Regular physical activity prevents development of chronic muscle pain through modulation of supraspinal opioid and serotonergic mechanisms

Abstract

The current study shows that blockade of opioid receptors systemically in the periaqueductal gray and the rostral ventromedial medulla prevents analgesia by 8 weeks of wheel running in a chronic muscle pain model. We further show increases in serotonin transporter expression and reversal of hyperalgesia with a selective reuptake inhibitor in the rostral ventromedial medulla in the chronic muscle pain model, and exercise normalizes serotonin transporter expression.

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the RVM

“…The current study showed that physically active animals have less dermorphin-488positive neurons, but not TPH-positive neurons, projecting to the spinal cord when compared to sedentary animals in the RVM, but not the NRO/NRP. These data are consistent with prior studies showing regular exercise produces analgesia through endogenous opioid systems in the RVM and spinal cord [6,39,60]. Since mu-opioid receptors are purported to be ON-cells and facilitate nociception [17,24], these data suggest that there is less descending facilitation from the RVM in physically active mice.…”

“…Since RVM and the NRO/NRP are key serotonergic nuclei, and increased serotonin in the RVM can reduce pain [6,39,51], we examined if there were differences in TPH immunoreactivity in dermorphin-488-positive cells. Figure 4 Figure 5).…”

“…Classically, the RVM is thought to modulate nociception while the NRO/NRP are thought to regulate motor function; however, there is overlap of function between these two regions with some neurons in the NRO/NRP responding to nociceptive input and some in the RVM responding to motor input. Both nuclei express mu-opioid receptors, p-NR1 and contain serotonergic neurons [23,58], alter expression of p-NR1 and the serotonin transporter after chronic muscle pain and exercise [6,39,58], and blockade of NMDA receptors in both nuclei is antinociceptive [13,14,56,62,67,68].…”

“…Regular physical activity/exercise is an important and effective non-pharmacological treatment for individuals with chronic pain [3,[8][9][10]26], and large population studies show that people who are physically active have a lower incidence of chronic pain [34,35,69]. In parallel, prior studies show that regular physical activity prevents development of chronic muscle pain, activity-induced pain, and neuropathic pain in animal models [4][5][6]19,37,39,58]. Central inhibitory mechanisms, involving serotonin and opioids, are critical to the analgesia produced by regular physical activity.…”

“…Specifically, there are increases in endogenous opioids in the rostral ventromedial medulla (RVM) and the periaqueuctal gray (PAG) with regular exercise, and blockade of opioid receptors systemically or supraspinally (RVM, PAG) reduces the analgesic effects of regular physical activity in animal models of chronic muscle pain and neuropathic pain [6,39,60]. Further, regular physical activity increases serotonin and decreases the serotonin transporter while systemic depletion of serotonin prevents the analgesia in animal models of chronic muscle pain and neuropathic pain [4,6,39]. These data show that central inhibitory pathways, including the RVM, are important components of exercise-induced analgesia.…”