High-Intensity Swimming Exercise Decreases Glutamate-Induced Nociception by Activation of G-Protein-Coupled Receptors Inhibiting Phosphorylated Protein Kinase A

Abstract

Several studies in humans have reported that improved pain control is associated with exercise in a variety of painful conditions, including osteoarthritis, fibromyalgia, and neuropathic pain. Despite the growing amount of experimental data on physical exercise and nociception, the precise mechanisms through which high-intensity exercise reduces pain remain elusive. Since the glutamatergic system plays a major role in pain transmission, we firstly analyzed if physical exercise could be able to decrease glutamate-induced nociception through G-protein-coupled receptor (G-PCR) activation. The second purpose of this study was to examine the effect of exercising upon phosphorylation of protein kinase A (PKA) isoforms induced by intraplantar (i.pl.) glutamate injection in mice. Our results demonstrate that high-intensity swimming exercise decreases nociception induced by glutamate and that i.pl. or intrathecal injections of cannabinoid, opioid, and adenosine receptor antagonists, AM281, naloxone, and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), respectively, prevent this effect. Furthermore, the peripheral A and opioid receptors, but not CB, are also involved in exercise's effect. We also verified that glutamate injection increases levels of phosphorylated PKA (p-PKA). High-intensity swimming exercise significantly prevented p-PKA increase. The current data show the direct involvement of the glutamatergic system on the hyponociceptive effect of high-intensity swimming exercise as well as demonstrate that physical exercise can activate multiple intracellular pathways through G-PCR activation, which share the same endogenous mechanism, i.e., inhibition of p-PKA.

Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena

“…; Martins et al . ), and treadmill running in chronic muscle pain (5‐day running) and neuropathic pain models (5‐weeks running) (Bement & Sluka, ; Stagg et al . ).…”

High‐intensity swimming exercise reduces inflammatory pain in mice by activation of the endocannabinoid system

“…However, in the studies of Galdino et al 10 and Martins et al 13 i.pl. injection of AM281 did not prevent high‐intensity swimming‐induced antinociception.…”

“…As low‐intensity PEx has no effect upon the eCB system, 31 this study followed a high‐intensity swimming protocol adapted from Mazzardo‐Martins et al 20 in which PEx decreased mechanical hyperalgesia induced by ischemia and reperfusion of the ankle in a murine model of complex regional pain syndrome, 34 as well as diminished somatic nociception induced by glutamate i.pl. injection 13 …”

“…Lactate concentration was analyzed with a lactate meter (Accutrend ® Roche) and BM‐Lactate tapes (Accutrend ® Roche). Blood lactate concentration was analyzed at 10 and 30 minutes during swimming exercise on day 7 13 …”

“…While exercise intervention is growing quickly as a clinical tool for many diseases, its primary use to reduce pain is still relatively new and the research available leaves an incomplete picture of the mechanisms and pathways involved 1,13 . For this reason, the present study was carried out to determine the contributions of the eCB system to the antihyperalgesic effects of cumulative high‐intensity swimming exercise (HISE), in addition to determining the that central (spinal) and/or peripheral (hindpaw) tissues play through different CB receptor subtypes.…”