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Papers of the Week

Papers: 28 Oct 2023 - 3 Nov 2023

2023 Nov 02

J Pharmacol Exp Ther


Mechanism of Analgesia by Gabapentinoid Drugs: Involvement of Modulation of Synaptogenesis and Trafficking of Glutamate-Gated Ion Channels


Varadi G


Gabapentinoids have clinically been used for treating epilepsy, neuropathic pain, and several other neurological disorders for >30 years, however, the definitive molecular mechanism responsible for their therapeutic actions remained uncertain. The conventional pharmacological observation regarding their efficacy in chronic pain modulation is the weakening of glutamate release at presynaptic terminals in the spinal cord. While the α2/δ-1 subunit of voltage-gated calcium channels (VGCCs) has been identified as the primary drug receptor for gabapentinoids, the lack of consistent effect of this drug class on VGCC function is indicative of a minor role in regulating this ion channel’s activity. This current review targets the efficacy and mechanism of gabapentinoids in treating chronic pain. The discovery of the interaction of α2/δ-1 with thrombospondins established this protein as a major synaptogenic neuronal receptor for thrombospondins. Other findings identified α2/δ-1 as a powerful regulator of NMDA and AMPA receptors by potentiating the synaptic expression, a putative pathophysiological mechanism of neuropathic pain. Further, the interdependent interactions between thrombospondin and α2/δ-1 contribute to chronic pain states, while gabapentinoid ligands efficaciously reverse such pain conditions. Gabapentin normalizes and even blocks NMDAR and AMPAR synaptic targeting and activity elicited by nerve injury. Gabapentinoid drugs are used to treat various neurological conditions including chronic pain. In chronic pain states gene expression of cacnα2/δ-1 and thrombospondins are upregulated and promote aberrant excitatory synaptogenesis. The complex trait of protein associations that involve interdependent interactions between α2/δ-1 and thrombospondins, further, an association of NMDAR and AMPAR with the C-tail of α2/δ-1 constitutes a macromolecular signaling complex that forms the crucial elements for the pharmacological mode of action of gabapentinoids.