genome. 52, 34703478. (2009). To address this, a modified Hargreaves test has been reported, that utilizes a feedback-controlled radiant heat source to apply a constant temperature to the hind paw. What are some disadvantages of using Wistar rats in research and some disadvantages in using rats over mice in general? But the missing genes signal a problem for using gene editing to de-extinct species. doi: 10.1016/j.jpain.2009.01.325, Yamamoto, K., Tsuboi, M., Kambe, T., Abe, K., Nakatani, Y., Kawakami, K., et al. Accordingly, as pain cannot be directly measured in rodents, it has been necessary to develop indirect methods to quantify and evaluate pain-like behaviors in non-anesthetized animals which are reliable, reproducible, sensitive and specific (Mogil, 2009). J. Pharmacol. This continues until at least four readings are obtained after the first change of direction. Their brains are larger than mice, and the animals are less timid and more intelligent. doi: 10.1371/journal.pone.0104458, Minett, M. S., Quick, K., and Wood, J. N. (2011). Eur. While not in routine clinical use, quantitative sensory testing has the potential to improve patient outcomes by classifying pain based on the mechanism and choosing treatments that target that mechanism (Baron et al., 2010; Cruz-Almeida and Fillingim, 2014). Disord. (B) Burrowing assay. Am. Clin. Significant progress was made in 2008 by Professor Austin Smiths lab at Cambridge, and Professor Qi-Long Yings lab at the University of Southern California with the first targeting of rat ES cells achieved. For people who choose to own rats at home, here are some of the benefits that they can receive: Rats are very intelligent animals. Behaviors that are analyzed include locomotive activity (still, walking, trotting, running), distance traveled, velocity, grooming, posture, eating/drinking and foraging. Exp. 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. The test is carried out on mesh floor and acetone is dabbed or sprayed on the plantar surface of the hind paw (Figure 4A), eliciting cooling of the skin to innocuous temperatures of 1521C (Colburn et al., 2007; Leith et al., 2010), although the actual temperature varies with ambient temperature, skin temperature, and the amount of acetone applied. Braz. 30, 49334942. (2002). Using the Mouse Grimace Scale to reevaluate the efficacy of postoperative analgesics in laboratory mice. PLoS One 10:e0125822. Robinson, I., Sargent, B., and Hatcher, J. P. (2012). The mouse with a human ear on its back may have been one of the more bizarre and visually unsettling experiments carried out on a rodent, but mice have been used for scientific experiments since. 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). Nonetheless, the thermal probe test remains to be validated in other pain models that cause more pronounced mechanical allodynia. In the conventional hot plate test, an unrestrained mouse or rat is placed on a metal surface maintained at a constant temperature, usually between 50C and 55C, and the response latency, which is the time taken to observe a nocifensive behavior, is recorded by the investigator (Figure 3B). Temperature 3, 7791. Berryman, E. R., Harris, R. L., Moalli, M., and Bagi, C. M. (2009). Sci. The device automatically records the force at which paw withdrawal occurs and the rate at which the force is applied can be changed. 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. 39, 18811890. ACS Chem. 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. A modified Hargreaves method for assessing threshold temperatures for heat nociception. Woolf, C. J., and Mannion, R. J. doi: 10.1097/NNR.0000000000000082, Gritsch, S., Bali, K. K., Kuner, R., and Vardeh, D. (2016). doi: 10.1016/j.jphs.2016.01.006, Yeomans, D. C., Pirec, V., and Proudfit, H. K. (1996). Cerebral palsy. It has since been applied to a variety of species, to leverage similarities between the brains of humans and different animals. A wide variety of other species make up the remaining 4%, from . Using the mouse grimace scale to assess pain associated with routine ear notching and the effect of analgesia in laboratory mice. 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. For detailed protocols of these methods see Minett et al. 11, 821830. Methods 224, 4857. 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). 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. Response latencies in the tail-flick test depend on tail skin temperature. 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. Simmons has worked as a freelance writer since 2009. 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. (2014). However, the majority of human subjects report cold pain upon cooling to at least 22C (Defrin et al., 2002; Ltsch et al., 2015). Facial expressions of mice can be used to score the subjective intensity of pain. The Behavioral Spectrometer (Behavioral Instruments) is purpose built apparatus consisting of an enclosed box (~30 30 30 cm) with a ceiling-mounted fish-eye lens, accelerometer and a row of wall-mounted photobeams (Figure 6E). 524, 107110. 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. Arch. The experiment begins by testing the response to a filament estimated to be close to the 50% withdrawal threshold. In contrast to CPN, which is more common in males, nephrocalcinosis is more common in female rats. 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. Pain 154, 19992006. A burrow filled with a suitable substrate (such as food pellets, sand, or marbles) is made from a long tube sealed at one end, secured and lifted by screws on the other end to prevent non-burrowing behaviors from displacing the substrate inside (Figure 6B). The sequence of outcomes ( for no response or + for response) is recorded and later used to calculate the 50% withdrawal threshold. Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. Monofilaments of differing forces are applied perpendicularly to the hind paw. 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). queen creek volleyball schedule, large batch sizes limit the ability to preserve options, was sam elliott the marlboro man,
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