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. 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). Sensitivity to cold is recorded either by quantifying the number or duration of nocifensive responses, or scoring of the severity of the response (e.g., 0, no response; 1, brisk withdrawal or flick of the paw; 2, repeated flicking of the paw; 3, repeated flicking of the hind paw and licking of the paw; Colburn et al., 2007; Xing et al., 2007). While validated using an incisional model of pain in rats, this method takes longer to perform than the normal Hargreaves test and is not available to purchase commercially. 27, 1368013690. (2014). Mouse Biol. Rat models are therefore still widely used. 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. Neurosci. Rev. This therefore provides measure of paw withdrawal threshold on a continual scale, as the force is applied continuously and not in steps. 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. Mol. Closely related to the last point is the subject of digital addiction. 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). Berryman, E. R., Harris, R. L., Moalli, M., and Bagi, C. M. (2009). 10, 283294. J. Neurosci. Burns 43, 304309. 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. A notable shift has taken place over the last two decades, with mice taking a more and more prominent role in biomedical science compared to rats. 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. Unequal weight distribution between the ipsilateral and contralateral paw are interpreted as a natural adjustment to the degree of nociception experienced, and have been observed in a number of models including monosodium iodoacetate (MIA)-induced osteoarthritis, bone cancer-induced pain, carrageenan-induced inflammation and sciatic nerve crush injury (Schtt et al., 1994; Medhurst et al., 2002; Bove et al., 2003; Buys and Alphonso, 2014). This work was supported by an Australian Research Council Future Fellowship (IV). 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. Neuropathic pain: aetiology, symptoms, mechanisms, and management. doi: 10.1016/j.jneumeth.2013.12.010, Bryden, L. A., Nicholson, J. R., Doods, H., and Pekcec, A. Methods Mol. This sample group should include individuals who are relevant to the survey's topic. 43, 1726. is defined as the deposition of in renal tissue, although a variety of additional terms are sometimes employed to reflect the localization of the mineral in the cortex, medulla, and so on. It is a low-cost, single-use product made from sterilized quarry sand and treated with a hydrophobic coating. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. 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. Sci. To evaluate thermal sensitivity, the time taken to settle in a temperature zone, as well as the temperature of the chosen zone, can be compared to control animals. Evaluation of the usefulness of two established pain assessment tools in a burn population. And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. Pain 9, 445452. 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). PLoS One 9:e104458. Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. Some of these behaviors can be sensitive to analgesics, although differences are observed depending on the type of behavior quantified. Exp. Pain 59, 369376. Pharmacol. 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. doi: 10.1016/s1474-4422(14)70102-4, Jensen, T. S., Gottrup, H., Sindrup, S. H., and Bach, F. W. (2001). Monkeys, rabbits, cats, ferrets, pigs, sheep and chimpanzees are just some of the animals used for biomedical experiments, science education, and product and cosmetics testing. Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. Rep. 5:14648. doi: 10.1038/srep14648. Research scientists worldwide agree that the use of rat models for disease research and experimentation has become more relevant in the past few years. It has since been applied to a variety of species, to leverage similarities between the brains of humans and different animals. The term nociception was coined by Charles Sherrington in the early 1900s to distinguish the sensation of paina result of central nervous system processingfrom the physiological phenomenon of the peripheral nervous system responding to potential harmful stimuli (Dubner, 1983; Coutaux et al., 2005). At least six responses around the estimated threshold are required for optimal calculation of the 50% threshold (Dixon, 1980). Increasing temperatures are applied for 10 s from 35C to 70C in intervals of 2.5C until a paw withdrawal behavior is observed (Banik and Kabadi, 2013). Pain 1:36. doi: 10.1186/1744-8069-1-36, Andrews, N., Legg, E., Lisak, D., Issop, Y., Richardson, D., Harper, S., et al. Anim. A.E. Sci. J. Water heated to 30C and applied the same way is usually used as a control (Carlton et al., 1994; Choi et al., 1994). 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. doi: 10.1016/s0165-0270(99)00004-7, Plone, M. A., Emerich, D. F., and Lindner, M. D. (1996). Lab. A radiant or infrared heat source is positioned underneath the animal and aimed at the plantar surface of the hind paw (Figure 3C). Behav. Rats are an ideal choice for many labs due to their physiological similarity to humans. 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. doi: 10.1089/neu.2010.1700, Scholz, J., Broom, D. C., Youn, D. H., Mills, C. D., Kohno, T., Suter, M. R., et al. doi: 10.1097/BCR.0b013e3182033359. It is a universal human experience that in the short term serves to protect an individual from harm, but in the long term can become a debilitating condition. Rumajogee P, Bregman T, Miller SP, Yager JY, Fehlings MG. 2016. 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. Brain Res. Mol. February 8, 2018| Kristen Coughlin | CRISPR, Rat Models, Last Updated on January 23, 2023 by ingenious. Sci. TRPM8 mechanism of cold allodynia after chronic nerve injury. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. Mechanical hyperalgesia and allodynia can be further subdivided into dynamic (triggered by brushing), punctate (triggered by touch) and static (triggered by pressure). doi: 10.1016/j.ejphar.2014.05.048, Jacobs, B. Y., Kloefkorn, H. E., and Allen, K. D. (2014). Nose bulge refers to the bulge noticeable on the bridge of the nose, whereas cheek bulge refers to the rounded projection of the cheek muscle compared to its typical appearance. (2006). J. Musculoskelet. doi: 10.1038/nrn2606, Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., et al. Researchers can now design experiments around the biological questions rather than the limitations of their animal model. Irwin, S., Houde, R. W., Bennett, D. R., Hendershot, L. C., and Seevers, M. H. (1951). doi: 10.1080/23328940.2016.1157668, Deuis, J. R., Whately, E., Brust, A., Inserra, M. C., Asvadi, N. H., Lewis, R. J., et al. 51, 4249. This alleviates the mosaicism common with targeting embryos, allowing for the production of specifically targeted germline rats in as little as 3 months. (B) Burrowing assay. 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). 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 . J. 104, 495502. For example, paw licking is diminished by opioids but not other analgesics, while other behaviors can also be affected by other classes of analgesics (Ankier, 1974; Hunskaar et al., 1985). PLoS One 12:e0175839. Brain Res. 3. The sheep grimace scale as an indicator of post-operative distress and pain in laboratory sheep. doi: 10.1002/ejp.871, Roughan, J. V., Wright-Williams, S. L., and Flecknell, P. A. The up-down method is practically limited by commercial filaments that are not equally spaced (therefore, the average increment is used for d), incorrect labeling of the force in log units, and the need for the first filament to be close to the mean threshold (which may be unknown; Bradman et al., 2015). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. doi: 10.1016/0166-4328(93)90035-o, Festing, M. F., and Altman, D. G. (2002). Rodents are placed individually in small enclosures with a glass floor. Pain 7:55. doi: 10.1186/1744-8069-7-55, Tappe-Theodor, A., and Kuner, R. (2014). Lab. Rep. 7:40883. doi: 10.1038/srep40883, Deuis, J. R., Yin, K., Cooper, M. A., Schroder, K., and Vetter, I. Behav. 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. Characterization of the foot withdrawal response to noxious radiant heat in the rat. A behavioral and pharmacological validation of the acetone spray test in gerbils with a chronic constriction injury. Facebook Sample size determination. Gene editing technologies allow scientists to use rats more often in their research. Key Takeaways. Both instruments have been validated against manual von Frey filaments and found to produce less variable data in addition to being easier to use. Coding of facial expressions of pain in the laboratory mouse. 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). doi: 10.1146/annurev.pa.20.040180.002301, Dubin, A. E., and Patapoutian, A. Similarities in pain descriptions of four different ethnic-culture groups. 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). 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). Eur. doi: 10.1258/la.2008.007156, Sandkhler, J. In humans, spontaneous or background pain is pain that occurs without an identifiable stimulus. 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. Cerebral palsy. Because of its simplicity, systematic sampling is popular with researchers. doi: 10.1016/s1063-4584(03)00163-8, Bradman, M. J., Ferrini, F., Salio, C., and Merighi, A. Weight bearing as an objective measure of arthritic pain in the rat. 1, 28282830. Eur. The time taken to settle in a temperature zone and/or the temperature of the chosen zone is recorded. Figure 4.Methods used to assess cold-evoked pain like behaviors and temperature preference in rodents. Nat. Therefore, the results of the survey will be skewed to reflect the opinions of those who visit the website. She specializes in business, consumer products, home economics and sports and recreation. doi: 10.1002/art.21403, Miller, A. L., and Leach, M. C. (2015). The behavioral methods used to measure nociception in rodents can be divided into stimulus-evoked (and further subdivided by the stimulus modalitymechanical, heat, cold) and non-stimulus evoked, with the most commonly used methods discussed in this review article. A wide variety of other species make up the remaining 4%, from . 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. As the test is performed in relatively unrestrained rodents, it relies heavily on the animal freely taking up the correct stance, which can be difficult to achieve in mice. The most common case of bias is a result of non-response. 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). However, with the use of animal models come challenges relating to the appropriate quantification of behavioral responses that could be considered equivalent to pain in humans. Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: J. For an overview of commonly used pain models in rodents see Gregory et al. opportunities for species-specific behaviour), handling, procedures at daytime in nocturnal species, changes in groups for randomization, and too many male animals caged together. 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. Some of these parameters are altered in rodent models of pain, making gait analysis a method that is increasingly used to quantify non-stimulus evoked or spontaneous nociception in rodents. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Cartil. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Neurosci. Eur. Clin. 198, 477480. Rotation of the handle of the hand-held device initiates heating from room temperature to 60C at a rate of 2.5C/s, which is terminated automatically by paw withdrawal, removal of the probe from the paw by the operator, or on reaching a predetermined cut-out (usually 60C; Figure 3D). Front. (E) Behavioral Spectrometer (Behavioral Instruments). The device automatically records the temperature that paw withdrawal occurred (in this case 50C). Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice. However, replacement or substitution of animals for nonsentient materials is difficult in pain research due to the nature of the behavioral experiments. doi: 10.1097/01.ajp.0000154048.68273.d8, Dell, R. B., Holleran, S., and Ramakrishnan, R. (2002). Ann Neurol 9(2): 131-41. doi: 10.1016/j.jpain.2013.01.770, Ogren, S. O., and Berge, O. G. (1984). Received: 04 April 2017; Accepted: 22 August 2017; Published: 06 September 2017. (2013). doi: 10.1016/0304-3959(92)90041-9, Knowlton, W. M., Bifolck-Fisher, A., Bautista, D. M., and McKemy, D. D. (2010). A number of parameters are automatically analyzed by the software, including paw intensity, print area, stance phase duration (time spent on paw) and swing phase duration (time spent off paw). A novel behavioral assay for measuring cold sensation in mice. Woolfe, G., and Macdonald, A. D. (1944). This falls into one of five main categories: Computer or gaming addiction. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. doi: 10.1007/bf00230429, Petrus, M., Peier, A. M., Bandell, M., Hwang, S. W., Huynh, T., Olney, N., et al. 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). 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. In this test, the unrestrained mouse or rat is placed on a metal surface starting at a non-noxious temperature (<42C), and the temperature is increased at a constant rate until a nocifensive behavior is observed. Sci. 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). Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Res. 160, 15731576. Third, aversive response to a cooling ramp can be used to determine the cold response threshold (Yalcin et al., 2009). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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). Mol. Pain cannot be directly measured in animals; instead pain is inferred from pain-like behaviors, such as withdrawal from a nociceptive stimulus, which is the most commonly used method to quantify nociception in animal studies. doi: 10.1523/JNEUROSCI.2203-07.2007, Yalcin, I., Charlet, A., Freund-Mercier, M. J., Barrot, M., and Poisbeau, P. (2009). Assessment of thermal sensitivity in rats using the thermal place preference test: description and application in the study of oxaliplatin-induced acute thermal hypersensitivity and inflammatory pain models. Mol. However, rodents do not vocalize in the audible range unless the pain is severe, making use vocalization as an endpoint ethically limited (Mogil, 2009). doi: 10.1213/01.ane.0000158471.41575.f0, Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., et al. (1991). Pain measurement: an overview. Behav. The criterion that constitutes a positive response to a filament varies between laboratories, with 20%40% withdrawal response rates over 510 applications being used typically (Scholz et al., 2005; Minett et al., 2011). Int. (2002). Alternatively, a continuous temperature gradienteither in linear (Figure 5B) or circular formcan be used to determine the preferred temperature in freely moving animals (Moqrich et al., 2005; Touska et al., 2016). (2013). Wistar rats are big rats. Adams, B. L., Guo, W., Gors, R. T., and Knopp, K. L. (2016). J. Med. (1974). 47, 810. Joint Bone Spine 72, 359371. Hyperalgesia and allodynia: peripheral mechanisms. (2016). Can quantitative sensory testing move us closer to mechanism-based pain management? 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. 13, 587599. Comparison of the antinociceptive action of and opioid receptor ligands in the periaqueductal gray matter, medial and paramedial ventral medulla in the rat as studied by the microinjection technique. (2013). White, V.M.D., M.S., DACLAM, Dipl. doi: 10.1016/0304-3940(89)90397-2, Gaston-Johansson, F., Albert, M., Fagan, E., and Zimmerman, L. (1990). Static hyperalgesia can be superficial or deep and is assessed by the application of pressure to the skin or underlying tissue by a finger or using a pressure algometer (Jensen and Finnerup, 2014). doi: 10.1016/j.jneumeth.2015.08.010, Brenner, D. S., Golden, J. P., and Gereau, R. W. IV (2012). doi: 10.1016/0304-3959(96)03048-5, Quadros, A. U., Pinto, L. G., Fonseca, M. M., Kusuda, R., Cunha, F. Q., and Cunha, T. M. (2015). Front Neurol 7: 57. Methods 53, 5563. 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. doi: 10.1213/ane.0000000000000291, Carlton, S. M., Lekan, H. A., Kim, S. H., and Chung, J. M. (1994). The study of nonhuman animals has actually played a huge role in psychology, and it continues to do so today. Sci. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Data 40, 611614.
Menü
