Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Abstract

The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for 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 alpha2-delta subunit, 2-1 or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The 2-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 2-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 NMDAsensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to 2-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 2-1 protein. However, recent findings show that the 2-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1, 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.

Do gabapentin or pregabalin directly modulate the µ receptor?

“…The analgesic effect is thought to be a result of these drug's interaction with the alpha-2delta subunit of the presynaptic voltage-gated calcium channel (Chincholkar, 2018). However, multiple potential mechanisms of action have been reported, including interaction with L-amino transport system, action at N-methy-D-aspartate (NMDA) receptors, blockade of voltage-gated sodium channels and increased conductance of potassium channels (Chincholkar, 2018;Manville & Abbott, 2018;Taylor & Harris, 2020).…”

Effects of Topical Gabapentin on Ocular Pain and Tear Secretion

“…GBT systemic administration has therapeutic efficacy for neurological and psychiatric disorders such as epilepsy, anxiety, and migraine, and, together with its derivatives, belongs to the most used drugs for neuropathic pain management ( Fornasari, 2017 ). The main target of GBT is the α2δ1 auxiliary subunit of presynaptic voltage-gated calcium channels through which GBT reduces the release of multiple excitatory neurotransmitters thus decreasing neuropathic pain ( Taylor and Harris, 2020 ). In addition, there is evidence that GBT may play a role in reducing nociceptive pain ( Hamidi et al, 2014 ; Scuteri et al, 2020 ).…”

“…The possibility that GBT may counteract ocular pain has been suggested by several studies ( Lichtinger et al, 2011 ; Pakravan et al, 2012 ; Wei et al, 2015 ; Ongun and Ongun, 2019 ; Yoon et al, 2020 ), since the first demonstration of systemic GBT efficacy in providing significant pain relief in glaucomatous patients ( Kavalieratos and Dimou, 2008 ). At least some of the clinical effects of GBT are due to high affinity interactions with the α2δ1 auxiliary subunit of presynaptic voltage-gated calcium channels ( Taylor and Harris, 2020 ). However, more work needs to be done to fully understand the mechanisms through which GBT may target ocular tissues, and ameliorate ocular pain.…”

Ketamine for post‐operative pain treatment in spinal surgery. A protocol for a systematic review with meta‐analysis and trial sequential analysis

“…The NMDA receptor plays a central role in the development of central sensitisation and secondary post‐operative hyperalgesia, which are key elements in regard to increased post‐operative pain 12,13 . Therefore, analgesics targeting the N‐methyl‐D‐aspartate (NMDA) receptors (eg gabapentinoids and ketamine) have the potential to improve post‐operative pain 14‐16 …”