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      Comparison of Burrowing and Stimuli-Evoked Pain Behaviors as End-Points in Rat Models of Inflammatory Pain and Peripheral Neuropathic Pain

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          Abstract

          Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤ 450 g of gravel on any 2 days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund's complete adjuvant (FCA) or saline, or underwent unilateral chronic constriction injury (CCI) of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA-and CCI- rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

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          A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.

          A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
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            Chronic pain epidemiology and its clinical relevance.

            Chronic pain affects ∼20% of the European population and is commoner in women, older people, and with relative deprivation. Its management in the community remains generally unsatisfactory, partly because of lack of evidence for effective interventions. Epidemiological study of chronic pain, through an understanding of its distribution and determinants, can inform the development, targeting, and evaluation of interventions in the general population. This paper reviews current knowledge of risk markers associated with chronic pain and considers how these might inform management and prevention. Risk factors include socio-demographic, clinical, psychological, and biological factors. These are relevant to our understanding of chronic pain mechanisms and the nature of, and responses to, current and future treatments.
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              Unmasking the tonic-aversive state in neuropathic pain.

              Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.
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                Author and article information

                Contributors
                Journal
                Front Behav Neurosci
                Front Behav Neurosci
                Front. Behav. Neurosci.
                Frontiers in Behavioral Neuroscience
                Frontiers Media S.A.
                1662-5153
                10 May 2016
                2016
                : 10
                : 88
                Affiliations
                [1] 1Centre for Integrated Preclinical Drug Development, The University of Queensland Brisbane, QLD, Australia
                [2] 2Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG Biberach, Germany
                [3] 3School of Pharmacy, The University of Queensland, St Lucia Campus Brisbane, QLD, Australia
                Author notes

                Edited by: Gal Richter-Levin, University of Haifa, Israel

                Reviewed by: Emma Robinson, Bristol University, UK; Femke Buisman-Pijlman, The University of Adelaide, Australia

                *Correspondence: Maree T. Smith maree.smith@ 123456uq.edu.au
                Article
                10.3389/fnbeh.2016.00088
                4862327
                27242458
                3daa66b7-06f3-4258-a212-92dbb7779793
                Copyright © 2016 Muralidharan, Kuo, Jacob, Lourdesamy, Carvalho, Nicholson, Corradini and Smith.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 December 2015
                : 22 April 2016
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 37, Pages: 9, Words: 6514
                Funding
                Funded by: Australian Research Council 10.13039/501100000923
                Award ID: LP120200623
                Categories
                Neuroscience
                Original Research

                Neurosciences
                burrowing,cci,fca,inflammatory pain,mechanical allodynia,mechanical hyperalgesia,paw volume,peripheral neuropathic pain

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