Pregabalin as a Pain Therapeutic: Beyond Calcium Channels

Abstract

Initially developed to generate new treatments for epilepsy, gabapentin, and pregabalin ("gabapentinoids") were engineered to mimic the action of GABA and to modulate GABA metabolism. Rather than their intended pharmacological action on GABA neurotransmission, instead, they exhibit a high affinity for the α2δ-1 and α2δ-2 subunits of voltage-activated calcium channels, wherein binding of gabapentinoids inhibits cellular calcium influx and attenuates neurotransmission. Despite a lack of activity on GABA levels, gabapentin and pregabalin are effective at suppressing seizures and subsequently approved as a new class of antiepileptic therapy for partial-onset epilepsy. Through the same hypothesized molecular mechanism and by controlling neuronal hyperexcitability, gabapentinoids demonstrate clear efficacy in pain management, which has arguably been their most extensively prescribed application to date. In this review, we focus on pregabalin as a second-generation gabapentinoid widely employed in the treatment of a variety of pain conditions. We also discuss the wider functional roles of α2δ subunits and the contributions that pregabalin might play in affecting physiological and pathophysiological processes.

Keywords: calcium channel; chronic pain; hyperexcitability; pregabalin (PGB); therapeutic targets.

Figure 1

Protein interactions of α2δ and their inhibition by pregabalin. Pregabalin is used to treat different types of chronic pain such as migraine, spinal cord injury pain or fibromyalgia. The effectiveness of pregabalin for treating each type of chronic pain for each individual patient may be reflected by the modulation of the protein interactions of α2δ such as with neurexins, thrombospondins, NMDA receptors, BK channels, prion proteins, LRP1 or GABA-A receptors.