Involvement of the Transient Receptor Channels in Preclinical Models of Musculoskeletal Pain

Abstract

Background: Musculoskeletal pain is a condition that affects bones, muscles, and tendons and is present in various diseases and/or clinical conditions. This type of pain represents a growing problem with enormous socioeconomic impacts, highlighting the importance of developing treatments tailored to the patient's needs. TRP is a large family of non-selective cation channels involved in pain perception. Vanilloid (TRPV1 and TRPV4), ankyrin (TRPA1), and melastatin (TRPM8) are involved in physiological functions, including nociception, mediation of neuropeptide release, heat/cold sensing, and mechanical sensation.

Objective: In this context, we provide an updated view of the most studied preclinical models of muscle hyperalgesia and the role of transient receptor potential (TRP) in these models.

Methods: This review describes preclinical models of muscle hyperalgesia induced by intramuscular administration of algogenic substances and/or induction of muscle damage by physical exercise in the masseter, gastrocnemius, and tibial muscles.

Results: The participation of TRPV1, TRPA1, and TRPV4 in different models of musculoskeletal pain was evaluated using pharmacological and genetic tools. All the studies detected the antinociceptive effect of respective antagonists or reduced nociception in knockout mice.

Conclusion: Hence, TRPV1, TRPV4, and TRPA1 blockers could potentially be utilized in the future for inducing analgesia in muscle hypersensitivity pathologies.

Keywords: CFA; Carrageenan.; Gastrocnemius; masseter; muscle afferents; tibial.

Fig. (1)

Models of muscular hyperalgesia in the gastrocnemius and masseter muscle in rodents and the participation of transient receptor potential receptors (TRPs). The different models of muscle hyperalgesia in the masseter muscle used algogenic substances, such as complete Freund's adjuvant (CFA), carrageenan, capsaicin (TRPV1 agonist), mustard oil (TRPA1 agonist), N-methyl-D-aspartate (NMDA, TRPA1 activator), alphabetameATP (αβmeATP, TRPA1 activator), dihydroxyphenylglycine (DPHG, mGlu1/5 agonist), phorbol 12-myristate 13-acetate (PMA, an activator of PKC), capsaicin (TRPV1 agonist), or mustard oil (TRPA1 and TRPV4 agonist). The models of muscle hyperalgesia in the gastrocnemius muscle used nociceptive substances such as CFA, carrageenan, nerve growth factor (NGF promotes proliferation, degranulation, and release of inflammatory mediators from immune cells), glial cell-derived neurotrophic factor (GDNF promotes proliferation, degranulation, and release of inflammatory mediators from immune cells), H₂O₂ (TRPA1 and TRPV4 agonist), and acid saline (promotes acidosis that activates TRPs and ASIC3), ATP (activates P2X₃). The indirect or direct release of calcium by activating these receptors leads to the activation of protein kinases such as PKA, PKC, PLC, and CAMKII. In this sense, these mechanisms have the capability to trigger multiple pain and inflammation signaling pathways.