Analg. doi: 10.1258/la.2008.007156, Sandkhler, J. 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). This can be achieved through a variety of techniques. Methods 25, 241250. doi: 10.1371/journal.pone.0039765, Brenner, D. S., Golden, J. P., Vogt, S. K., and Gereau, R. W. (2015). Direct intrathecal drug delivery in mice for detecting in vivo effects of cGMP on pain processing. doi: 10.1016/j.jbspin.2004.01.010, Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., et al. (2013). Front Neurol 7: 57. The rat grimace scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. doi: 10.1016/s0165-0270(03)00241-3, Balayssac, D., Ling, B., Ferrier, J., Pereira, B., Eschalier, A., and Authier, N. (2014). Rep. 5:14648. doi: 10.1038/srep14648. The time taken to flick or withdraw the tail from the heat stimulus is recorded. Importantly, the pain appears to be spontaneous, with no identifiable stimulus. 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). Although expensive to produce and not always precise, this became the preferred method to target rats in a specific manner. 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. Pharmacol. 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. Exp. Rat ES cells are very unstable, with any disturbance leading them to activate, so that they could not be implanted in an embryo and brought to term. Although animal research may have ethical concerns, the US has regulated its practice since 1966. 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. Eur. 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). The main advantage of the thermal probe test is that the mice are placed in individual runs standing on bars instead of glass enabling access to the plantar surface, which allows simultaneous assessment of mechanical thresholds by von Frey, removing the need for acclimation in two different enclosures. The main advantage of electronic Von Frey compared to manual Von Frey is that an increasing force is applied by a single filament. Can quantitative sensory testing move us closer to mechanism-based pain management? 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. Pain 68, 133140. J. Neurosci. The dynamic hot plate test, first described in 1984, uses an increasing temperature ramp rather than a constant temperature. Studying ongoing and spontaneous pain in rodentschallenges and opportunities. Life Sci. The sheep grimace scale as an indicator of post-operative distress and pain in laboratory sheep. In addition, as for manual Von Frey tests, animals still need to be habituated to the cages until exploratory behaviors have ceased. (B) Hot plate test. 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. 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. doi: 10.1016/j.pain.2006.01.041, Roughan, J. V., Bertrand, H. G., and Isles, H. M. (2016). Woolf, C. J., and Mannion, R. J. (2005). Irwin, S., Houde, R. W., Bennett, D. R., Hendershot, L. C., and Seevers, M. H. (1951). Similarly, measures to improve data quality, including appropriate randomization and blinding procedures, are key to ensure validity of the obtained results. Sampling errors can significantly affect the precision and interpretation of the results, which can in turn lead to high costs for businesses or government agencies, or harm to populations of people or living organisms being studied. 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). doi: 10.1016/j.jneumeth.2004.07.005, Hargreaves, K., Dubner, R., Brown, F., Flores, C., and Joris, J. Pain Symptom Manage. The distinction between nociception and pain thus underlines a key difference in terminology when referring to communicating and non-communicating subjects. Rep. 4:6370. doi: 10.1038/srep06370, Bove, S. E., Calcaterra, S. L., Brooker, R. M., Huber, C. M., Guzman, R. E., Juneau, P. L., et al. Brain Res. The term nociception was coined by Charles Sherrington in the early 1900s to distinguish the sensation of paina result of central nervous system processingfrom the physiological phenomenon of the peripheral nervous system responding to potential harmful stimuli (Dubner, 1983; Coutaux et al., 2005). A behavioral and pharmacological validation of the acetone spray test in gerbils with a chronic constriction injury. 2 The human, social, and economic burden of burns is considerable with an estimated annual expenditure of >$2 billion . 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. The MouseMet or RatMet electronic Von Frey systems deliver a mechanical stimulus via a hand-held probe (Figure 1B). Brain 125, 501510. (2015). This raises a moral issue in animal experimentation. However, concerns over the clinical translatability of stimulus-evoked nociception in recent years has led to the development and increasing implementation of non-stimulus evoked methods, such as grimace scales, burrowing, weight bearing and gait analysis. doi: 10.1016/j.jneumeth.2013.06.005, Baron, R., Binder, A., and Wasner, G. (2010). 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). Lab. Both instruments have been validated against manual von Frey filaments and found to produce less variable data in addition to being easier to use. Life Sci. Burrowing behavior as an indicator of post-laparotomy pain in mice. General adaptation syndrome was discovered accidentally by Selye whilst he was conducting experiments on rats at McGill University in Montreal, Canada. However, as the testing surface can influence the results of von Frey, it is possible that values obtained using MouseMet or RatMet are not directly comparable to other methods (Pitcher et al., 1999). Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. Methods 31, 7983. Particular mention should also go to timely publication of data, be it positive or negative results, in order to reduce experimental duplication and unnecessary use of animals. Mol. J. Pharmacol. 67, 705713. 72, 7479. (2010). 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). 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. Mol. This review article will provide an overview of the current behavioral methods that are used to assess pain behaviors in mice and rats. PLoS One 9:e104458. 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. These decades of work will enable the integration of new techniques and technologies for cerebral palsy research and maximize the utility of the hypoxia-ischemia model. Allowing rodents to have several trial runs prior to the actual experiment can increase burrowing behaviors and reduce variability (Deacon, 2006b). They have distinctive personality, which is a manifestation of their friendliness to people. Eur. Meloxicam prevents COX-2-mediated post-surgical inflammation but not pain following laparotomy in mice. 23, 16051612. The Behavioral Spectrometer has been validated in a mouse model of carrageenan-induced hind paw inflammation, where the frequency of grooming was increased and the number of ambulations were decreased (Brodkin et al., 2014). A modified Hargreaves method for assessing threshold temperatures for heat nociception. 120, 37603772. Prior to the development of automated digitized platforms, this test was performed by coloring the animals paws with ink; the animal was then allowed to walk freely on a paper, which could be scanned for analysis (Ishikawa et al., 2014). (2017a). Pain 66, 265270. 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. 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. Figure 3.Methods used to assess heat-evoked pain like behaviors in rodents. 2023 Leaf Group Ltd. / Leaf Group Media, All Rights Reserved. For people who choose to own rats at home, here are some of the benefits that they can receive: Rats are very intelligent animals. Guidelines for the design and statistical analysis of experiments using laboratory animals. Figure 4.Methods used to assess cold-evoked pain like behaviors and temperature preference in rodents. doi: 10.1126/science.1108609, Morgan, D., Mitzelfelt, J. D., Koerper, L. M., and Carter, C. S. (2012). J. Med. J. Pharmacol. doi: 10.1213/01.ane.0000158471.41575.f0, Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., et al. A Biol. Rice JE 3rd, Vannucci RC, Brierley JB. (2013). 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. Braz. A response is considered positive if the animal exhibits any nocifensive behaviors, including brisk paw withdrawal, licking, or shaking of the paw, either during application of the stimulus or immediately after the filament is removed. Invest. Experimenters experienced in the technique are able to distinguish between touch on or false positive responses, however, this can be difficult for inexperienced researchers and extensive training is usually required to produce high quality data. They helped shape the ideas of operant conditioning in behaviorism. Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: behavioral evidence. 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. Exp. Copyright 2017 Deuis, Dvorakova and Vetter. Eur. 47, 810. The advantage of this approach is that each animal receives the same number and type of stimuli, although the number of tests per hind paw could exceed 50 (e.g., five different von Frey filaments each applied 10 times), which is not only time consuming, but potentially exposes animals with mechanical hind paw sensitivity to a disproportionate number of more aversive stimuli. Figure 5.Temperature preference assays. Mice are cost effective because they are cheap and easy to look after. A survey posted only on its website limits the number of people who will participate to those who already had an interest in their products, which causes a voluntary response bias. 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). Int. Ishikawa, G., Nagakura, Y., Takeshita, N., and Shimizu, Y. Both versions of the test require the animal to be loosely restrained. Front. Rev. International standards and guidelines, as well as country-specific codes and legislation, have been developed to protect the welfare of animals used for research. Undoubtedly, nociception, or the ability to detect a potentially harmful stimulus, is a fundamental physiological function in mammals and indeed many other species. Mol. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. doi: 10.1016/s0304-3959(00)00307-9, Kim, S. H., and Chung, J. M. (1992). The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. One way to evaluate nociception in non-communicating subjects is through observation of behavior. An additional disadvantage of the hot plate test is that all four paws and the tail are exposed to the heat stimulus. Science 307, 14681472. Z., Rodriguez, K. B., Gallo, M. S., Pritchett-Corning, K., Karas, R. H., et al. Am. It is estimated that more than 50 million animals are used in experiments each year in the United States. 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). 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). Ther. 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 addition, the Hargreaves test enables quantification of heat thresholds in unrestrained animals, reducing the likelihood of stress-induced responses. 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. (2016). (C) The percent response method. Nociceptors: the sensors of the pain pathway. 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). Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. Pain 20, 231240. 3. doi: 10.1016/s0885-3924(05)80022-3, Giglio, C. A., Defino, H. L., da-Silva, C. A., de-Souza, A. S., and Del Bel, E. A. Rev. A soft transducer ensures minimal vibration and reduces touch-on responses. Methods 113, 9197. This therefore provides measure of paw withdrawal threshold on a continual scale, as the force is applied continuously and not in steps. The evaluation of the analgesic action of pethidine hydrocholoride (Demerol). The framework for these standards and guidelines are based on the principles of the 3Rs (replacement, reduction, refinement). doi: 10.1016/s0304-3959(96)03176-4, Yeomans, D. C., and Proudfit, H. K. (1994). A modified version of the thermal probe test suitable for quantifying heat thresholds in rats is still to be developed. Arthritis Rheum. doi: 10.1038/nature05910, Bennett, D. L., and Woods, C. G. (2014). In addition, welfare benefits in form of testing of unrestrained mice and exposure of only a single hind paw to a noxious heat stimulus are favorable. doi: 10.1016/0304-3959(85)90145-9, Choi, Y., Yoon, Y. W., Na, H. S., Kim, S. H., and Chung, J. M. (1994). 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. 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. 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. Other advantages of this methodology include eliminating the phenomenon of clustered selection and a low .
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