Fig. 2.

Potential effects of gabapentinoids in musculoskeletal tissues. Ca²⁺ influx through VSCCs regulates many physiological processes, including neurotransmitter release, bone, and chondrocyte mechanosensation, and muscle contraction. In neurons, elevated neuronal α₂δ₁ expression contributes to specific pain states through a mechanism partially mediated by enhanced VSCC activity (green square). Thus, gabapentinoids modulate VSCC activity by acting through α₂δ₁, which underlies the analgesic actions of these drugs (purple circle). However, the binding of gabapentinoids to α₂δ subunits in bone, muscle, and cartilage potentially interferes with normal VSCC function (orange squares), resulting in adverse physiological impairments in patients treated long-term with these drugs