Abstract
Voluntary exercise is sufficient to protect against neuropathic pain. However, it is unclear whether voluntary exercise reduces immobilization-induced hyperalgesia. We examined the effect of voluntary forelimb exercise on immobilized-induced hyperalgesia in hind paws of rats. Wistar rats were randomly divided into the (1) both hind limbs immobilized group (IM group), (2) immobilization and exercise with nonimmobilized fore limbs group (EX group), and (3) control group. In the IM and EX groups, the bilateral ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for eight weeks. In the EX group, voluntary exercise using nonimmobilized forelimbs in the running wheel was administered during the immobilization period, while hind limbs were kept immobilized (60 min/day, 5 days/week). Mechanical hyperalgesia in the hind paw was measured using a digital von Frey device every week. To investigate the abnormality of primary sensory neurons and central sensitization, the number of calcitonin gene-related peptide-positive cells in the dorsal root ganglion and the expression level of calcitonin gene-related peptide in the spinal dorsal horn were analyzed by immunohistochemical staining. Immobilization-induced mechanical hyperalgesia was inhibited in the EX group compared to the IM group at three weeks after immobilization. In the EX group, the number of calcitonin gene-related peptide-positive cells in the dorsal root ganglion and the expression level of calcitonin gene-related peptide were significantly decreased compared to those in the IM group. Our results therefore suggest that voluntary forelimb exercise during hind limb immobilization partially reduces immobilization-induced hyperalgesia by suppressing that the plastic changes of the primary sensory nerves that excessively transmit pain and increased responsiveness of nociceptive neurons in the spinal dorsal horn.
Highlights
Limb immobilization is a widely used medical treatment for injuries
A previous animal study [6] reported that limb immobilization with cast causes the increase in calcitonin gene-related peptide (CGRP) expression in both the superficial and deep layers of the dorsal horn and altered expression of CGRP in dorsal root ganglia, i.e., increased expression in mediumsized neuron and decreased expression in small-sized neuron, which is called phenotype switch. ese alterations in the nervous system are thought to be involved in immobilization-induced hyperalgesia [6, 7] and that immobilization-induced hyperalgesia may shift to chronic pain when cast immobilization is prolonged [3, 4]. erefore, interventions should be developed to prevent the development and progression of immobilization-induced hyperalgesia even when the affected limb is immobilized
At baseline and the first week, there were no significant differences between the groups. e Paw Withdrawal Response (PWR) in the IM and EX groups began to decrease significantly, two weeks after immobilization compared to that in the control group. e decrease in PWR in the IM group persisted throughout the experimental period
Summary
Limb immobilization is a widely used medical treatment for injuries. joint immobilization causes various degenerative and atrophic changes in intact organs and tissues, including muscular disuse atrophy and joint contractures in human and animal experiments [1, 2]. CGRP is a neurotransmitter of nociceptive primary afferents and is mainly produced in dorsal root ganglion (DRG) of small neurons with nonmyelinated axons (C-fibers) and medium-sized neurons with myelinated axons (Aδ-fibers). It releases to the superficial (laminae I-II) and deep layers (laminae III–VI) of the dorsal horn of the spinal cord, respectively. A previous animal study [6] reported that limb immobilization with cast causes the increase in CGRP expression in both the superficial and deep layers of the dorsal horn and altered expression of CGRP in dorsal root ganglia, i.e., increased expression in mediumsized neuron and decreased expression in small-sized neuron, which is called phenotype switch. A previous animal study [6] reported that limb immobilization with cast causes the increase in CGRP expression in both the superficial and deep layers of the dorsal horn and altered expression of CGRP in dorsal root ganglia, i.e., increased expression in mediumsized neuron and decreased expression in small-sized neuron, which is called phenotype switch. ese alterations in the nervous system are thought to be involved in immobilization-induced hyperalgesia [6, 7] and that immobilization-induced hyperalgesia may shift to chronic pain when cast immobilization is prolonged [3, 4]. erefore, interventions should be developed to prevent the development and progression of immobilization-induced hyperalgesia even when the affected limb is immobilized
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