Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Abstract

Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL-10, acting on its canonical receptor in muscle nociceptors.

Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming

“…Results were analyzed using computer-assisted densitometry with levels of TLR4 immunoreactivity normalized with respect to the ␤-actin control levels in the same sample. The percentage decrease in TLR4 expression was calculated as follows: [normalized density for AS/normalized density for MM ϫ 100] Ϫ 100 (Summer et al, 2008;Alvarez et al, 2017).…”

Nociceptor Interleukin 33 Receptor/ST2 Signaling in Vibration-Induced Muscle Pain in the Rat

“…Changes in protein expression of IL-33 in skeletal muscle and IL-33R/ST2 in L4-L5 DRGs were evaluated by Western blot as previously described. 1,2,6 Briefly, rats were killed by exsanguination, while under deep isoflurane anesthesia, 24 hours after vibration or last i.t. ODN injection.…”

“…12,24,35,37 Although the role of IL-33 in muscle pain is unknown, evidence indicates that nociceptors dynamically sense local levels of cytokines after muscle injury, modifying their responses to mechanical stimulation, in a time-dependent manner. 1,2,6,8 Therefore, by sensing local IL-33 levels, nociceptors could also provide important inputs for adaptive behaviors after muscle injury. Such a functional arrangement is possible, since the canonical receptor for IL-33, IL-33R (also known as suppression of tumorigenicity 2 [ST2] or interleukin 1 receptor-like 1 [IL1RL1]), and its co-partner for IL-33 signaling, the interleukin 1 receptor accessory protein (IL1RAcP, also known as IL1RAP), are expressed in human and mouse DRG neurons.…”

Unpredictable stress delays recovery from exercise-induced muscle pain: contribution of the sympathoadrenal axis

“…We have recently demonstrated that physical resilience, the intrinsic capacity to recover from tissue injury, exhibits a cytokine signature, which is detected by muscle nociceptors. 2 Disruption of a nociceptor's capacity to detect this signature prevents the recovery of baseline nociceptive threshold. 2 The fact that nociceptors also respond to the sympathoadrenal mediator epinephrine 12,35 suggests that stress can also modulate the function of nociceptors as sensors of the physical resilience status.…”