Thin‐fibre receptors expressing acid‐sensing ion channel 3 contribute to muscular mechanical hypersensitivity after exercise

Abstract

Background Delayed onset muscle soreness (DOMS) is characterized by mechanical hyperalgesia after lengthening contractions (LC). It is relatively common and causes disturbance for many people who require continuous exercise, yet its molecular and peripheral neural mechanisms are poorly understood. Methods We examined whether muscular myelinated Aδ‐fibres, in addition to unmyelinated C‐fibres, are involved in LC‐induced mechanical hypersensitivity, and whether acid‐sensing ion channel (ASIC)‐3 expressed in thin‐fibre afferents contributes to this type of pain using a rat model of DOMS. The peripheral contribution of ASIC3 was investigated using single‐fibre electrophysiological recordings in extensor digitorum longus muscle‐peroneal nerve preparations in vitro. Results Behavioural tests demonstrated a significant decrease of the muscular mechanical withdrawal threshold following LC to ankle extensor muscles, and it was improved by intramuscular injection of APETx2 (2.2 μM), a selective blocker of ASIC3. The lower concentration of APETx2 (0.22 µM) and its vehicle had no effect on the threshold. Intramuscular injection of APETx2 (2.2 μM) in naïve rats without LC did not affect the withdrawal threshold. In the ankle extensor muscles that underwent LC one day before the electrophysiological recordings, the mechanical response of Aδ‐ and C‐fibres was significantly facilitated (i.e. decreased response threshold and increased magnitude of the response). The facilitated mechanical response of the Aδ‐ and C‐fibres was significantly suppressed by selective blockade of ASIC3 with APETx2, but not by its vehicle. Conclusions These results clearly indicate that ASIC3 contributes to the augmented mechanical response of muscle thin‐fibre receptors in delayed onset muscular mechanical hypersensitivity after LC. Significance Here, we show that not only C‐ but also Aδ‐fibre nociceptors in the muscle are involved in mechanical hypersensitivity after lengthening contractions, and that acid‐sensing ion channel (ASIC)‐3 expressed in the thin‐fibre nociceptors is responsible for the mechanical hypersensitivity. ASIC3 might be a novel pharmacological target for pain after exercise.

Effects of nociceptive and mechanosensitive afferents sensitization on central and peripheral hemodynamics following exercise-induced muscle damage

“…Despite the exact mechanisms are not fully understood, it has been postulated that the alteration of the muscle chemical milieu after exercise induced muscle damage (EIMD) (6), due to increase metabolites production and accumulation (i.e., prostaglandins, lactate, protons), could sensitize and or increase muscle nerve afferents and related nociceptor activity (4,7,8). Indeed, inflammation following muscle damage may cause mechanical hyperalgesia (tenderness and movement induced-pain) (9)(10)(11) better known as delayed onset of muscle soreness (DOMS) (12,13) that is suggested to be linked to an increased activity and sensitization of Aδ-(III) and C-fiber (IV) nerve endings (14,15). Indeed, inflammation, injuries or muscle damage events (as EIMD) are thought to induce afferent nerve sensitization with related increases in expression of purinergic 2X receptor (P2X), acid sensing-ion channel receptor (ASIC), transient receptors potential vanilloid channels receptors (TRPV) (9)(10)(11).…”

Synergistic interaction of nerve growth factor and glial cell‐line derived neurotrophic factor in muscular mechanical hyperalgesia in rats

“…Antagonist experiments with amiloride and capsazepine in this study showed that high NGF‐induced mechanical hyperalgesia involves TRPV1 and high GDNF‐induced mechanical hyperalgesia involved ASICs (possibly ASIC3, Matsubara et al . 2019), whereas mechanical hyperalgesia induced by the mixture of low NGF and low GDNF involved both receptor channels. In addition, previous single‐fibre experiments from our group showed that NGF sensitized mainly C‐fibre afferents innervating the muscle (Murase et al .…”

Nonsteroidal anti-inflammatory drugs and acetaminophen ameliorate muscular mechanical hyperalgesia developed after lengthening contractions via cyclooxygenase-2 independent mechanisms in rats

“…ASIC3 and ASIC1 have been reported to play a critical role in the development of acidic saline-induced muscular hyperalgesia [55–57]. ASIC3 has been shown to be involved in the LC-induced muscular mechanical hyperalgesia [58]. Voilley et al .…”