Scientists often cite the similarities between animals and humans as the rationale for animal experimentation. 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. 23, 16051612. (2010). This sample group should include individuals who are relevant to the survey's topic. Similarly, the terms nociception and pain are often used interchangeably, although the term pain is rarely appropriate to use in reference to animal studies. The use of ultrasonic (inaudible) vocalization as an endpoint has also been studied, however it has not consistently been shown to increase in response to noxious stimuli (Han et al., 2005; Wallace et al., 2005; Williams et al., 2008). Systematic Sampling: Advantages and Disadvantages - Investopedia 7 Unconscious Biases That Still Affect Black Women Today - Bustle Veterinarians are required to inspect the living conditions of the animals. It is the premier source of information on the laboratory rat. 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. 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. J. Pharmacol. (2014). (2011). doi: 10.1111/ejn.12643, Tetreault, P., Dansereau, M. A., Dor-Savard, L., Beaudet, N., and Sarret, P. (2011). 14:14. doi: 10.1186/1471-2474-14-14, Pertovaara, A., Kauppila, T., and Hmlinen, M. M. (1996). Am. Development of a piglet grimace scale to evaluate piglet pain using facial expressions following castration and tail docking: a pilot study. 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. 5, 94100. An advantage of this assay is that the endpoint is objective and requires minimal experience by the investigator to perform. Scientists recovered most of the Christmas Island rat's genome. Research scientists worldwide agree that the use of rat models for disease research and experimentation has become more relevant in the past few years. This research has almost exclusively used a single procedure to induce the condition in animal models. However, as animals cannot be said to be reporting pain, any reaction to such stimuli does not necessarily evidence experience of pain (Sandkhler, 2009). doi: 10.1016/j.ejpain.2011.07.012, Ankier, S. I. (A) Acetone evaporation test. The device automatically records the temperature that paw withdrawal occurred (in this case 50C). Am. Nevertheless, the acetone evaporation test has been validated in multiple models of inflammatory and neuropathic pain in both mice and rats (Choi et al., 1994; Colburn et al., 2007; Yamamoto et al., 2016). Neurosci. Animals are stressed - there are many reasons for stress in the animals: transportation, insufficient time for adapting, cages without enrichment (e.g. (B) The ascending stimulus method. 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). doi: 10.1002/ejp.871, Roughan, J. V., Wright-Williams, S. L., and Flecknell, P. A. Lancet 353, 19591964. (2007). Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine. (A) Grimace scales. Behavioral measures of pain thresholds. Annu. (B) Burrowing assay. Unfortunately, no accurate figures are available to determine precisely how many animals are used in experiments in the U.S. or worldwide. This falls into one of five main categories: Computer or gaming addiction. The exception is use of the test on the tail of mice (Minett et al., 2014), although this may not be useful to assess nociceptive behaviors in commonly used models that are localized to the hind paw. 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. In this experiment, a previously unafraid baby was conditioned to become afraid of a rat. Life Sci. Picking up rats by the tail is stressful and should be avoided . Pain 87, 149158. (2014). (1988). The pressure is then increased at a constant rate until a nociceptive behavioral response is observed. Analgesic treatment of ciguatoxin-induced cold allodynia. J. Neurotrauma 29, 898904. (2011). Methods 113, 9197. It should be noted that rather than flinching or licking, some rat strains tend to simply avoid weight bearing on the affected paw or reposition their stance to minimize contact with the cool surface, so all observation should be adapted to the specific model animal. Toxicol. doi: 10.1016/1056-8719(94)90046-9, Sotocinal, S. G., Sorge, R. E., Zaloum, A., Tuttle, A. H., Martin, L. J., Wieskopf, J. S., et al. Pain 59, 369376. Lab. J. LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. Despite these advantages of automation, experimenters still need to be experienced to distinguish true responses from touch-on responses and ambulation. In mice, ES cells can be maintained in their pluripotent state easily. Gait analysis in freely walking rodents is used to study changes in limb movement and positioning in models with sensori-motor dysfunction, including Parkinsons disease, spinal cord injury and stroke. Advantages of the cold plate test are its relative speed and the ability for accurate temperature control. 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. Exp. | All rights reserved. The force is increased by rotation of the handheld device until paw withdrawal occurs. (2017). It was around this time that gene editing came into being, specifically Zn Finger nucleases and TALENS. In this model, the lateral plantar skin of the hind paw, which is the area of innervation of the sural nerve, has the greatest reduction in mechanical thresholds compared to other innervation areas of the plantar skin (Decosterd and Woolf, 2000). Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration. (2013). Rev. A touch-on reaction is more likely to occur if the filament is not applied perpendicularly, if the filament is not applied smoothly, or if the filament moves horizontally during application, inducing scratching. The Randall-Selitto or paw pressure test was developed as a tool to assess response thresholds to mechanical pressure stimulation and is often considered a measure of mechanical hyperalgesia (Figure 1C; Randall and Selitto, 1957). Facial expression is subjectively scored for severity of pain based on five facial features (ear position, eye closing, cheek bulging, whisker position, and nose bulging). Methods used to assess mechanically evoked pain like behaviors in rodents. This normally protective response, which is absent in these individuals, leads to frequent injuries and often results in higher mortality rates early in life (Bennett and Woods, 2014). In this assay rodents walk freely across an enclosed elevated glass floor. J. Use of dynamic weight bearing as a novel end-point for the assessment of Freunds Complete Adjuvant induced hypersensitivity in mice. BBC - Ethics - Animal ethics: Experimenting on animals doi: 10.1080/23328940.2016.1157668, Deuis, J. R., Whately, E., Brust, A., Inserra, M. C., Asvadi, N. H., Lewis, R. J., et al. Typically, the experimental setup consists of a test plate at a fixed temperature (usually between 5C and 55C) that is placed adjacent to a reference plate at neutral temperature (usually between 25C and 30C; Figure 5A). Many of these original stocks harbored a variety of natural, or indigenous, pathogens. 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). 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). TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Although the ability to target rat ES cells was then available, doing so was still difficult. doi: 10.1258/la.2008.007156, Sandkhler, J. Lett. 101, 132143. doi: 10.1016/0304-3959(94)90090-6, Carter, R. B. Pain 12:1744806916665366. doi: 10.1177/1744806916665366, Yoburn, B. C., Morales, R., Kelly, D. D., and Inturrisi, C. E. (1984). The sequenced genome will also unveil new targets for drug intervention. Mol. In cases of sensory loss, hypoalgesia may be present, which is defined as decreased sensitivity to a nociceptive stimulus. 43, 207213. 96, 312317. Rodents are allowed to freely move along a liner or circular surface with a temperature gradient. Eur. 6, 17511758. The power of mouse models proved to be so clear however that the same abilities in rat continued to be desired and pursued. TRPM8 mechanism of cold allodynia after chronic nerve injury. 13, 924935. You want to survey as large a sample size as possible; smaller sample sizes get decreasingly representative of the entire population. doi: 10.1016/j.neulet.2012.07.017. 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. The LabSand Option. Pain Med. The Rat Grimace Scale is also scored 02 depending on observed changes in facial features, and evaluates the extent of orbital tightening, nose/cheek flattening, ear change and whisker change (Sotocinal et al., 2011). 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). For instance, if you are conducting a survey on whether a certain kitchen cleaner is preferred over another brand, then you should survey a large number of people who use kitchen cleaners. 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). (2013). J. Pharmacol. Rep. 5:14648. doi: 10.1038/srep14648. doi: 10.1016/s0304-3959(00)00307-9, Kim, S. H., and Chung, J. M. (1992). Figure 4.Methods used to assess cold-evoked pain like behaviors and temperature preference in rodents. A.E. Limitations of the Animal Model. It should be noted that the absolute values obtained using manual and electronic Von Frey can differ significantly. In fact, over 90% of test subjects are mice, birds and rats. All we can possibly learn from high-dose experiments is what might happen in overdose situations. J. Figure 2.Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. 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). 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). 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. doi: 10.1590/s0100-879x2006001200013, Gregory, N. S., Harris, A. L., Robinson, C. R., Dougherty, P. M., Fuchs, P. N., and Sluka, K. A. Eur. Differentiating analgesic and non-analgesic drug activities on rat hot plate: effect of behavioral endpoint. 80, 300307. Is it Right or Not to Use Rats for Experiments? (2007). A modified version of the thermal probe test suitable for quantifying heat thresholds in rats is still to be developed. 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. 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). Curr. 1, 118121. 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). Spinal processing of noxious and innocuous cold information: differential modulation by the periaqueductal gray. 10, 283294. Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice. Biol. BMC Musculoskelet. The spectrometer is capable of recording 23 different types of behaviors in real time, including ambulation (still, walking, trotting, running), grooming behaviors, and rearing behaviors, as well as distance traveled and average velocity (Brodkin et al., 2014). Neurosci. Assoc. (1974). Assoc. Therefore grimace scales have the potential to monitor and improve the welfare of animals used not only in research, but also in farming and industry. McGrath, J. C., Drummond, G. B., McLachlan, E. M., Kilkenny, C., and Wainwright, C. L. (2010). Undoubtedly, nociception, or the ability to detect a potentially harmful stimulus, is a fundamental physiological function in mammals and indeed many other species. Exp. Temperature 3, 7791. For example, in models of burn pain, chemotherapy-induced neuropathy, and intra-articular carrageenan, changes in mechanical allodynia as measured by Von Frey and changes in gait parameters do not always correlate (Gabriel et al., 2009; Boehmerle et al., 2014; Yin et al., 2016; Deuis et al., 2017b). 150, 165171. 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). Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. Physiol. 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). Lancet 383(9924): 1240-9. While paw withdrawal temperature can be derived from the time to withdrawal (Hargreaves et al., 1988), the actual temperature applied to the skin would need to be experimentally determined by attaching a thermocouple probe to the skin. Sci. Pain 16, 485495. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Mouse model: Pros & Cons - SlideShare 27, 14. 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. doi: 10.1371/journal.pone.0039765, Brenner, D. S., Golden, J. P., Vogt, S. K., and Gereau, R. W. (2015). 95% of animals used in experiments are not protected by the federal Animal Welfare Act (AWA), which excludes birds, rats and mice bred for research, and cold-blooded animals such as reptiles and most fish. 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). Weight distribution between the hind paws is recorded. The amount of substrate displaced over a set period of time is recorded. 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. Pain 66, 265270. Individual differences in the hotplate test and effects of habituation on sensitivity to morphine. 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. Front Neurol 7: 57. Hyperalgesia is defined as an increased or exaggerated pain response to a normally noxious stimulus, while allodynia is defined as a painful response to a normally non-noxious or innocuous stimulus. 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). Analg. Accordingly, translation of research using experimental nociceptive assays to pain treatment in the clinic has met with some difficulties. Pain 14, 12551269. Oxaliplatin administration increases expression of the voltage-dependent calcium channel 2-1 subunit in the rat spinal cord. The evaluation of the analgesic action of pethidine hydrocholoride (Demerol). 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. Digigait quantitation of gait dynamics in rat rheumatoid arthritis model. It is estimated that more than 50 million animals are used in experiments each year in the United States. doi: 10.1371/journal.pone.0098856, Huang, S. M., Li, X., Yu, Y., Wang, J., and Caterina, M. J. 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). Nature 448, 204208. Protoc. J. Neurosci. In addition to burrowing, other spontaneous behaviors can be assessed, including nesting construction and food hoarding (Deacon, 2006a; Rock et al., 2014). Some animals, however, are more preferred by laboratories. [ 1] [ 2] [ 3] 2. (A) Two-temperature choice assay. 372, 301312. Guidelines for the design and statistical analysis of experiments using laboratory animals. 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. J. Neurosci. Br. doi: 10.1016/S0014-2999(01)01302-4, Jensen, T. S., and Yaksh, T. L. (1986). Pain 20, 231240. Rats are often used to study behaviour in psychology experiments. (A) Tail flick test (radiant heat). The pressure is increased until withdrawal or vocalization occurs. Lancet Neurol. doi: 10.1016/j.neuron.2007.04.017, Coutaux, A., Adam, F., Willer, J. C., and Le Bars, D. (2005). Consistent application of acetone can be challenging, as acetone has a lower surface tension than water (25.2 mN/m and 72.8 mN/m respectively), making it difficult to form uniform drops with a pipette or syringe (Vazquez et al., 1995), with some laboratories opting to use a spray instead (Yamamoto et al., 2016). (2017a). Animal studies in psychology - American Psychological Association Skinner's Box Experiment | Behaviorism | Practical Psychology 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: 10.1016/0304-3959(94)90051-5, Yeomans, D. C., and Proudfit, H. K. (1996). . doi: 10.1038/nrn2606, Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., et al. Neurosci. The ascending stimulus method provides an estimate of the mechanical withdrawal threshold. Gait analysis of C57BL/6 mice with complete Freunds adjuvant-induced arthritis using the CatWalk system. However, theyre more widely used in studying cardiovascular and metabolic disorders, as well as the onset of conditions that relate to the brain, digestive system, and various health problems related to behavior. For example, in the spared nerve injury model, the tibial and common peroneal nerves are axotomized, leaving only the sural nerve intact. A., Howick, J., Aronson, J. K., Roberts, N., Perera, R., Koshiaris, C., et al. The Advanced Dynamic Weight Bearing apparatus (Bioseb) was developed as a modification from static weight bearing or incapacitance tests and computes weight bearing for each of the front and rear paws, weight ratio and paw surface area in freely moving animals (Griffioen et al., 2015). PLoS One 10:e0125822. Assessing hoarding in mice. Both instruments have been validated against manual von Frey filaments and found to produce less variable data in addition to being easier to use. 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 . Mammalian Model Organisms: Contributions and Limitations - BenchSci The study of nonhuman animals has actually played a huge role in psychology, and it continues to do so today. Researchers can now design experiments around the biological questions rather than the limitations of their animal model. doi: 10.1152/physrev.00025.2008, Santos-Nogueira, E., Redondo Castro, E., Mancuso, R., and Navarro, X. doi: 10.1093/ilar.43.4.244, Gabriel, A. F., Marcus, M. A., Walenkamp, G. H., and Joosten, E. A. Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. doi: 10.1016/s1474-4422(14)70102-4, Jensen, T. S., Gottrup, H., Sindrup, S. H., and Bach, F. W. (2001). To conduct a survey properly, you need to determine your sample group. Physiol. 1, 383412. doi: 10.1038/nprot.2006.171, Deacon, R. M. (2006b). The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). The biggest challenge of temperature preference tests is choosing the optimal temperature pairs, so that preference for one side is either exaggerated or overcome in experimental animals compared with control animals. doi: 10.1093/brain/awf055, Defrin, R., Shachal-Shiffer, M., Hadgadg, M., and Peretz, C. (2006). In this test, animals are placed individually in small cages with a mesh or otherwise penetrable bottom. doi: 10.1016/j.jpain.2009.01.325, Yamamoto, K., Tsuboi, M., Kambe, T., Abe, K., Nakatani, Y., Kawakami, K., et al. But the missing genes signal a problem for using gene editing to de-extinct species. Characterization of the foot withdrawal response to noxious radiant heat in the rat. 25, 73177323. doi: 10.1016/j.physbeh.2011.05.015, Tjolsen, A., Rosland, J. H., Berge, O. G., and Hole, K. (1991). The RatMet or MouseMet von Frey filament (0.3 and 0.5 mm tip diameter, delivering forces of 180 g and 0.17 g, respectively) is placed against the plantar surface of the paw and the force is linearly increased via rotation of the device handle (Deuis and Vetter, 2016). doi: 10.1213/01.ane.0000158471.41575.f0, Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., et al. Influence of skin temperature on heat pain threshold in humans. The Laboratory Rat - 3rd Edition - Elsevier doi: 10.1016/j.jbspin.2004.01.010, Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., et al. 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). Disord. However, the majority of human subjects report cold pain upon cooling to at least 22C (Defrin et al., 2002; Ltsch et al., 2015). doi: 10.1016/s0165-0270(03)00241-3, Balayssac, D., Ling, B., Ferrier, J., Pereira, B., Eschalier, A., and Authier, N. (2014). In addition, a programmable hold step with constant force application can also be incorporated in the experimental setup to determine the time to withdrawal (Lu and Schmidtko, 2013). 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. 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). Methods 255, 92103. A novel behavioral assay for measuring cold sensation in mice. Joint Bone Spine 72, 359371. Gene editing technologies allow scientists to use rats more often in their research. As many animal models of pain using stimulus-evoked measures of nociception have failed in the past to translate into the clinic, spontaneous pain as an efficacy endpoint may be more relevant to the human condition and increase the clinical validity of animal models of pain in the future (Mogil, 2009). Med. 14 Articles, This article is part of the Research Topic, Creative Commons Attribution License (CC BY). Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. Temperature 3, 199207. TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Their brains are larger than mice, and the animals are less timid and more intelligent. 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). 10:284. doi: 10.3389/fnmol.2017.00284. 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.
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