13840110d2d515487e83b87 disadvantages of using rats in research 13840110d2d515487e83b87 disadvantages of using rats in research

doi: 10.1016/0166-4328(93)90035-o, Festing, M. F., and Altman, D. G. (2002). 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). J. Clin. The temperature at which this occurs is designated as the response temperature (Ogren and Berge, 1984; Tjolsen et al., 1991). Sci. (2012). Sci. 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. 9, 8998. Studying ongoing and spontaneous pain in rodentschallenges and opportunities. Coding of facial expressions of pain in the laboratory mouse. This sample - and the results - are biased, as most workers are at their jobs during these hours. Pain 68, 133140. Anim. The force ramp and paw withdrawal force are displayed by the software post-test. 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). Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. doi: 10.1523/JNEUROSCI.1526-05.2005, Schtt, E., Berge, O. G., Angeby-Mller, K., Hammarstrm, G., Dalsgaard, C. J., and Brodin, E. (1994). 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 141, 261269. 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). doi: 10.1038/nprot.2006.19, Decosterd, I., and Woolf, C. J. 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. Rodents are placed in an enclosed box with a camera, accelerometer and wall-mounted photobeams for a set period of time. While not in routine clinical use, quantitative sensory testing has the potential to improve patient outcomes by classifying pain based on the mechanism and choosing treatments that target that mechanism (Baron et al., 2010; Cruz-Almeida and Fillingim, 2014). The force at which this response occurs is recorded automatically by the apparatus and is designated as the paw withdrawal threshold. Science 307, 14681472. 47, 810. Monkeys, rabbits, cats, ferrets, pigs, sheep and chimpanzees are just some of the animals used for biomedical experiments, science education, and product and cosmetics testing. All we can possibly learn from high-dose experiments is what might happen in overdose situations. Under the direction of the researcher, the apparatus applies a von Frey (0.5 mm) filament to the plantar surface, increasing the force incrementally (050 g) until the paw withdrawal threshold is reached. Direct intrathecal drug delivery in mice for detecting in vivo effects of cGMP on pain processing. An overview of animal models of pain: disease models and outcome measures. 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). Front. Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice. 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. Methods 87, 185193. 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. Quantitative somatosensory testing of warm and heat-pain thresholds: the effect of body region and testing method. In the conventional hot plate test the rodent is placed on a metal surface maintained at a constant temperature (in this case 54C) and the time taken to elicit a nocifensive behavior (e.g., hind paw withdrawal or licking) is recorded. Digigait quantitation of gait dynamics in rat rheumatoid arthritis model. Pain 10, 767773. An additional confounding factor in the hot plate test is the tendency for learned behavioral responses, which lead to diminished reaction times during subsequent exposures to the hot plate (Gamble and Milne, 1989; Plone et al., 1996). Evaluation of the usefulness of two established pain assessment tools in a burn population. doi: 10.1111/ejn.12643, Tetreault, P., Dansereau, M. A., Dor-Savard, L., Beaudet, N., and Sarret, P. (2011). 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. Both versions of the test require the animal to be loosely restrained. Sci. 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. Almost all disease-linked human genes have counterparts in the rat. Three main ethical attitudes towards animals are reviewed here. 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. J. Methods 131, 9397. (2010). An additional disadvantage of the hot plate test is that all four paws and the tail are exposed to the heat stimulus. However, it is unclear to what degree changes in gait in rodent models reflect altered pain or nociception, or conversely, anti-nociception or analgesia. (1999). 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. The mouse with a human ear on its back may have been one of the more bizarre and visually unsettling experiments carried out on a rodent, but mice have been used for scientific experiments since. The sheep grimace scale as an indicator of post-operative distress and pain in laboratory sheep. 7. 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). Behav. 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. doi: 10.1016/s0304-3959(96)03177-6, Yin, K., Deuis, J. R., Lewis, R. J., and Vetter, I. 10:284. doi: 10.3389/fnmol.2017.00284. The temperature preference is used as a surrogate measure of thermal aversion and aims to assess temperature preference in rodents. Ther. Painful and painless channelopathies. Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. A camera below records the paw prints, which are illuminated by internally reflected light in the glass. doi: 10.1016/0160-5402(91)90014-v, Touska, F., Winter, Z., Mueller, A., Vlachova, V., Larsen, J., and Zimmermann, K. (2016). It is the premier source of information on the laboratory rat. Similar to the Hargreaves test, the thermal probe tests enables quantification of ipsilateral and contralateral heat thresholds in unrestrained mice, but with a shorter habituation time of 510 min. Rats are often used to study behaviour in psychology experiments. Pain 88, 5360. In the Mouse Grimace Scale (Figure 6A), five facial features are scored: orbital tightening, nose bulge, cheek bulge, ear position, and whisker position (Langford et al., 2010). J. Pharmacol. 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. Pain 22, 130136. 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). 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. J. The effects of morphine methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation. Eng. As the test is performed in relatively unrestrained rodents, it relies heavily on the animal freely taking up the correct stance, which can be difficult to achieve in mice. Different methodological approaches are used to determine mechanical sensitivity using manual Von Frey, including the up-down, ascending stimulus or percent response method, all of which will be discussed below. 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. Alternatively, a continuous temperature gradienteither in linear (Figure 5B) or circular formcan be used to determine the preferred temperature in freely moving animals (Moqrich et al., 2005; Touska et al., 2016). J. Pain studies in humans are difficult to perform, are subjective, and are limited by ethical considerations, leading to the widespread use of animals as models to study pain, with the most commonly used species being mice and rats (Mogil, 2009). The Practical Mouse Despite the advantages rats have over mice as human analogs, mice have dominated the modern genetic and biomedical research landscape. Pain in rodents is associated with decreased burrowing behaviors. Both instruments have been validated against manual von Frey filaments and found to produce less variable data in addition to being easier to use. 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. Nat. Alternatively, the number of flinches over a set period of time can be recorded at a specific temperature (Yalcin et al., 2009; Deuis et al., 2013; Zimmermann et al., 2013), although care must be taken that the chosen temperature and duration do not induce tissue damage or nocifensive behavior in nave animals. (2005). Pain research in animals. Novel use of perineural pregabalin infusion for analgesia in a rat neuropathic pain model. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. While the underlying principle of the temperature gradient assay is similar to the two-temperature choice assay, the animal is free to explore along the gradient (usually between 4C and 65C over a length of 120 cm) until they settle within their preferred temperature or comfort zone. Eur. 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: 10.1258/la.2008.007156, Sandkhler, J. It is estimated that more than 50 million animals are used in experiments each year in the United States. 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). Pain Med. doi: 10.1016/j.jpain.2013.01.770, Ogren, S. O., and Berge, O. G. (1984). The mouse genome is very similar to our own, making mouse genetic research particularly useful for the study of human diseases. doi: 10.1016/0006-8993(86)91138-8, Jirkof, P., Cesarovic, N., Rettich, A., Nicholls, F., Seifert, B., and Arras, M. (2010). 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). doi: 10.1016/S1474-4422(10)70143-5, Bautista, D. M., Siemens, J., Glazer, J. M., Tsuruda, P. R., Basbaum, A. I., Stucky, C. L., et al. J. Pharmacol. The experiment begins by testing the response to a filament estimated to be close to the 50% withdrawal threshold. J. Neurosci. Nurs. 1. Nat. Lett. Facial expressions of mice can be used to score the subjective intensity of pain. The HomeCageScan has been validated in mouse models of post-surgical pain following vasectomy and laparotomy (Roughan et al., 2009, 2016). Figure 1. Methods 224, 4857. 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. (2007). Rodents are placed individually in small enclosures with a glass floor. However, irrespective of the method used, the endpoint is paw withdrawal to a stimulus that is not normally aversive, and thus both methods can measure mechanical allodynia. (E) Behavioral Spectrometer (Behavioral Instruments). Exp. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Mice are cost effective because they are cheap and easy to look after. 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. 13, 587599. Differentiating thermal allodynia and hyperalgesia using dynamic hot and cold plate in rodents. Behav. Res. Practical mechanical threshold estimation in rodents using von Frey hairs/Semmes-Weinstein monofilaments: towards a rational method. Animals 6:47. doi: 10.3390/ani6080047. The main advantage of electronic Von Frey compared to manual Von Frey is that an increasing force is applied by a single filament. doi: 10.1371/journal.pone.0098856, Huang, S. M., Li, X., Yu, Y., Wang, J., and Caterina, M. J. (2011). 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 . Not only does your survey suffer due to timing, but the number of subjects does not help make up for this deficiency. Lancet 353, 19591964. The rodent is restrained and the hind paw (or tail) is placed between a pointed probe tip and flat surface. The framework for these standards and guidelines are based on the principles of the 3Rs (replacement, reduction, refinement). LabSand is a natural, contaminant free, hydrophobic sterile sand that is spread in a. doi: 10.1016/j.jpain.2009.01.325, Yamamoto, K., Tsuboi, M., Kambe, T., Abe, K., Nakatani, Y., Kawakami, K., et al. The first (1880-1950) was when mice and rats became common research animals. (2009). Behav. Mol. 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. (C) Weight bearing (incapacitance test). The most common case of bias is a result of non-response. Its characterized primarily by motor impairment, but there are also a range of accompanying conditions such as seizure disorders and cognitive defects. doi: 10.1111/pme.12230, Dalla Costa, E., Stucke, D., Dai, F., Minero, M., Leach, M. C., and Lebelt, D. (2016). This shift was primarily instigated by the availability of a much . Braz. PLoS One 7:e39765. Models and mechanisms of hyperalgesia and allodynia. The Hargreaves test permits measurement of ipsilateral and contralateral heat thresholds, allowing each animal to serve as its own internal control in unilateral pain models. Anesth. 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. The device automatically records the force at which paw withdrawal occurs and the rate at which the force is applied can be changed. (2011). Rep. 7:40883. doi: 10.1038/srep40883, Deuis, J. R., Yin, K., Cooper, M. A., Schroder, K., and Vetter, I. Neurosci. While the method carries the disadvantage that the rodent has to be restrained, the tail flick test is of very short duration so handling can be minimized easily. Analg. Mol. The same methods that allow this to be so in mice have failed in rats. For an overview of commonly used pain models in rodents see Gregory et al. Lett. However, this requires the animals to be acclimatized to the apparatus to minimize ambulation so that withdrawal latencies can be accurately determined. Neuron 70, 482494. 1981. 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). Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. 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). Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence. In addition, as for manual Von Frey tests, animals still need to be habituated to the cages until exploratory behaviors have ceased. If the response rate is less than 40% (i.e., a withdrawal response is elicited in none or one out of five applications) the next filament is tested. Animal models of pain: progress and challenges. 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 . Lancet 383(9924): 1240-9. Of acute wounds, burns are one of the most devastating injuries known to mankind. Some animals, however, are more preferred by laboratories. An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. This review article will provide an overview of the current behavioral methods that are used to assess pain behaviors in mice and rats. Physiol. Sample size determination. In its simplest form, the animal can choose between two adjacent areas maintained at different temperatures. Mol. Click the button below to get a quote! Mol. (1988). To quantify temperature sensitivity, the time the animal spends on the test plate relative to the reference plate is measured over a set period and is then compared to control animals. *Correspondence: Irina Vetter, i.vetter@uq.edu.au, View all 119, 481488. Mol. And more precise technologies have become available as well, such as using CRISPR to targeting rat spermatogonial stem cells. doi: 10.1016/j.ejpain.2004.10.006, Wibbenmeyer, L., Sevier, A., Liao, J., Williams, I., Latenser, B., Lewis, R., et al. 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). In this experiment, a previously unafraid baby was conditioned to become afraid of a rat. 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. Sci. Rat models are therefore still widely used. Pharmacodyn. Rice JE 3rd, Vannucci RC, Brierley JB. Neuropathic pain: aetiology, symptoms, mechanisms, and management. 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. Analysis of behaviors in unrestrained animals using automated technologies is increasingly being used to study non-stimulus evoked pain in rodents. 1, 28282830. Exp. PLoS One 10:e0125822. 39, 16131623. The hypoxia-ischemia model, first published in 1981, has brain damage similar to that observed in cerebral palsy patients. 64, 8187. Figure 5.Temperature preference assays. The need for randomization in animal trials: an overview of systematic reviews. Figure 4.Methods used to assess cold-evoked pain like behaviors and temperature preference in rodents. Behav. PLoS One 12:e0175839. 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). doi: 10.1016/0304-3959(94)90023-x, Colburn, R. W., Lubin, M. L., Stone, D. J. Jr., Wang, Y., Lawrence, D., DAndrea, M. R., et al.