Rice JE 3rd, Vannucci RC, Brierley JB. (B) Cold plantar assay. (2007). Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: behavioral evidence. The hypoxia-ischemia model, first published in 1981, has brain damage similar to that observed in cerebral palsy patients. The Kantian view denies moral value to animals because they lack reason. (2013). 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. Because of its simplicity, systematic sampling is popular with researchers. Burrhus Frederic Skinner, also known as B.F. Skinner, is considered the "father of Operant Conditioning.". 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. doi: 10.1523/JNEUROSCI.2203-07.2007, Yalcin, I., Charlet, A., Freund-Mercier, M. J., Barrot, M., and Poisbeau, P. (2009). (A) The up-down method. The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. (2014). (2016). Accordingly, dynamic weight bearing or gait analysis may provide similar data without the need for extensive animal and experimenter training. The same methods that allow this to be so in mice have failed in rats. Pain Headache Rep. 18:456. doi: 10.1007/s11916-014-0456-x, Jensen, T. S., and Finnerup, N. B. Mol. Of acute wounds, burns are one of the most devastating injuries known to mankind. In fact, over 90% of test subjects are mice, birds and rats. Similarities in pain descriptions of four different ethnic-culture groups. doi: 10.1126/science.1108609, Morgan, D., Mitzelfelt, J. D., Koerper, L. M., and Carter, C. S. (2012). 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.jpain.2013.06.008, Griffioen, M. A., Dernetz, V. H., Yang, G. S., Griffith, K. A., Dorsey, S. G., and Renn, C. L. (2015). 4:51. doi: 10.3389/fvets.2017.00051, Vissers, K., and Meert, T. (2005). Sci. doi: 10.1016/j.jneumeth.2004.07.005, Hargreaves, K., Dubner, R., Brown, F., Flores, C., and Joris, J. In contrast to CPN, which is more common in males, nephrocalcinosis is more common in female rats. Sci. This problem can be overcome by restraining the rodent and only placing the plantar surface of a one hind paw on the metal surface and recording the time to withdrawal, however this method requires significant handling and associated stress (Menndez et al., 2002). J. Neurosci. JRD, LSD and IV contributed to the preparation, revision and approval of the final manuscript. Behavioral and physiological methods for early quantitative assessment of spinal cord injury and prognosis in rats. N Y Acad. Rodents are placed individually in small cages with a mesh or barred floor. 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. However, it is unclear to what degree changes in gait in rodent models reflect altered pain or nociception, or conversely, anti-nociception or analgesia. Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. 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). Diabetes Res. DAmour, F. E., and Smith, D. L. (1941). Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice. Eur. Pain Med. 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. Invest. Lancet Neurol. 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. 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. In the process of finding a cure, the development of medicines to treat cerebral palsy is hampered by incomplete understanding of the conditions earliest stages, when the brain first responds to an injury. J. Med. Experimenters experienced in the technique are able to distinguish between touch on or false positive responses, however, this can be difficult for inexperienced researchers and extensive training is usually required to produce high quality data. Anim. The CatWalk method: assessment of mechanical allodynia in experimental chronic pain. Lab. Ther. doi: 10.1016/S1474-4422(10)70143-5, Bautista, D. M., Siemens, J., Glazer, J. M., Tsuruda, P. R., Basbaum, A. I., Stucky, C. L., et al. Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. Methods 87, 185193. To quantify temperature sensitivity, the time the animal spends on the test plate relative to the reference plate is measured over a set period and is then compared to control animals. Therefore, the results of the survey will be skewed to reflect the opinions of those who visit the website. 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). 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. TRPM3 is a nociceptor channel involved in the detection of noxious heat. doi: 10.1016/0304-3959(91)90207-e, Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M., and Yaksh, T. L. (1994). Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice. Assoc. 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. Adams, B. L., Guo, W., Gors, R. T., and Knopp, K. L. (2016). An additional confounding factor in the hot plate test is the tendency for learned behavioral responses, which lead to diminished reaction times during subsequent exposures to the hot plate (Gamble and Milne, 1989; Plone et al., 1996). 95% of all animals used in research are rats because their genetic, biological and behavioral characteristics are so similar to that of humans. Pharmacodyn. Exp. The clinical picture of neuropathic pain. 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. Mouse Model: Pros and Cons Ankita Das Chetana Tamadaddi Prashant Waiker Indian Institute of Science Education & Research Bhopal ; MOUSE : Mammalian model organism ; Genome Mammalian 20 chromosomes 2.6 Gb ~25000 genes 99% have human counterpart Strains Inbred Outbred Recombinant inbred Consomic Fluorescent Life Cycle 4-day oestrus 20-day gestation 4-8 pups per litter 2 . It should be noted that the absolute values obtained using manual and electronic Von Frey can differ significantly. (E) Behavioral Spectrometer (Behavioral Instruments). Rats as Pets Pros and Cons - HRF This falls into one of five main categories: Computer or gaming addiction. 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). 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). (2002). Twitter Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. Nat. 16 Integral Pros and Cons of Animal Experimentation 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). Colver A, Fairhurst C, Pharoah PO. (2014). Pain 10, 767773. Neurosci. The benefits and limitations of animal models for translational Interested in using rats for your next research project? 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. The only way to achieve 100 percent accurate results is to survey every single person who uses kitchen cleaners; however, as this is not feasible, you will need to survey as large a sample group as possible. Email: inquiry@genetargeting.com (2011). (B) Continuous temperature gradient assay. Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. Rep. 5:14648. doi: 10.1038/srep14648. Neurosci. When rodents are unwell, the amount of material removed from the burrow is decreased. Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration. BMC Musculoskelet. In addition, the Hargreaves test enables quantification of heat thresholds in unrestrained animals, reducing the likelihood of stress-induced responses. Circadian pattern of spontaneous behavior in monarthritic rats: a novel global approach to evaluation of chronic pain and treatment effectiveness. Nociceptors: the sensors of the pain pathway. 86, 284288. Mol. ACS Chem. Facial expressions of mice can be used to score the subjective intensity of pain. Mouse Biol. As each researcher cultivates a slightly different cut off point in their minds as to what constitutes a behavior on this spectrum, results can vary significantly between laboratories. Eur. It also demonstrates two additional concepts, originally outlined by Pavlov. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. The LabSand Option. doi: 10.1172/jci42843, Dubner, R. (1983). J. Pharmacol. 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). The mouse genome is very similar to our own, making mouse genetic research particularly useful for the study of human diseases. And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. (B) The ascending stimulus method. The evaluation of the analgesic action of pethidine hydrocholoride (Demerol). Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands. (D) Thermal probe test. Sci. Nat. His experiments, conducted in what is known as "Skinner's box," are some of the most well-known experiments in psychology. doi: 10.1016/j.jpain.2013.01.770, Ogren, S. O., and Berge, O. G. (1984). [ 120] Methods 219, 4151. Different methodological approaches are used to determine mechanical sensitivity using manual Von Frey, including the up-down, ascending stimulus or percent response method, all of which will be discussed below. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Automated behavioral analysis can be performed in a dedicated apparatus (Behavioral Spectrometer, Behavioral Instruments) or in a home cage (HomeCageScan, CleverSys; PhenoTyper, Noldus), using automated video analysis, vibration sensors, photobeams, and combinations thereof. Lancet 353, 19591964. TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Wistar rats are big rats. 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). 119, 481488. Why are Rats Used in Research? | Kent Scientific However, as the animal is required to explore, habituation, time of day, and light levels may significantly affect results and diminish reproducibility (Millecamps et al., 2005; Balayssac et al., 2014). Coding of facial expressions of pain in the laboratory mouse. As pain cannot be directly measured in rodents, many methods that quantify pain-like behaviors or nociception have been developed. doi: 10.1097/fbp.0000000000000026, Banik, R. K., and Kabadi, R. A. The pressure is then increased at a constant rate until a nociceptive behavioral response is observed. 107, 497503. Protoc. doi: 10.1016/0006-8993(86)91138-8, Jirkof, P., Cesarovic, N., Rettich, A., Nicholls, F., Seifert, B., and Arras, M. (2010). Pain 3:40. doi: 10.1186/1744-8069-3-40, Pitcher, G. M., Ritchie, J., and Henry, J. L. (1999). doi: 10.1016/0024-3205(85)90227-9. Cooling of the glass leads to unilateral exposure of the hind paws to a cooled surface, the temperature of which can be determined by attaching a thermocouple probe to the glass or skin. 372, 301312. (2011). The exposure of peripheral sensory nerve endings to elevated temperatures can evoke sensations of warm, hot, or pain. The software records the duration of different behavior types, including movement, grooming and rearing behaviors. An SCN9A channelopathy causes congenital inability to experience pain. A survey posted only on its website limits the number of people who will participate to those who already had an interest in their products, which causes a voluntary response bias. 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. 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: 10.1016/0304-3959(94)90023-x, Colburn, R. W., Lubin, M. L., Stone, D. J. Jr., Wang, Y., Lawrence, D., DAndrea, M. R., et al. LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. This test is also referred to as the two-temperature choice assay or thermal place preference test and can be used to assess both cold or heat avoidance or preference (Moqrich et al., 2005). Neuropharmacology 23, 915924. This review article provides an overview, as well as discussion of the advantages and disadvantages of the most commonly used behavioral methods of stimulus-evoked and non-stimulus-evoked nociception used in rodents. Burrowing, a spontaneous and self-motivated behavior, can be used as a measure of spontaneous or non-stimulus evoked nociception in mice and rats. J. Clin. Methods 31, 7983. doi: 10.1038/nprot.2006.171, Deacon, R. M. (2006b). doi: 10.1523/JNEUROSCI.1526-05.2005, Schtt, E., Berge, O. G., Angeby-Mller, K., Hammarstrm, G., Dalsgaard, C. J., and Brodin, E. (1994). Curr. Mechanical hyperalgesia and allodynia can be further subdivided into dynamic (triggered by brushing), punctate (triggered by touch) and static (triggered by pressure). However mice are less likely to survive the hypoxia-ischemia procedure, display a wider variety of brain damage, and have dramatic strain-to-strain differences. Nocifensive behaviors include forepaw withdrawal or licking, hind paw withdrawal or licking, stamping, leaning posture and jumping (Espejo and Mir, 1993). (2006). 10:284. doi: 10.3389/fnmol.2017.00284. Given the variability in cold pain thresholds, it may be difficult to differentiate between cold allodynia and cold hyperalgesia in the clinic. The Randall-Selitto test can be performed using bench-top (e.g., Analgesy-Meter, Ugo Basile; Paw and Tail Pressure Meter; Harvard Apparatus) or hand-held devices (e.g., Paw Pressure Test Apparatus, IITC) with animals either restrained in a hammock that provides access to the hind paws, a towel, or in a plastic cone or cylinder. doi: 10.1016/j.jbspin.2004.01.010, Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., et al. If the rodent withdraws, licks or shakes the paw, it is considered to have had a positive response. The temperature preference is used as a surrogate measure of thermal aversion and aims to assess temperature preference in rodents. Three main ethical attitudes towards animals are reviewed here. 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). 96, 312317. Brain Res. Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. doi: 10.1038/nature05910, Bennett, D. L., and Woods, C. G. (2014). Ultrasonic sound as an indicator of acute pain in laboratory mice. Behavioral measures of pain thresholds. (2009). In human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. A disadvantage of systems that only use video recordings (e.g., DigiGait, GaitScan/TreadScan) is that they cannot measure paw print intensity or pressure (weight bearing parameters), which is relevant for pain models. One area where rats have contributed to major insights is the field of cerebral palsy research. 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. 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. What are some disadvantages of using Wistar rats in research and some disadvantages in using rats over mice in general? Differentiating thermal allodynia and hyperalgesia using dynamic hot and cold plate in rodents. Sci. engagement in scientific research and . As the animal is unaware of the researcher and neither needs to be restrained or trained, this technique eliminates operator subjectivity and reduces animal stress. Neuro Oncol. Sci. Lancet Neurol. Nature 444, 894898. Figure 2.Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. J. Gerontol. A behavioral and pharmacological validation of the acetone spray test in gerbils with a chronic constriction injury. Meloxicam prevents COX-2-mediated post-surgical inflammation but not pain following laparotomy in mice. Eur. Osteoarthr. People who are at work and unable to answer the phone may have a different answer to the survey than people who are able to answer the phone in the afternoon. J. Neurosci. Quantitative somatosensory testing of warm and heat-pain thresholds: the effect of body region and testing method. Animal models of pain: progress and challenges. 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. Gene editing technologies allow scientists to use rats more often in their research. In the case of researchers conducting surveys, for example, sample size is essential. Pain 22, 130136. White, V.M.D., M.S., DACLAM, Dipl. Figure 5.Temperature preference assays. The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. (2000). Animal Testing | Pros & Cons | ProCon.org 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. 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). 32, 5260. Matsumiya, L. C., Sorge, R. E., Sotocinal, S. G., Tabaka, J. M., Wieskopf, J. S., Zaloum, A., et al. 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).
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