13840110d2d515487e83b87 disadvantages of using rats in research

Stimulus-evoked methods, which include manual and electronic von Frey, Randall-Selitto and the Hargreaves test, were the first to be developed and continue to be in widespread use. Not only does your survey suffer due to timing, but the number of subjects does not help make up for this deficiency. 4:165. doi: 10.3389/fnbeh.2010.00165, Kayser, V., and Christensen, D. (2000). Similar to the Hargreaves test, the thermal probe tests enables quantification of ipsilateral and contralateral heat thresholds in unrestrained mice, but with a shorter habituation time of 510 min. Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target. 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). (2010). A Biol. This alleviates the mosaicism common with targeting embryos, allowing for the production of specifically targeted germline rats in as little as 3 months. If an individual is on a company's website, then it is likely that he supports the company; he may, for example, be looking for coupons or promotions from that manufacturer. In practice, this test is useful for assessment of nociceptive thresholds in rats rather than mice as animals need to be heavily physically restrained with the tested paw held out, and mice rarely tolerate such handling (Anseloni et al., 2003; Minett et al., 2011; Santos-Nogueira et al., 2012). The manual Von Frey test, developed by the physiologist Maximilian von Frey, is a method of evaluating mechanical allodynia in mice and rats. A number of endpoints can be obtained from the cold plate test, similar to the hot plate test. N Y Acad. 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. J. Pain 50, 355363. 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). 39, 18811890. (2011). Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. The main advantage of electronic Von Frey compared to manual Von Frey is that an increasing force is applied by a single filament. Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice. (2015). (2014). Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. doi: 10.1016/0024-3205(85)90227-9. ILAR J. In mice, ES cells can be maintained in their pluripotent state easily. Researchers can now design experiments around the biological questions rather than the limitations of their animal model. As pain cannot be directly measured in rodents, many methods that quantify pain-like behaviors or nociception have been developed. 53, 2428. Xing, H., Chen, M., Ling, J., Tan, W., and Gu, J. G. (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. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. In this assay rodents walk freely across an enclosed elevated glass floor. 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. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. doi: 10.1523/JNEUROSCI.0122-10.2010, Ltsch, J., Dimova, V., Lieb, I., Zimmermann, M., Oertel, B. G., and Ultsch, A. Thus, the term nociception is used to describe the peripheral neuronal response to noxious stimuli, which encompasses any stimuli, being mechanical, thermal, electrical or chemical, that have the potential to damage are damaging to tissue (Dubin and Patapoutian, 2010). 406, 128132. Protoc. The Dynamic Plantar Aesthesiometer (or Plantar Von Frey), houses rodents in an enclosure with a mesh screen floor, under which a movable touch-stimulator unit is placed. 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. Behavioral and physiological methods for early quantitative assessment of spinal cord injury and prognosis in rats. Arch. (2015). Mol. J. Pharmacol. Lab. 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). 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). (B) Hot plate test. Despite some degree of uncertainty about the validity of the anthropomorphization of pain in animals, the capacity to experience pain and distress, particularly resulting from procedures or conditions that would cause pain and distress in humans, must be assumed unless there is evidence to the contrary. 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. 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. 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. And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. Development of a piglet grimace scale to evaluate piglet pain using facial expressions following castration and tail docking: a pilot study. (2012). The temperature preference is used as a surrogate measure of thermal aversion and aims to assess temperature preference in rodents. doi: 10.1007/bf00230429, Petrus, M., Peier, A. M., Bandell, M., Hwang, S. W., Huynh, T., Olney, N., et al. Pain 9, 445452. doi: 10.1016/S0014-2999(01)01302-4, Jensen, T. S., and Yaksh, T. L. (1986). The hot plate test, first described in 1944, can be used to determine heat thresholds in mice and rats (Woolfe and Macdonald, 1944). Pharmacodyn. 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. Similarly, it overcomes some of the experimental difficulties of static weight bearing analysis, albeit no information on gait can be obtained. - Quora Answer: I'm going to answer this purely from the point of view of toxicology studies, because that's where my experience is. Am. Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. The Kantian view denies moral value to animals because they lack reason. J. Neurosci. 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). The term cerebral palsy denotes a highly variable syndrome affecting up to 3 out of every 1000 children born. Reaction thresholds to pressure in edematous hindpaws of rats and responses to analgesic drugs. (2014). Neuron 70, 482494. Their brains are larger than mice, and the animals are less timid and more intelligent. Coding of facial expressions of pain in the laboratory mouse. doi: 10.1093/neuonc/nou048, Deuis, J. R., and Vetter, I. 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. Advantages of the cold plate test are its relative speed and the ability for accurate temperature control. doi: 10.1371/journal.pone.0175839, Han, J. S., Bird, G. C., Li, W., Jones, J., and Neugebauer, V. (2005). (A) Tail flick test (radiant heat). Lancet Neurol. Several commercial automated gait analysis systems have been developed, including the CatWalk XT (Noldus) and GaitLab (ViewPoint Behavior Technology), which use internally reflected light to illuminate paw prints as an animal walks across an elevated glass floor (Figure 6D), and DigiGait (Mouse Specifics Inc.) and GaitScan/TreadScan (CleverSys), which use video recordings and automated software to analyze paw prints of animals walking on a transparent belt treadmill or clear floor walkway (Berryman et al., 2009; Parvathy and Masocha, 2013; Adams et al., 2016). ingenious was very competitively priced compared to other reputable transgenic companies. (2017b). 1020, 215221. The most common case of bias is a result of non-response. One area where rats have contributed to major insights is the field of cerebral palsy research. Cartil. 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. doi: 10.1172/jci42843, Dubner, R. (1983). (2005). 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. A.E. 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). 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). 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. Although animal models of pain have undoubtedly provided key advances, the advantages and disadvantages of each model and behavioral test should be taken into account to obtain objective and meaningful results that will improve our understanding and management of pain. 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). 130, 117122. The larger size when compared to mice makes handling, sampling and performing procedures easier. Phenotypic changes in diabetic neuropathy induced by a high-fat diet in diabetic C57BL/6 mice. [ 120] Sci. (2006). 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. Quantitative somatosensory testing of warm and heat-pain thresholds: the effect of body region and testing method. These values are not absolute, as heat thresholds are influenced by the ambient temperature, rate of heating (110C/s), the type (hairy or glabrous) and location of test skin, method of heat transfer, experimental design and skin temperature (for radiant heat only; Pertovaara et al., 1996; Defrin et al., 2006; Rolke et al., 2006). Analg. 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. (2014). Robinson, I., Sargent, B., and Hatcher, J. P. (2012). This research has almost exclusively used a single procedure to induce the condition in animal models. Scientists recovered most of the Christmas Island rat's genome. 25, 73177323. Assessing hoarding in mice. Pain 96, 129140. Clin. (2009). Burns 43, 304309. Therefore, the results of the survey will be skewed to reflect the opinions of those who visit the website. doi: 10.1016/s0165-0270(01)00483-6, Millecamps, M., Jourdan, D., Leger, S., Etienne, M., Eschalier, A., and Ardid, D. (2005). Cartil. (2013). Nocifensive behaviors include forepaw withdrawal or licking, hind paw withdrawal or licking, stamping, leaning posture and jumping (Espejo and Mir, 1993). Unfortunately, many introductory . Methods 131, 9397. Static weight bearing or incapacitance assays measure the distribution of weight across the hind paws and typically involve placing the animal in an inclined holder forcing placement of the hind paws on two independent pressure sensors (Figure 6C). The rats ability to learn, remember, and interact gives them an advantage over other species, allowing for insights into the basic principles behind learning and behavior which can then be translated to human behavior and learning. J. Exp. 9, 8998. Activation of opioid receptors in cutaneous nerve endings by conorphin-1, a novel subtype-selective conopeptide, does not mediate peripheral analgesia. Neurosci. (2016). Nociceptive signals are then sent to the spinal cord and brain for processing as the sensation of pain. 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. The Rat Grimace Scale is able to detect spontaneous pain induced by intraarticular kaolin-carrageenan, intraplantar Complete Freunds Adjuvant (CFA), and post-surgical pain. Front. In 2001 however with the development of targeted genetic manipulation in mouse embryonic stem (ES) cells, rats took somewhat of a back seat as the rodent of choice for specific gene targeting because this technology was not yet available in the rat. Analysis of behaviors in unrestrained animals using automated technologies is increasingly being used to study non-stimulus evoked pain in rodents. Technology Addiction. But the missing genes signal a problem for using gene editing to de-extinct species. 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). Rev. Most studies focus on either testing how a specific genetic pathway responds to the brain injury, or how administering a drug affects the severity of damage after injury. doi: 10.1126/science.1108609, Morgan, D., Mitzelfelt, J. D., Koerper, L. M., and Carter, C. S. (2012). As for the static hot plate test, cut off times should be carefully designed and strictly adhered to in order to avoid unnecessary nociceptive stimulation and tissue damage. Anim. doi: 10.3791/52640, Brodkin, J., Frank, D., Grippo, R., Hausfater, M., Gulinello, M., Achterholt, N., et al. In human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. B., and Hole, K. (1985). (2009). 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. The rodent is placed in an inclined holder with the hind paws resting on two separate pressure sensors. Consistent and precise placement of the filament is important to reduce intra-subject and inter-subject variability, with the specific placement dependent on the innervation territories of the test area and the model used. Lab. Figure 1. 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. The temperature at which paw withdrawal occurred is automatically recorded, enabling recording of the paw withdrawal temperature without the delay of an investigator manually noting the temperature (Deuis and Vetter, 2016). doi: 10.1016/j.physbeh.2011.05.015, Tjolsen, A., Rosland, J. H., Berge, O. G., and Hole, K. (1991). However, rodents do not vocalize in the audible range unless the pain is severe, making use vocalization as an endpoint ethically limited (Mogil, 2009). Researchers are often advised to begin their studies using rat models in these areas, not only because they are a suitable model, but also due to the fact that rats have already helped scientists reach a few significant breakthroughs in these areas. doi: 10.1016/S0304-3959(01)00437-7, Menndez, L., Lastra, A., Hidalgo, A., and Baamonde, A. The up-down Von Frey method is used to determine the mechanical force required to elicit a paw withdrawal response in 50% of animals, based on the statistical formula used to determine LD50s (Dixon, 1980; Chaplan et al., 1994). The 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. 738, 111117. 160, 15731576. In this experiment, a previously unafraid baby was conditioned to become afraid of a rat. In its simplest form, the animal can choose between two adjacent areas maintained at different temperatures. Adams, B. L., Guo, W., Gors, R. T., and Knopp, K. L. (2016). Fill out the form for a quote consultation with one of our scientific consultants. Ultrasonic sound as an indicator of acute pain in laboratory mice. An advantage of this method is that it avoids excessive application of Von Frey filaments that elicit aversive behaviors. The sequence of outcomes ( for no response or + for response) is recorded and later used to calculate the 50% withdrawal threshold. 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. 23, 16051612. Twitter 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. 16, 13241332. (B) Burrowing assay. Gait and weight bearing of rodents can be analyzed as a surrogate measure of nociception and are typically considered measures of non-evoked or stimulus-independent pain. Pain 7:55. doi: 10.1186/1744-8069-7-55, Tappe-Theodor, A., and Kuner, R. (2014). If you've taken an introductory psychology class, then you have probably read about seminal psychological research that was done with animals: Skinner's rats, Pavlov's dogs, Harlow's monkeys. 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. Cold thresholds in humans can be determined in a similar manner to heat thresholds, where a metal probe is applied to skin that decreases in temperature (usually starting at 32C) until a cooling sensation or pain threshold is reached. Methods 87, 185193. Because of its simplicity, systematic sampling is popular with researchers. Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior. 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. Nat. Nonetheless, consistent measurements are possible in acclimatized animals, although guarding or altered weight distribution may lead to errors. Non-response occurs when some subjects do not have the opportunity to participate in the survey. Quantitative sensory testing in the german research network on neuropathic pain (DFNS): standardized protocol and reference values. The rat grimace scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. 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. 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. Second, the number of flinches over a set period of time can be recorded at a specific temperature (Deuis et al., 2013; Zimmermann et al., 2013). A small metal probe is applied to the hind paw, and heating is triggered by rotation of the handheld device until the mouse withdraws the paw. However, as animals cannot be said to be reporting pain, any reaction to such stimuli does not necessarily evidence experience of pain (Sandkhler, 2009). Stimulus-evoked pain can be evaluated in humans using quantitative sensory testing. Almost all disease-linked human genes have counterparts in the rat. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. 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. 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. 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). (1974). Neurosci. 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). The dynamic weight-bearing test is able to detect reduced weight bearing behaviors of the affected hind limb in multiple pain models, including CFA-induced inflammation, chronic constriction injury, bone cancer pain and antigen-induced arthritis (Tetreault et al., 2011; Robinson et al., 2012; Quadros et al., 2015). doi: 10.1016/j.jphs.2016.01.006, Yeomans, D. C., Pirec, V., and Proudfit, H. K. (1996). 101, 132143. 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. engagement in scientific research and . doi: 10.1016/0014-2999(74)90195-2, Anseloni, V. C., Ennis, M., and Lidow, M. S. (2003). A wide variety of other species make up the remaining 4%, from . Anim. A major advantage of the thermal probe test is the reduced time required for acclimatization to the testing environment, enabling characterization of models or compounds with short duration of action, as well as testing of mechanical and thermal thresholds in the same enclosure. In nave C57BL/6 mice, the paw withdrawal temperature occurs at ~50C, and in unilateral models of inflammation the paw withdrawal temperature reduces to 4344C, providing a sufficient window to detect heat allodynia as well as hypoalgesia (Deuis and Vetter, 2016; Deuis et al., 2017a). J. Neurosci. 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). Weight bearing evaluation in inflammatory, neuropathic and cancer chronic pain in freely moving rats. However, this requires the animals to be acclimatized to the apparatus to minimize ambulation so that withdrawal latencies can be accurately determined. Z., Rodriguez, K. B., Gallo, M. S., Pritchett-Corning, K., Karas, R. H., et al. The effects of morphine methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation.

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