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). Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: behavioral evidence. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. 37, 18351841. | All rights reserved. The CatWalk method: assessment of mechanical allodynia in experimental chronic pain. If a stimulus is applied that does not normally evoke a withdrawal response, and the animal withdraws from the stimulus, the animal is considered to have allodynia. 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. Twitter First, the response to a specific temperature (typically 5C to 15C) can be recorded (Allchorne et al., 2005). The ascending stimulus method provides an estimate of the mechanical withdrawal threshold. In this experiment, a previously unafraid baby was conditioned to become afraid of a rat. 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). 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). This raises a moral issue in animal experimentation. 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. The Little Albert Experiment demonstrated that classical conditioning could be used to create a phobia. Int. A.E. The test begins by assessing the response to a filament of the lowest force (in this case 0.4 grams-force) for a set number of applications (in this case five times). Rodents are placed in an enclosed box with a camera, accelerometer and wall-mounted photobeams for a set period of time. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. Neurosci. 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. Some animals, however, are more preferred by laboratories. Sample size determination. An additional disadvantage of the hot plate test is that all four paws and the tail are exposed to the heat stimulus. Quantitative sensory testing in the german research network on neuropathic pain (DFNS): standardized protocol and reference values. (1989). Pain 68, 133140. doi: 10.1213/ane.0000000000000291, Carlton, S. M., Lekan, H. A., Kim, S. H., and Chung, J. M. (1994). 67, 705713. doi: 10.1016/j.burns.2016.09.001, Deuis, J. R., Lim, Y. L., Rodrigues de Sousa, S., Lewis, R. J., Alewood, P. F., Cabot, P. J., et al. 25, 73177323. 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. 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 . J. And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. 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). The Laboratory Rat - 3rd Edition - Elsevier Pain 32, 7788. Rock, M. L., Karas, A. Rodent models in neuroscience research: is it a rat race? In humans, spontaneous or background pain is pain that occurs without an identifiable stimulus. Genetically engineered mouse models recapitulate aspects of the corresponding human diseases and are instrumental in studying disease mechanisms and testing therapeutic strategies. 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 . The cold plate test is one of the simplest assays to determine behavioral responses to both noxious and innocuous cold temperatures in both mice and rats. 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). This continues until at least four readings are obtained after the first change of direction, and the sequence of outcomes ( for no response or + for response) is recorded (Figure 2A). Evaluation of the usefulness of two established pain assessment tools in a burn population. doi: 10.1016/j.jneumeth.2004.07.005, Hargreaves, K., Dubner, R., Brown, F., Flores, C., and Joris, J. From a physiological standpoint, more is known about the responses and pathways in rats than in other species due to the wealth of data collected over the years. Key Takeaways. Pain 10, 767773. Rats are an ideal choice for many labs due to their physiological similarity to humans. Mol. 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). (2010). The hot plate test, first described in 1944, can be used to determine heat thresholds in mice and rats (Woolfe and Macdonald, 1944). Reaction thresholds to pressure in edematous hindpaws of rats and responses to analgesic drugs. In recent years mice have been used with increasing frequency, to take advantage of genetically modified lines as well as the relatively lower costs compared with rats. Toxicol. 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. 9, 807819. 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. However, replacement or substitution of animals for nonsentient materials is difficult in pain research due to the nature of the behavioral experiments. Figure 3.Methods used to assess heat-evoked pain like behaviors in rodents. The same methods that allow this to be so in mice have failed in rats. The response temperature is dependent on the starting temperature, ambient temperature and rate of heating, with faster heat ramps resulting in higher response temperatures (Tjolsen et al., 1991; Yalcin et al., 2009). 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. doi: 10.1111/ejn.12643, Tetreault, P., Dansereau, M. A., Dor-Savard, L., Beaudet, N., and Sarret, P. (2011). Mol. Physiol. 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. doi: 10.1016/s0304-3959(00)00307-9, Kim, S. H., and Chung, J. M. (1992). doi: 10.1002/art.21403, Miller, A. L., and Leach, M. C. (2015). Received: 04 April 2017; Accepted: 22 August 2017; Published: 06 September 2017. Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice. The time taken to withdraw from the heat stimulus is recorded as the withdrawal latency, and depending on the model of the Hargreaves apparatus, may either be recorded manually by the investigator or automatically by the apparatus. Lab. 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. 20, 441462. So far, no single behavioral assay can capture the full spectrum of nociception in non-communicating subjects. The mouse genome is very similar to our own, making mouse genetic research particularly useful for the study of human diseases. This sample group should include individuals who are relevant to the survey's topic. Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. Animals are stressed - there are many reasons for stress in the animals: transportation, insufficient time for adapting, cages without enrichment (e.g. J. Pharmacol. doi: 10.1038/nature05413, Cruz-Almeida, Y., and Fillingim, R. B. doi: 10.1016/j.pain.2013.06.015, Keywords: pain, rodent, hyperalgesia, allodynia, spontaneous pain, mechanical, heat, cold, Citation: Deuis JR, Dvorakova LS and Vetter I (2017) Methods Used to Evaluate Pain Behaviors in Rodents. 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. A caveat is, however, that no pain-specific behaviors are captured, leading to potential interference from drug or phenotype effects that could mask nociception, or anti-nociception. Brain Res. (2014). 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. Non-response occurs when some subjects do not have the opportunity to participate in the survey. Both versions of the test require the animal to be loosely restrained. 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). Osteoarthr. J. Neurosci. doi: 10.1016/j.neulet.2012.07.017. However, while application of the ice pellet to the glass generates a cooling ramp that can be approximately correlated to estimates of the paw withdrawal temperature, the paw being tested needs to remain in contact with the glass to achieve efficient temperature transfer. In terms of the diseases that they are used to study, rats are usually not the model of choice when it comes to disorders related to neoplasms, blood and immune function. Lab. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. His experiments, conducted in what is known as "Skinner's box," are some of the most well-known experiments in psychology. Quantitative assessment of tactile allodynia in the rat paw. A., Possani, L. D., Cabot, P. J., Lewis, R. J., et al. This falls into one of five main categories: Computer or gaming addiction. (2011). Mol. Thus, the focus is often on reduction of the number of animals necessary to obtain data, and refinement of the method with the aim to decrease the amount of nociception caused to the animal. Eur. 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. Weight distribution between the hind paws is recorded. Coding of facial expressions of pain in the laboratory mouse. While the Randall-Selitto test often results in similar types of outcomes to the Von Frey filament tests (Santos-Nogueira et al., 2012), the mechanical stimulation differs fundamentally from Von Frey filaments, which may also activate low-threshold mechanoreceptors in addition to nociceptors. 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. If the response rate is 40% or more (i.e., withdrawal response is elicited in two or more out of five applications) testing stops and the force of the last von Frey filament is designated as the mechanical withdrawal threshold (in this case 2 grams-force). Nat. In this test, animals are placed individually in small cages with a mesh or otherwise penetrable bottom. Development of the Rodent Face Finder, which captures stills of rodent faces that a researcher then scores according to the relevant scale, has automated some of the experimental process (Sotocinal et al., 2011) albeit development of automatic facial expression scoring will make this approach even more widely useful. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. Rodents are placed individually in a small cage with a barred floor. Woolfe, G., and Macdonald, A. D. (1944). The acetone evaporation test, first described in 1994, is a technique used to measure aversive behaviors triggered by evaporative cooling and is typically considered as a measure of cold allodynia (Carlton et al., 1994; Choi et al., 1994; Vissers and Meert, 2005). J. Pharmacol. 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). Obviously this cannot be done in rodents, making spontaneous pain difficult to quantify; however new methods to evaluate spontaneous pain are increasingly being reported, including grimace scales, burrowing assays, gait analysis, weight bearing and automated behavioral analysis (for a summary on behavioral tests used in non-stimulus evoked nociception, see Tappe-Theodor and Kuner, 2014). If there is no response, the next filament with a higher force is tested; if there is a response, the next lower force filament is tested. These neurons are pseudo-unipolar, with a peripheral branch that terminates in the skin or viscera and a central branch that terminates in the spinal cord. 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). 72, 7479. Rev. 25, 99111. An estimated 71% of all NIH grant applications from 2008 to 2015 mentioned the keywords mus musculus, mouse, or mice. 1981. doi: 10.1093/brain/awf055, Defrin, R., Shachal-Shiffer, M., Hadgadg, M., and Peretz, C. (2006). 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. The power of mouse models proved to be so clear however that the same abilities in rat continued to be desired and pursued. 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). 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. Assoc. Pain 20, 231240. 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. 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. For example, in C57BL/6 mice, the 50% withdrawal threshold determined using manual Von Frey is ~0.61 g, while using electronic Von Frey, the paw withdrawal thresholds are generally higher, with values of ~4 g obtained using MouseMet and ~6 g using Dynamic Plantar Aesthesiometer (Petrus et al., 2007; Minett et al., 2014; Deuis and Vetter, 2016; Gritsch et al., 2016). Pain research in animals. Pain in rodents is associated with decreased burrowing behaviors. (2011). Interested in using rats for your next research project? (2005). (2007). The same is likely to be true of other rodent species, many of . doi: 10.1093/gerona/glr210, OBrien, D. E., Brenner, D. S., Gutmann, D. H., and Gereau, R. W. IV (2013). BMC Musculoskelet. When pain continues beyond the expected time of wound healing or without a clear reason, it is termed chronic pain. The Disadvantages of a Small Sample Size | Sciencing Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. The intensity of the light source should be adjusted to produce withdrawal latencies of 1012 s in nave animals, providing a sufficient window to detect heat allodynia and hypoalgesia, with a pre-determined cut off time to prevent tissue damage. doi: 10.1016/j.jphs.2016.01.006, Yeomans, D. C., Pirec, V., and Proudfit, H. K. (1996). The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). Invest. Pharmacol. Models and mechanisms of hyperalgesia and allodynia. However, the contribution of supraspinal processing to the tail flick response depends at least in part on the heating slope and temperature, with stimuli that lead to more delayed withdrawal responses generally considered to involve higher central nervous system functions considered necessary to process pain (Jensen and Yaksh, 1986). Analg. General Adaptation Syndrome - Psychologist World doi: 10.1016/0014-2999(74)90195-2, Anseloni, V. C., Ennis, M., and Lidow, M. S. (2003). 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. 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). 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). (2010). 10:284. doi: 10.3389/fnmol.2017.00284. J. Med. Wistar rats are big rats. 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. J. Pharmacol. Ther. 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). The most common case of bias is a result of non-response. Cerebral palsy. 56, 171176. A modified Hargreaves method for assessing threshold temperatures for heat nociception. Advantages Of Rat Models and Their Uses in Disease Research Becoming overdependent and even addicted to our gadgets is another of the main disadvantages in technology. It also demonstrates two additional concepts, originally outlined by Pavlov. Spinal processing of noxious and innocuous cold information: differential modulation by the periaqueductal gray. 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. Animal studies in psychology - American Psychological Association 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 dynamic hot plate test, first described in 1984, uses an increasing temperature ramp rather than a constant temperature. The manual Von Frey test, developed by the physiologist Maximilian von Frey, is a method of evaluating mechanical allodynia in mice and rats. J. Pharmacol. Rodents are commonly used to study the pathophysiological mechanisms of pain as studies in humans may be difficult to perform and ethically limited. Given the variability in cold pain thresholds, it may be difficult to differentiate between cold allodynia and cold hyperalgesia in the clinic. Br. Protoc. Braz. Their premise is based on the presumption that because we share similar biological processes, and because animals are whole, complex organisms, data obtained from an animal model can be extrapolated and . Well-established strains of rat are used to study a number of human diseases such as: obesity and diabetes cancer cardiovascular disease (including high blood pressure and heart failure). Researchers choose rats over other species for a number of reasons: 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. Gait analysis of C57BL/6 mice with complete Freunds adjuvant-induced arthritis using the CatWalk system. Address: 2200 Smithtown Avenue Am. The rodent is restrained and the hind paw (or tail) is placed between a pointed probe tip and flat surface. doi: 10.1152/physrev.00025.2008, Santos-Nogueira, E., Redondo Castro, E., Mancuso, R., and Navarro, X. This shift was primarily instigated by the availability of a much . At least six responses around the estimated threshold are required for optimal calculation of the 50% threshold (Dixon, 1980). But the missing genes signal a problem for using gene editing to de-extinct species. Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. Some of these behaviors can be sensitive to analgesics, although differences are observed depending on the type of behavior quantified. Fill out the form for a quote consultation with one of our scientific consultants. Here, the rodent is placed on the plate after it has been cooled to the desired temperature and the time taken to evoke nociceptive behavior such as shaking, jumping or licking in the animal is recorded as the response time. Nature 448, 204208. 1. 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. J. Musculoskelet. Pain 123, 231243. 130, 117122. Berryman, E. R., Harris, R. L., Moalli, M., and Bagi, C. M. (2009). Painful and painless channelopathies. Mouse model: Pros & Cons. To conduct a survey properly, you need to determine your sample group. Handling and restraint: General principles | NC3Rs Exp. Neurosci. Rev. The second view, by Singer, considers animals as sentient creat Mice count morally because they can be harmed. In its simplest form, the animal can choose between two adjacent areas maintained at different temperatures. 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. Water heated to 30C and applied the same way is usually used as a control (Carlton et al., 1994; Choi et al., 1994). 11, 821830. Despite these advantages of automation, experimenters still need to be experienced to distinguish true responses from touch-on responses and ambulation. 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. In unilateral pain models, many changes in gait parameters are observed, including reduced intensity (paw pressure), reduced print area, reduced stance phase duration (time spent on paw), increased swing phase duration (time spent off paw) in the ipsilateral hind paw compared to contralateral hind paw, consistent with reduced weight bearing and guarding behaviors (Parvathy and Masocha, 2013; Yin et al., 2016). 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. However, this requires the animals to be acclimatized to the apparatus to minimize ambulation so that withdrawal latencies can be accurately determined.
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