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      Improvements in impaired GABA and GAD65/67 production in the spinal dorsal horn contribute to exercise-induced hypoalgesia in a mouse model of neuropathic pain

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          Abstract

          Background

          Physical exercise effectively attenuates neuropathic pain, and multiple events including the inhibition of activated glial cells in the spinal dorsal horn, activation of the descending pain inhibitory system, and reductions in pro-inflammatory cytokines in injured peripheral nerves may contribute to exercise-induced hypoalgesia. Since fewer GABAergic hypoalgesic interneurons exist in the dorsal horn in neuropathic pain model animals, the recovery of impaired GABAergic inhibition in the dorsal horn may improve pain behavior. We herein determined whether the production of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD) in the dorsal horn is restored by treadmill running and contributes to exercise-induced hypoalgesia in neuropathic pain model mice. C57BL/6 J mice underwent partial sciatic nerve ligation (PSL). PSL-Runner mice ran on a treadmill at 7 m/min for 60 min/day, 5 days/week, from two days after PSL.

          Results

          Mechanical allodynia and heat hyperalgesia developed in PSL-Sedentary mice but were significantly attenuated in PSL-Runner mice. PSL markedly decreased GABA and GAD65/67 levels in neuropils in the ipsilateral dorsal horn, while treadmill running inhibited these reductions. GABA+ neuronal nuclei+ interneuron numbers in the ipsilateral dorsal horn were significantly decreased in PSL-Sedentary mice but not in PSL-Runner mice. Pain behavior thresholds positively correlated with GABA and GAD65/67 levels and GABAergic interneuron numbers in the ipsilateral dorsal horns of PSL-Sedentary and -Runner mice.

          Conclusions

          Treadmill running prevented PSL-induced reductions in GAD65/67 production, and, thus, GABA levels may be retained in interneurons and neuropils in the superficial dorsal horn. Therefore, improvements in impaired GABAergic inhibition may be involved in exercise-induced hypoalgesia.

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          Most cited references50

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          Two genes encode distinct glutamate decarboxylases.

          gamma-Aminobutyric acid (GABA) is the most widely distributed known inhibitory neurotransmitter in the vertebrate brain. GABA also serves regulatory and trophic roles in several other organs, including the pancreas. The brain contains two forms of the GABA synthetic enzyme glutamate decarboxylase (GAD), which differ in molecular size, amino acid sequence, antigenicity, cellular and subcellular location, and interaction with the GAD cofactor pyridoxal phosphate. These forms, GAD65 and GAD67, derive from two genes. The distinctive properties of the two GADs provide a substrate for understanding not only the multiple roles of GABA in the nervous system, but also the autoimmune response to GAD in insulin-dependent diabetes mellitus.
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            Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.

            To clarify whether inhibitory transmission in the superficial dorsal horn of the spinal cord is reduced after peripheral nerve injury, we have studied synaptic transmission in lamina II neurons of an isolated adult rat spinal cord slice preparation after complete sciatic nerve transection (SNT), chronic constriction injury (CCI), or spared nerve injury (SNI). Fast excitatory transmission remains intact after all three types of nerve injury. In contrast, primary afferent-evoked IPSCs are substantially reduced in incidence, magnitude, and duration after the two partial nerve injuries, CCI and SNI, but not SNT. Pharmacologically isolated GABA(A) receptor-mediated IPSCs are decreased in the two partial nerve injury models compared with naive animals. An analysis of unitary IPSCs suggests that presynaptic GABA release is reduced after CCI and SNI. Partial nerve injury also decreases dorsal horn levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) 65 kDa ipsilateral to the injury and induces neuronal apoptosis, detected by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining in identified neurons. Both of these mechanisms could reduce presynaptic GABA levels and promote a functional loss of GABAergic transmission in the superficial dorsal horn.
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              Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids.

              Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems. After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry. Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area. Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.
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                Author and article information

                Journal
                Mol Pain
                Mol Pain
                MPX
                spmpx
                Molecular Pain
                SAGE Publications (Sage CA: Los Angeles, CA )
                1744-8069
                7 March 2016
                2016
                : 12
                : 1744806916629059
                Affiliations
                [1 ]Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama City, Wakayama, Japan
                [2 ]Department of Physical Therapy, Osaka Yukioka College of Health Science, Ibaraki City, Osaka, Japan
                Author notes
                [*]Katsuya Kami, PhD, Department of Rehabilitation Medicine, Wakayama Medical University, Kimiidera-811-1, Wakayama City, Wakayama 641-8509, Japan. Email: kami@ 123456wakayama-med.ac.jp
                Article
                10.1177_1744806916629059
                10.1177/1744806916629059
                4956002
                27030712
                41080526-4f47-4d73-b56c-5c7d1d5b5854
                © The Author(s) 2016

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 14 October 2015
                : 4 December 2015
                Categories
                Original Article
                Custom metadata
                January-December 2016

                Molecular medicine
                gamma-aminobutyric acid,glutamic acid decarboxylase,neuropathic pain,exercise-induced hypoalgesia,treadmill running

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