These measures can have a profound effect on the apparent anti-nociceptive efficacy of test compounds and should thus be carefully considered during experimental design (Winter and Flataker, 1965). J. doi: 10.1016/0304-3959(88)90026-7, Harvey, V. L., and Dickenson, A. H. (2009). It should be noted that behavioral assessment of animals in groups (even if blinded) is typically not sufficient, with a preferred method being measurements performed on animals in random order by an investigator blinded to the treatment group each animal has been allocated to. (2011). (B) Electronic von Frey (MouseMet, TopCat Metrology). Similarly, human scoring lends itself to bias, although this can be avoided with appropriate randomization, allocation concealment and blind outcome assessment (Hirst et al., 2014). 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. J. Neurosci. 86, 284288. What are some disadvantages of using Wistar rats in research - Quora Testing should also be avoided while the animal is engaged in grooming behaviors, as this can produce false negative responses. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Exp. Nonetheless, the thermal probe test remains to be validated in other pain models that cause more pronounced mechanical allodynia. 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. Lett. It is now possible to more easily manipulate the rat genome to produce specific gene knockouts and knockins and apply results to our understanding of human genetic disorders. Pain 88, 5360. Research scientists worldwide agree that the use of rat models for disease research and experimentation has become more relevant in the past few years. Why are Rats Used in Research? | Kent Scientific Mechanical hyperalgesia and allodynia can be further subdivided into dynamic (triggered by brushing), punctate (triggered by touch) and static (triggered by pressure). 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. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. 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. This therefore provides measure of paw withdrawal threshold on a continual scale, as the force is applied continuously and not in steps. 1, 383412. 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. (2009). The latency to paw withdrawal is recorded and used to quantify cold allodynia and hyperalgesia. The sheep grimace scale as an indicator of post-operative distress and pain in laboratory sheep. It should be noted that the paw withdrawal threshold can be considered a measure of spinal reflex, with some researchers favoring vocalization as an end-point (Winter and Flataker, 1965; Kayser and Christensen, 2000; Santos-Nogueira et al., 2012). Lab. Individual differences in the hotplate test and effects of habituation on sensitivity to morphine. 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/s0165-0270(99)00004-7, Plone, M. A., Emerich, D. F., and Lindner, M. D. (1996). 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. Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. Biol. 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. Cerebral palsy. Dogs, cats, and nonhuman primates together account for less than 1% of all animals necessary for medical research. doi: 10.3791/52640, Brodkin, J., Frank, D., Grippo, R., Hausfater, M., Gulinello, M., Achterholt, N., et al. Quantitative assessment of tactile allodynia in the rat paw. 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. 372, 301312. Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain. 10, 283294. Cartil. Spinal processing of noxious and innocuous cold information: differential modulation by the periaqueductal gray. Other advantages of this methodology include eliminating the phenomenon of clustered selection and a low . 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). Veterinarians; researchers who use rats in their experiments on aging, drug addiction, cancer, spinal cord injury, cardiovascular disease, Alzheimer's disease . 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. The device automatically records the temperature that paw withdrawal occurred (in this case 50C). Rock, M. L., Karas, A. (2014). 64, 8187. Animal Testing | Pros & Cons | ProCon.org These people will not be included in the survey, and the survey's accuracy will suffer from non-response. In this assay rodents walk freely across an enclosed elevated glass floor. 738, 111117. A method for determining loss of pain sensation. Behavioral measures of pain thresholds. This book condenses information from many sources on topics related to the care and use of rats in research. 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. Sci. The Little Albert Experiment demonstrated that classical conditioning could be used to create a phobia. An additional disadvantage of incapacitance or static weight bearing tests is that only models with unilateral hind paw nociception can be assessed in this manner. Gene editing technologies allow scientists to use rats more often in their research. Toxicol. (E) Behavioral Spectrometer (Behavioral Instruments). The larger size when compared to mice makes handling, sampling and performing procedures easier. The most common case of bias is a result of non-response. 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). 24, 19281939. 107, 497503. The menthol receptor TRPM8 is the principal detector of environmental cold. Frontiers | Methods Used to Evaluate Pain Behaviors in Rodents (2017). And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. J. Pharmacol. J. Pharmacol. doi: 10.1093/gerona/glr210, OBrien, D. E., Brenner, D. S., Gutmann, D. H., and Gereau, R. W. IV (2013). This sample - and the results - are biased, as most workers are at their jobs during these hours. 111, 409419. It should be noted that the absolute values obtained using manual and electronic Von Frey can differ significantly. Woolf, C. J., and Mannion, R. J. In this experiment, a previously unafraid baby was conditioned to become afraid of a rat. | All rights reserved. Temperature preference assays are typically relatively fast and require little rodent handling or restraint (Morgan et al., 2012). An overview of animal models of pain: disease models and outcome measures. The withdrawal response is detected visually by the researcher, resulting in subjective measurement of the threshold. The mouse genome is very similar to our own, making mouse genetic research particularly useful for the study of human diseases. 49, 117120. 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). Nocifensive behaviors include forepaw withdrawal or licking, hind paw withdrawal or licking, stamping, leaning posture and jumping (Espejo and Mir, 1993). doi: 10.1016/s0165-0270(03)00241-3, Balayssac, D., Ling, B., Ferrier, J., Pereira, B., Eschalier, A., and Authier, N. (2014). Static hyperalgesia can be superficial or deep and is assessed by the application of pressure to the skin or underlying tissue by a finger or using a pressure algometer (Jensen and Finnerup, 2014). "Its brain is larger than that of a mouse, so it's easier to study the structures," said Joyce. 104, 495502. 43, 207213. The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). Variability is determined by the standard deviation of the population; the standard deviation of a sample is how the far the true results of the survey might be from the results of the sample that you collected. The method is based on the application of monofilaments with increasing force until a withdrawal response is elicited, and the force of the von Frey filament that elicits this positive response is designated as the mechanical withdrawal threshold (Figure 2B). The rat had historically been the preferred animal model for biomedical research due to genetic and physiological similarities to humans. 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). B., and Hole, K. (1985). 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). However, it is unclear to what degree changes in gait in rodent models reflect altered pain or nociception, or conversely, anti-nociception or analgesia. 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). Williams, W. O., Riskin, D. K., and Mott, A. K. (2008). A single, un-bending filament is applied perpendicularly to the hind paw. Despite these advantages of automation, experimenters still need to be experienced to distinguish true responses from touch-on responses and ambulation. Colver A, Fairhurst C, Pharoah PO. Unlike the hot plate test, the cold plate test is particularly useful for models where only one paw is affected or sensitized by the experimental compound (unilateral pain) as guarding of the affected limb can be easily achieved, and thus can be easily quantified. A.E. Facial expressions of mice can be used to score the subjective intensity of pain. Res. Winter, C. A., and Flataker, L. (1965). doi: 10.1523/JNEUROSCI.0122-10.2010, Ltsch, J., Dimova, V., Lieb, I., Zimmermann, M., Oertel, B. G., and Ultsch, A. J. Neurotrauma 29, 898904. Differentiating analgesic and non-analgesic drug activities on rat hot plate: effect of behavioral endpoint. The Hargreaves test, first described in 1988, is a method used to quantify heat thresholds in the hind paws of mice and rats upon application of a radiant or infrared heat stimulus (Hargreaves et al., 1988). However, as animals cannot be said to be reporting pain, any reaction to such stimuli does not necessarily evidence experience of pain (Sandkhler, 2009). Technology Addiction. Weight bearing as an objective measure of arthritic pain in the rat. Neurosci. Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice. The amount of substrate displaced over a set period of time is recorded. Then in 2012, CRISPR/Cas9 changed genome manipulation as we know it. Cybersex and pornography addiction. PDF A Guide to Research Rodent Housing - Charles River Laboratories Nurs. 2011:848307. doi: 10.1155/2011/848307, Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., et al. Models and mechanisms of hyperalgesia and allodynia. 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. Brain Res. Mouse model: Pros & Cons. Ann Neurol 9(2): 131-41. PLoS One 9:e98856. (2002). February 8, 2018| Kristen Coughlin | CRISPR, Rat Models, Last Updated on January 23, 2023 by ingenious. This work was supported by an Australian Research Council Future Fellowship (IV). An additional advantage of the acetone drop test is the unilateral application of the thermal stimulus, enabling comparison to the contralateral side in unilateral models, and a perhaps more ethical stimulus in bilateral models. Quantitative somatosensory testing of warm and heat-pain thresholds: the effect of body region and testing method. Pain 7:55. doi: 10.1186/1744-8069-7-55, Tappe-Theodor, A., and Kuner, R. (2014). Pain, as defined by the International Association for the Study of Pain (IASP), is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. doi: 10.1213/ane.0000000000000291, Carlton, S. M., Lekan, H. A., Kim, S. H., and Chung, J. M. (1994). 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. 5, 94100. Neuropharmacology 23, 915924. Typically, noxious stimuli activate nociceptors, a subset of peripheral sensory neurons, which have a range of specialized ion channels and receptors that transduce noxious stimuli into electrical signals. Functional characterization of a mouse model for central post-stroke pain. doi: 10.1016/s0304-3959(96)03177-6, Yin, K., Deuis, J. R., Lewis, R. J., and Vetter, I. As pain cannot be directly measured in rodents, many methods that quantify pain-like behaviors or nociception have been developed. 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. (2014). The need for randomization in animal trials: an overview of systematic reviews. (2005). 120, 37603772. 1, 118121. To conduct a survey properly, you need to determine your sample group. In addition, the Hargreaves test enables quantification of heat thresholds in unrestrained animals, reducing the likelihood of stress-induced responses. It is descended from wild Norway rats, Rattus norvegicus, which despite their name likely originated in Asia.
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