13840110d2d515487e83b87 disadvantages of using rats in research

86, 284288. (2014). (2006). (2013). It is an estimate, as the force applied by manual von Frey filaments can only be applied in discrete steps, and not continuously like electronic von Frey (see below). The effects of morphine methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation. doi: 10.1038/nprot.2006.19, Decosterd, I., and Woolf, C. J. The clinical picture of neuropathic pain. engagement in scientific research and . J. Pharmacol. As for heat pain, these values are likely influenced by a number of factors including ambient temperature, rate of cooling and anatomical location. Non-response occurs when some subjects do not have the opportunity to participate in the survey. 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). J. Pharmacol. While the method carries the disadvantage that the rodent has to be restrained, the tail flick test is of very short duration so handling can be minimized easily. Rodents are placed individually in small enclosures with a glass floor. Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain. The larger size when compared to mice makes handling, sampling and performing procedures easier. Exp. J. Neurosci. J. LinkedIn. (B) Cold plantar assay. In addition to displaying force at which paw withdrawal occurs, the rate at which the force was applied is also displayed post-test by the software, to ensure the force ramp was applied consistently. The exposure of peripheral sensory nerve endings to elevated temperatures can evoke sensations of warm, hot, or pain. 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. 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. Irwin, S., Houde, R. W., Bennett, D. R., Hendershot, L. C., and Seevers, M. H. (1951). 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. Methods 224, 4857. Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. Typically, the sensation of warm is elicited at temperatures of 3437C, while the sensation of pain is elicited at temperatures of 4248C (Pertovaara et al., 1996; Defrin et al., 2006; Rolke et al., 2006). 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. 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). Pain 66, 265270. At least six responses around the estimated threshold are required for optimal calculation of the 50% threshold (Dixon, 1980). Methods 87, 185193. Monofilaments of differing forces are applied perpendicularly to the hind paw. A modified Hargreaves method for assessing threshold temperatures for heat nociception. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. For detailed protocols of these methods see Minett et al. Biol. Evaluation of dynamic weight bearing for measuring nonevoked inflammatory hyperalgesia in mice. However, replacement or substitution of animals for nonsentient materials is difficult in pain research due to the nature of the behavioral experiments. Wistar rats are big rats. J. Pharmacol. This book condenses information from many sources on topics related to the care and use of rats in research. In addition, welfare benefits in form of testing of unrestrained mice and exposure of only a single hind paw to a noxious heat stimulus are favorable. Characterization of the foot withdrawal response to noxious radiant heat in the rat. They have distinctive personality, which is a manifestation of their friendliness to people. The thermal probe test: a novel behavioral assay to quantify thermal paw withdrawal thresholds in mice. The most common case of bias is a result of non-response. 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). An estimated 71% of all NIH grant applications from 2008 to 2015 mentioned the keywords mus musculus, mouse, or mice. Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. (2006). (A) The up-down method. Acetylsalicylic acid, paracetamol and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin. Physiol. For people who choose to own rats at home, here are some of the benefits that they can receive: Rats are very intelligent animals. (2007). By comparing the frequencies of behaviors in animal models of pain as opposed to control states, inference about different pain states (and especially spontaneous nociception) can be made. However, it is unclear to what degree changes in gait in rodent models reflect altered pain or nociception, or conversely, anti-nociception or analgesia. Although expensive to produce and not always precise, this became the preferred method to target rats in a specific manner. Analg. Rats are often used to study behaviour in psychology experiments. Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate. J. Clin. (2017a). A method for measurement of analgesic activity on inflamed tissue. In humans, acute pain is defined as short-lasting (36 months) and is directly related to injury or tissue damage, such as a cut, burn or broken bone. doi: 10.1016/j.bbr.2008.12.018, Gamble, G. D., and Milne, R. J. Cartil. Hyperalgesia and allodynia: peripheral mechanisms. (B) Burrowing assay. Exceptionally adaptable, these rodents now inhabit almost all environments on Earth, especially near human settlements where they are often seen as pests. Ther. (2007). The rodent is restrained and the hind paw (or tail) is placed between a pointed probe tip and flat surface. (2012). They know how to use their own litter tray at home. Evaluation of the usefulness of two established pain assessment tools in a burn population. In addition, skin and ambient temperature, the location of stimulus application on the tail, as well as learnt avoidance behaviors can affect the withdrawal response (Yoburn et al., 1984; Berge et al., 1988). Methods 131, 9397. The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. doi: 10.1016/j.ejpain.2011.07.012, Ankier, S. I. doi: 10.1016/j.jneumeth.2015.08.010, Brenner, D. S., Golden, J. P., and Gereau, R. W. IV (2012). The experiment begins by testing the response to a filament estimated to be close to the 50% withdrawal threshold. Front Neurol 7: 57. Lett. This review article will provide an overview of the current behavioral methods that are used to assess pain behaviors in mice and rats. 43, 1726. Punctate mechanical allodynia and hyperalgesia can be evoked with a pinprick or monofilament, and in practice can be assessed by the application of von Frey filaments of varying forces (0.082940 mN). Rolke, R., Baron, R., Maier, C., Tlle, T. R., Treede, R. D., Beyer, A., et al. doi: 10.1016/0024-3205(84)90575-7, Zimmermann, K., Deuis, J. R., Inserra, M. C., Collins, L. S., Namer, B., Cabot, P. J., et al. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. Researchers choose rats over other species for a number of reasons: In this test, animals are placed individually in small cages with a mesh or otherwise penetrable bottom. The software records the duration of different behavior types, including movement, grooming and rearing behaviors. Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. Cybersex and pornography addiction. The HomeCageScan (CleverSys) uses automated video analysis to classify 38 pre-defined behaviors of mice in a home cage, including walking, rearing, sniffing, stretching, jumping, digging, foraging, sleeping, eating, drinking, hanging and grooming as well as distance traveled (Roughan et al., 2009). However, it is proving useful as a tool to monitor animal welfare, not only in rodents, but also in other species, with grimace scales being developed for pigs, sheep and horses (Matsumiya et al., 2012; Miller and Leach, 2015; Dalla Costa et al., 2016; Hager et al., 2017; Viscardi et al., 2017). J. Guidelines for the design and statistical analysis of experiments using laboratory animals. Rodents are placed individually in small enclosures with a glass floor. Unlike the hot plate test, the cold plate test is particularly useful for models where only one paw is affected or sensitized by the experimental compound (unilateral pain) as guarding of the affected limb can be easily achieved, and thus can be easily quantified. 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. 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. 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. 64, 8187. Science 307, 14681472. In this test, monofilaments of varying forces (in this case 0.6, 1, 1.4, 2, 4 and 6 grams-force) are applied in ascending order an equal number of times (in this case five times) and the response to each trial is recorded. doi: 10.1038/nprot.2006.171, Deacon, R. M. (2006b). Behaviors that are analyzed include locomotive activity (still, walking, trotting, running), distance traveled, velocity, grooming, posture, eating/drinking and foraging. And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. However, irrespective of the method used, the endpoint is paw withdrawal to a stimulus that is not normally aversive, and thus both methods can measure mechanical allodynia. The Wistar outbred albino rat is perhaps the most popular rat model due to its multi-purpose characteristics, making it a powerful species for medical research into infectious diseases, or as a surgical model. While several systems are commercially available, the Dynamic Plantar Aesthesiometer (Ugo Basile) and MouseMet or RatMet (TopCat Metrology) are particularly robust and user-friendly systems. J. Pharmacol. 406, 128132. The term cerebral palsy denotes a highly variable syndrome affecting up to 3 out of every 1000 children born. General adaptation syndrome was discovered accidentally by Selye whilst he was conducting experiments on rats at McGill University in Montreal, Canada. Neuropathic pain: aetiology, symptoms, mechanisms, and management. FIGURE 2 Figure 2 .Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. Reaction thresholds to pressure in edematous hindpaws of rats and responses to analgesic drugs. This test can be carried out using the same mouse enclosures as the electronic von Frey test (MouseMet) and is based on the application of a 2 mm thermal probe to the hind paw. 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. Thus, pain is an experience that encompasses both sensory and emotional components; therefore the term pain is not interchangeable with nociception. It should be noted that no test can therefore measure pain in animals directlythe presumably unpleasant emotional experience of pain is inferred from pain-like behaviors which can include the withdrawal of a body part from a stimulus, reduced ambulation, agitation, an increase in grooming of the affected area, and vocalizations upon sensory stimulation. Click the button below to get a quote! 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. 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). (2006). 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. It is the premier source of information on the laboratory rat. 67, 705713. A burrow is placed in the cage of a rodent filled with a suitable substrate (such as food pellets, sand, or marbles). The Rat Grimace Scale is able to detect spontaneous pain induced by intraarticular kaolin-carrageenan, intraplantar Complete Freunds Adjuvant (CFA), and post-surgical pain. Mol. The first (1880-1950) was when mice and rats became common research animals. (2015). It has since been applied to a variety of species, to leverage similarities between the brains of humans and different animals. In the case of researchers conducting surveys, for example, sample size is essential. 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 human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. Some results suggest that the rat more accurately reflects human physiology than other species, mimicking human disease more accurately in many cases. Sci. Med. Optimization of the mechanical nociceptive threshold testing with the Randall-Selitto assay. The device automatically records the force at which paw withdrawal occurs and the rate at which the force is applied can be changed. Assessing hoarding in mice. Key Takeaways. Rev. They helped shape the ideas of operant conditioning in behaviorism. 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. 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). doi: 10.1038/nrn2606, Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., et al. 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. Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine. 14:14. doi: 10.1186/1471-2474-14-14, Pertovaara, A., Kauppila, T., and Hmlinen, M. M. (1996). She specializes in business, consumer products, home economics and sports and recreation. 52, 34703478. 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. (B) Electronic von Frey (MouseMet, TopCat Metrology). This continues until at least four readings are obtained after the first change of direction. | All rights reserved. In fact, it is a requirement for publication of in vivo data in high quality journals that relevant standards and guidelines are strictly adhered to (McGrath et al., 2010). J. Med. Rats are an ideal choice for many labs due to their physiological similarity to humans. Nat. (D) Thermal probe test. 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. Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: doi: 10.1016/j.pain.2006.01.041, Roughan, J. V., Bertrand, H. G., and Isles, H. M. (2016). 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. 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. Efficacy of drugs with different mechanisms of action in relieving spontaneous pain at rest and during movement in a rat model of osteoarthritis. 5, 94100. Winter, C. A., and Flataker, L. (1965). Rodent models of cerebral palsy have been studied for almost forty years to fill the gaps in our knowledge, hopefully pointing the way to future treatments. Pain 7:55. doi: 10.1186/1744-8069-7-55, Tappe-Theodor, A., and Kuner, R. (2014). Research scientists worldwide agree that the use of rat models for disease research and experimentation has become more relevant in the past few years. Protoc. Depending on the species and strain of rodent used, at least 12 different behaviors have been noted in the hot plate test, including sniffing, grooming, stamping of the legs, freezing, licking, leaning and jumping (Espejo and Mir, 1993). Sci. Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. Non-response occurs when some subjects do not have the opportunity to participate in the survey. The same methods that allow this to be so in mice have failed in rats. Email: [email protected] An organisms response to nociception and the subsequent antinociceptive treatment is likewise varied, creating a need for a reliable way to assess pain levels and prospective treatments despite this variation. 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. When pain continues beyond the expected time of wound healing or without a clear reason, it is termed chronic pain. (1988). doi: 10.1016/j.neulet.2012.07.017. Figure 6.Methods used to assess non-stimulus evoked pain behaviors in rodents. There are protections in place for the animals. 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). Ultrasonic sound as an indicator of acute pain in laboratory mice. To conduct a survey properly, you need to determine your sample group. (1957). Sci. Coding of facial expressions of pain in the laboratory mouse. 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). 101, 132143. doi: 10.1016/j.jneumeth.2013.12.010, Bryden, L. A., Nicholson, J. R., Doods, H., and Pekcec, A. Am. The pressure is increased until withdrawal or vocalization occurs. Therefore, there is an urgent need to increase our understanding of the underlying mechanisms of pain and to develop new treatments. 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. Neurosci. The Kantian view denies moral value to animals because they lack reason. Meloxicam prevents COX-2-mediated post-surgical inflammation but not pain following laparotomy in mice. Temperature 3, 199207. Nat. 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. While the underlying protocols and principles are different, it remains to be determined if electronic Von Frey activates a different subset of sensory neurons compared to manual Von Frey (e.g., high-threshold vs. low threshold mechanoreceptors). Neurosci. Anim. 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. The sequenced genome will also unveil new targets for drug intervention. 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. Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target. Many of these original stocks harbored a variety of natural, or indigenous, pathogens. Despite the development of electronic Von Frey tests, manual Von Frey remains the gold standard for determining mechanical thresholds in mice. 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). 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). Exp. doi: 10.1111/pme.12230, Dalla Costa, E., Stucke, D., Dai, F., Minero, M., Leach, M. C., and Lebelt, D. (2016). 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. Eur. doi: 10.1093/gerona/glr210, OBrien, D. E., Brenner, D. S., Gutmann, D. H., and Gereau, R. W. IV (2013). Pharmacol. 4:165. doi: 10.3389/fnbeh.2010.00165, Kayser, V., and Christensen, D. (2000). 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. ILAR J. 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). Rodents are commonly used to study the pathophysiological mechanisms of pain as studies in humans may be difficult to perform and ethically limited. Behavioral measures of pain thresholds. Methods Mol. 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). Using the horse grimace scale (HGS) to assess pain associated with acute laminitis in horses (Equus caballus). 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. Similarities in pain descriptions of four different ethnic-culture groups. doi: 10.1016/s0304-3959(96)03176-4, Yeomans, D. C., and Proudfit, H. K. (1994). However, in practice it is difficult to distinguish between allodynia and hyperalgesia in animals, and the terms allodynia and hyperalgesia are often used incorrectly or interchangeably in the literature. Methods 31, 7983. Int. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Lancet 353, 19591964. doi: 10.1016/0006-8993(86)91138-8, Jirkof, P., Cesarovic, N., Rettich, A., Nicholls, F., Seifert, B., and Arras, M. (2010). This falls into one of five main categories: Computer or gaming addiction. 34, 17551762. Protoc. LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. What are some disadvantages of using Wistar rats in research and some disadvantages in using rats over mice in general? Pain 32, 7788. 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. (2005). Br. A modified version of the thermal probe test suitable for quantifying heat thresholds in rats is still to be developed. (2012). 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). 39, 16131623. Osteoarthr. So far, no single behavioral assay can capture the full spectrum of nociception in non-communicating subjects. 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. 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. Studying ongoing and spontaneous pain in rodentschallenges and opportunities. Using the mouse grimace scale to assess pain associated with routine ear notching and the effect of analgesia in laboratory mice. These techniques provide an insight into how sensitive to cold temperatures the animal is, and thus provides an indirect measure of cold-induced hyperalgesia and allodynia. 7. 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. 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). 95% of all animals used in research are rats because their genetic, biological and behavioral characteristics are so similar to that of humans. 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 historic struggle against pathogens of laboratory rodents is often divided into three periods. (2013). Interested in using rats for your next research project? The mouse has many similarities to humans in terms of anatomy, physiology and genetics. 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). Neurosci. Behavioural research shows rats are more suited to studies on learning and cognition because they are more capable of learning tasks than other species. In the Mouse Grimace Scale (Figure 6A), five facial features are scored: orbital tightening, nose bulge, cheek bulge, ear position, and whisker position (Langford et al., 2010). Of acute wounds, burns are one of the most devastating injuries known to mankind. Methods 53, 5563. 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. J. Toxicol. Rice JE 3rd, Vannucci RC, Brierley JB. The manual Von Frey test, developed by the physiologist Maximilian von Frey, is a method of evaluating mechanical allodynia in mice and rats.

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