Role of TRPV1+ and TRPA1+ nociceptive neurons in delayed-onset muscle soreness: inhibition by hesperidin methyl chalcone.

Abstract

Objective: Delayed-onset muscle soreness (DOMS) is a type of pain caused by muscle injury provoked by eccentric, high intensity, or long-duration exercise. Hesperidin methyl chalcone (HMC) is a flavonoid with analgesic and anti-inflammatory actions. We investigated the effects of HMC against DOMS.

Methods: Mice received AMG9810 (100 nmol) or HC-030031 (10 μg) once intrathecally, or HMC twice (12 h plus 30 min before) intraperitoneally (1, 3, or 10 mg/kg) and were subjected to a single uninterrupted acute swimming session of 120 min to induce DOMS. Sham animals were subjected to swimming just for 30 s, and naïve mice were not exposed to water. Calcium imaging of dorsal root ganglia (DRG) neurons was used to assess nociceptive neuron activation. Muscle mechanical hyperalgesia was assessed 12-48 h later. Oxidative parameters (superoxide anion, lipid peroxidation, and antioxidant activity) and leukocyte recruitment (macrophages and neutrophils) were evaluated 2 and 24 h later, respectively.

Results: DRG neurons from mice that underwent intense acute swimming showed higher levels of calcium at 24 h post-session relative to naïve mice. Capsaicin [transient receptor potential vanilloid 1 (TRPV1 agonist)] or AITC [transient receptor potential ankyrin 1 (TRPA1 agonist)] were used as agonists controls to identify the populations of responsive neurons positive for TRPV1/A1. KCl was used as a cell viability control. Counterproof pharmacologic functional tests targeting TRPV1 or TRPA1 with receptor antagonists reduce muscle mechanical hyperalgesia and DRG neuron increased activity. HMC (3 mg/kg) reduced muscle mechanical hyperalgesia, activation of DRG nociceptive neurons at 24 h post-swimming session and upon TRPV1 or TRPA1 agonists and inhibited oxidative stress and the recruitment of neutrophils and macrophages to muscle in DOMS mice.

Conclusions: Thus, HMC prevented DOMS in mice caused by unaccustomed exercise. The underlying mechanisms of HMC involve targeting oxidative stress, inflammation, and reduced activity of TRPV1⁺ and TRPA1⁺ nociceptive neurons.