TY - JOUR T1 - Analgesia with Gabapentin and Pregabalin May Involve <em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptors, Neurexins, and Thrombospondins JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 161 LP - 174 DO - 10.1124/jpet.120.266056 VL - 374 IS - 1 AU - Charles P. Taylor AU - Eric W. Harris Y1 - 2020/07/01 UR - http://jpet.aspetjournals.org/content/374/1/161.abstract N2 - The gabapentinoid drugs gabapentin and pregabalin (Neurontin and Lyrica) are mainstay treatments for neuropathic pain and preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the α2δ-subunit type 1 [α2δ-1], or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin and is required for the efficacy of these drugs. The α2δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α2δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of N-methyl-d-aspartate–sensitive glutamate receptors, neurexin-1α, and thrombospondin proteins by binding to α2δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action.SIGNIFICANCE STATEMENT It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α2δ-1 protein. However, recent findings show that the α2δ-1 protein also interacts with N-methyl-d-aspartate–sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects. ER -