Most of the animals needed for medical and scientific inquiry in the U.S. are rodents (for example, rats and mice), and they are specifically bred for this purpose. Veterinarians are required to inspect the living conditions of the animals. While application of a contact heat stimulus achieves consistent and efficient thermal transfer, it also represents a mechanical stimulus that may lead to premature paw withdrawal in models with mechanical allodynia. 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). Thus, pain is an experience that encompasses both sensory and emotional components; therefore the term pain is not interchangeable with nociception. ECLAM Corporate VP, Veterinary and Professional Services BACKGROUND Laboratory rodents have been used in the United States as research animals since the late 1800s. Research scientists worldwide agree that the use of rat models for disease research and experimentation has become more relevant in the past few years. 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. Differentiating analgesic and non-analgesic drug activities on rat hot plate: effect of behavioral endpoint. The framework for these standards and guidelines are based on the principles of the 3Rs (replacement, reduction, refinement). Pain 12:1744806916665366. doi: 10.1177/1744806916665366, Yoburn, B. C., Morales, R., Kelly, D. D., and Inturrisi, C. E. (1984). Behaviors tend to occur on a spectrum of intensity, but are usually scored in binary as either present or absent. The clinical picture of neuropathic pain. J. Neurosci. The clinically translatability of the tail flick test is therefore unclear. Disadvantage 2: Uncoverage Bias 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. Pain Headache Rep. 18:456. doi: 10.1007/s11916-014-0456-x, Jensen, T. S., and Finnerup, N. B. A soft transducer ensures minimal vibration and reduces touch-on responses. Rev. This continues until at least four readings are obtained after the first change of direction. Br. Pharmacol. 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 . 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. 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). J. This raises a moral issue in animal experimentation. Undoubtedly, nociception, or the ability to detect a potentially harmful stimulus, is a fundamental physiological function in mammals and indeed many other species. Neurosci. doi: 10.1038/nmeth.1455, Leith, J. L., Koutsikou, S., Lumb, B. M., and Apps, R. (2010). Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice. Automated behavioral analysis can be performed in a dedicated apparatus (Behavioral Spectrometer, Behavioral Instruments) or in a home cage (HomeCageScan, CleverSys; PhenoTyper, Noldus), using automated video analysis, vibration sensors, photobeams, and combinations thereof. The pressure is then increased at a constant rate until a nociceptive behavioral response is observed. Rats have since been used to answer a wide range of basic science questions related to common human diseases in the fields of physiology, immunology, pharmacology, toxicology, nutrition, behavior and learning. It is descended from wild Norway rats, Rattus norvegicus, which despite their name likely originated in Asia. (2017). Randall, L. O., and Selitto, J. J. doi: 10.1213/ane.0000000000000291, Carlton, S. M., Lekan, H. A., Kim, S. H., and Chung, J. M. (1994). Acetone is applied to the hind paw and the nocifensive response(s) is counted, timed or scored. doi: 10.1016/0028-3908(84)90005-4, Parvathy, S. S., and Masocha, W. (2013). (2014). Figure 2.Visual representation of the different methodological approaches used to determine mechanical sensitivity using manual Von Frey. When rodents are unwell, the amount of material removed from the burrow is decreased. J. 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). One way to evaluate nociception in non-communicating subjects is through observation of behavior. ACS Chem. Neurosci. The software records the duration of different behavior types, including movement, grooming and rearing behaviors. Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration. (2013). Exp. doi: 10.1016/j.bbr.2008.12.018, Gamble, G. D., and Milne, R. J. Acetylsalicylic acid, paracetamol and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin. 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. She specializes in business, consumer products, home economics and sports and recreation. 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. The force at which this response occurs is recorded automatically by the apparatus and is designated as the paw withdrawal threshold. A phobia is an irrational fear, that is out of proportion to the danger. These people will not be included in the survey, and the survey's accuracy will suffer from non-response. It is a low-cost, single-use product made from sterilized quarry sand and treated with a hydrophobic coating. Behaviors that are analyzed include locomotive activity (still, walking, trotting, running), distance traveled, velocity, grooming, posture, eating/drinking and foraging. doi: 10.1258/la.2008.007156, Sandkhler, J. (2012). Pain 59, 369376. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. The time taken to settle in a temperature zone and/or the temperature of the chosen zone is recorded. The historic struggle against pathogens of laboratory rodents is often divided into three periods. A Guide to Research Rodent Housing William J. In human patients, a distinction is made between stimulus-evoked pain and stimulus-independent or spontaneous pain. In the past, housing of rodents used for research was designed primarily to prevent J. Pharmacol. Rodents are placed individually in a small cage with a barred floor. In anesthetized rats, steep temperature gradients and high skin temperatures are associated with activation of A fibers, while slower heating and lower temperatures lead to firing of C fibers (Yeomans and Proudfit, 1994, 1996; Yeomans et al., 1996). 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). Brain 125, 501510. 14:14. doi: 10.1186/1471-2474-14-14, Pertovaara, A., Kauppila, T., and Hmlinen, M. M. (1996). Neuropathic pain: aetiology, symptoms, mechanisms, and management. Behav. The withdrawal response is detected visually by the researcher, resulting in subjective measurement of the threshold. doi: 10.1016/S0304-3959(01)00437-7, Menndez, L., Lastra, A., Hidalgo, A., and Baamonde, A. 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). When animals such as mice or rats are selected as models for genetic experimentation, the main reason is the similarity of their genetic makeup to human DNA. As the nocifensive response can be too fast for an investigator to quantify in real time, video recordings that are played back in slow motion may be required to accurately analyze the response to acetone. Painful and painless channelopathies. doi: 10.1172/jci42843, Dubner, R. (1983). Ear position denotes the ears being pulled back and apart from their standard position (may feature vertical ridges). 101, 132143. This problem can be overcome by restraining the rodent and only placing the plantar surface of a one hind paw on the metal surface and recording the time to withdrawal, however this method requires significant handling and associated stress (Menndez et al., 2002). J. Pharmacol. Although expensive to produce and not always precise, this became the preferred method to target rats in a specific manner. Nature 444, 894898. Pain 150, 340350. 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). Other advantages of this methodology include eliminating the phenomenon of clustered selection and a low . (2010). J. Pharmacol. Anim. Sci. Pain 7:37. doi: 10.1186/1744-8069-7-37, Hunskaar, S., Fasmer, O. Twitter Neuron 54, 379386. Anim. The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. Sci. (B) Burrowing assay. 1, 28282830. 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. 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). Toxicol. Eur. Biol. J. Digigait quantitation of gait dynamics in rat rheumatoid arthritis model. Lett. 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. A method for measurement of analgesic activity on inflamed tissue. 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. Weight distribution between the hind paws is recorded. In the case of researchers conducting surveys, for example, sample size is essential. The rodent is placed in an inclined holder with the hind paws resting on two separate pressure sensors. Pain in rodents is associated with decreased burrowing behaviors. 89, 707758. At least six responses around the estimated threshold are required for optimal calculation of the 50% threshold (Dixon, 1980). (1989). Anesth. doi: 10.1093/gerona/glr210, OBrien, D. E., Brenner, D. S., Gutmann, D. H., and Gereau, R. W. IV (2013). In addition, as for manual Von Frey tests, animals still need to be habituated to the cages until exploratory behaviors have ceased. Using the Mouse Grimace Scale to reevaluate the efficacy of postoperative analgesics in laboratory mice. Monofilaments of differing forces are applied perpendicularly to the hind paw. 120, 37603772. Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. Unlike the tail flick test, the hot plate test and other tests that apply heat stimuli to the hind paws are considered to integrate supraspinal pathways, as rats with spinal transection do not withdraw the hind limbs in the hot plate test (Giglio et al., 2006). 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). J. Neurosci. Researchers and scientists conducting surveys and performing experiments must adhere to certain procedural guidelines and rules in order to insure accuracy by avoiding sampling errors such as large variability, bias or undercoverage. 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. 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. doi: 10.1111/j.1476-5381.2010.00873.x, Medhurst, S. J., Walker, K., Bowes, M., Kidd, B. L., Glatt, M., Muller, M., et al. Black Women Are At A Double Disadvantage In The Hiring Process GIPHY Not only do black women face pressure to make their blackness more palatable at work, but they also struggle to get their foot. In addition, the experimental time is dramatically reduced, as few applications (usually 34) are needed to determine the paw withdrawal threshold (Deuis et al., 2014, 2015). Spared nerve injury: an animal model of persistent peripheral neuropathic pain. A Biol. Eng. Influence of skin temperature on heat pain threshold in humans. doi: 10.1371/journal.pone.0104458, Minett, M. S., Quick, K., and Wood, J. N. (2011). Assoc. (E) Behavioral Spectrometer (Behavioral Instruments). Tags: CRISPR, CRISPR gene editing, Custom animal model, Share this: 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. - Quora Answer: I'm going to answer this purely from the point of view of toxicology studies, because that's where my experience is. This suggests that the tail flick response may be impacted by changes in motor processing (Chapman et al., 1985). 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. 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). Neuro Oncol. Front. If the rodent withdraws, licks or shakes the paw, it is considered to have had a positive response. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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. A number of endpoints can be obtained from the cold plate test, similar to the hot plate test. 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). The three Rs are a set of principles that scientists are encouraged to follow in order to reduce the impact of research on animals.
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