Involvement of Spinal Cannabinoid CB2 Receptors in Exercise-Induced Antinociception

Abstract Muscle pain affects approximately 11–24% of the global population. Several studies have shown that exercise is a non-pharmacological therapy to pain control. It has been suggested that the endocannabinoid system is involved in this antinociceptive effect. However, the participation of this pathway is unclear. The present study aimed to investigate whether spinal cannabinoid CB2 receptors participate in the exercise-induced antinociception. The inflammatory muscle pain model was induced by the intramuscular injection of carrageenan. Tactile allodynia and thermal hyperalgesia were determined with the von Frey filaments and hot-plate tests. C57BL/6J female mice underwent a swimming training protocol that lasted 3 weeks. This protocol of exercise reduced carrageenan-induced tactile allodynia and thermal hyperalgesia and this effect was prevented by the cannabinoid CB2 receptors inverse agonist AM630 and potentiated by MAFP (inhibitor of the enzyme that metabolizes endocannabinoids) and minocycline (microglia inhibitor). In addition, exercise increased the endocannabinoid anandamide levels and cannabinoid CB2 receptors expression whereas it reduced Iba1 (microglial marker) protein expression as well as pro-inflammatory cytokines (TNF-α and IL-1β) in the spinal cord of mice with inflammatory muscle pain. Swimming training also reduced muscle temperature of carrageen-treated animals. The present study suggests that activation of spinal cannabinoid CB2 receptors and reduction of activated microglia are involved in exercise-induced antinociception.