(366) Voluntary activity prevents muscle IL1β upregulation to inhibit the development of ischemic myalgia

Abstract

Issues of peripheral circulation have been increasingly suggested as an underlying cause of musculoskeletal pain in many clinical conditions. In a model of ischemia and reperfusion injury (I/R), we have previously shown in male Swiss Webster mice that I/R induces alterations in chemosensitivity and mechanical thresholds of individual group III and IV muscle afferents as assessed with an ex vivo muscle-nerve-dorsal root ganglion (DRG)-spinal cord recording preparation. We have also shown that I/R increases pain-related behaviors while decreasing muscle strength and voluntary activity. This appeared to be due to enhanced interleukin 1β (IL1β) in the injured muscles and its receptor IL1 receptor 1 (IL1r1) within the DRGs, as an afferent-specific knockdown of IL1r1 inhibited I/R-induced changes in afferent response properties and animal behaviors. Here we show that voluntary wheel running prior to I/R prevented the injury-induced increase in muscle IL1β and the subsequent development of spontaneous (guarding) and evoked (von Frey mechanical stimulation) pain-related behaviors, as well as attenuating I/R-induced deficits in grip strength and voluntary activity. In addition, systemic injection of the IL1 receptor antagonist (IL1RA), which would block effects of IL1β during I/R, was also found to prevent injury-induced upregulation of IL1r1 within the DRGs, and recapitulated most of the preventative effects of exercise or nerve-specific IL1r1 knockdown on I/R-related behaviors. IL1RA-treated animals, however, still experienced an I/R-induced grip strength deficit, suggesting that systemic inhibition of IL1β may potentially have other effects on muscle function. Nevertheless, IL1RA was still found to block I/R-induced changes in mechanical thresholds and chemosensitive muscle afferent prevalence. Altogether, these data strengthen the evidence that increased IL1β in the muscles during I/R sensitizes group III and IV muscle afferents, leading to the development of muscle pain. This work also suggests potential therapies for prevention of persistent muscle pain initiated by an ischemic insult. Issues of peripheral circulation have been increasingly suggested as an underlying cause of musculoskeletal pain in many clinical conditions. In a model of ischemia and reperfusion injury (I/R), we have previously shown in male Swiss Webster mice that I/R induces alterations in chemosensitivity and mechanical thresholds of individual group III and IV muscle afferents as assessed with an ex vivo muscle-nerve-dorsal root ganglion (DRG)-spinal cord recording preparation. We have also shown that I/R increases pain-related behaviors while decreasing muscle strength and voluntary activity. This appeared to be due to enhanced interleukin 1β (IL1β) in the injured muscles and its receptor IL1 receptor 1 (IL1r1) within the DRGs, as an afferent-specific knockdown of IL1r1 inhibited I/R-induced changes in afferent response properties and animal behaviors. Here we show that voluntary wheel running prior to I/R prevented the injury-induced increase in muscle IL1β and the subsequent development of spontaneous (guarding) and evoked (von Frey mechanical stimulation) pain-related behaviors, as well as attenuating I/R-induced deficits in grip strength and voluntary activity. In addition, systemic injection of the IL1 receptor antagonist (IL1RA), which would block effects of IL1β during I/R, was also found to prevent injury-induced upregulation of IL1r1 within the DRGs, and recapitulated most of the preventative effects of exercise or nerve-specific IL1r1 knockdown on I/R-related behaviors. IL1RA-treated animals, however, still experienced an I/R-induced grip strength deficit, suggesting that systemic inhibition of IL1β may potentially have other effects on muscle function. Nevertheless, IL1RA was still found to block I/R-induced changes in mechanical thresholds and chemosensitive muscle afferent prevalence. Altogether, these data strengthen the evidence that increased IL1β in the muscles during I/R sensitizes group III and IV muscle afferents, leading to the development of muscle pain. This work also suggests potential therapies for prevention of persistent muscle pain initiated by an ischemic insult.