What Is the Mechanism of Therapeutic and Adverse Effects of Gabapentinoids?

Voltage-gated calcium channels (VGCCs) are essential for the function of excitable cells by permitting Ca2+ entry in response to membrane depolarization. The high-voltage-activated channels, including the presynaptic P/Q-type (Cav2.1) and N-type (Cav 2.2) channels, comprise the main pore-forming subunit, α1, along with the auxiliary subunits β and α2δ. Although not directly involved in Ca2+ transport, Cavβ and Cavα2δ are critical for VGCC function by regulating kinetics and cell surface expression of these channels. Gabapentinoids, including gabapentin and pregabalin, are extensively used for treatment of neuropathic pain, restless legs syndrome, and focal seizures. Their efficacy in these disorders is primarily attributed to their effects in inhibiting the functions of the α2δ subunit of presynaptic VGCCs, thereby reducing neurotransmitter release. Recent studies on Cα2δ function and effects of gabapentinoids provide further insight into both the therapeutic and adverse effects of these drugs (figure).