Novel therapeutic agents: The analgesic actions of pregabalin are mediated through its binding to the α 2-δ-1 subunit of voltage-gated calcium channels

Abstract

Neuropathic pain resulting from damage to or dysfunction of the nervous system affects the lives of millions of people suffering from conditions including diabetes and postherpetic neuralgia. This severe pain is very difficult to treat, but pregabalin has proven clinical efficacy. This compound is unlike traditional analgesics, such as nonsteroidal–anti-inflammatory drugs or narcotics. It has no anti-inflammatory actions and no effect on physiologic pain. Despite extensive preclinical research, including the isolation and sequencing of the binding protein and its identification as the α2-δ subunit of voltage-gated calcium channels, proof of the importance of this auxiliary protein in the mechanism of action of pregabalin has remained elusive. Here, we show that pregabalin has reduced binding affinity and no analgesic action in mice expressing a mutated gene encoding a specific auxiliary subunit protein (α2-δ-1) of voltage-dependant calcium channels. The R217A mutant mouse has a single amino acid substitution at position 217 in the α2 protein which prevents the binding of pregabalin. The mutant demonstrates normal pain phenotypes, indistinguishable from the wild-type controls derived from the same breeding cohort. Pregabalin (30 to 100 mg/kg, s.c.) failed to block the late-phase response in the formalin test and the static allodynia induced by Chronic Constriction Injury (CCI) in the mutants but was fully active in the wild-type mice. Both wild-type and mutant mice showed typical responses to morphine (3 mg/kg, s.c.) in the formalin test and to amitriptyline (2 to 8 mg/kg, p.o.) in the CCI model. These are the first data demonstrating that the analgesic actions of pregabalin are mediated through its binding to the α2-δ-1 subunit of voltage-gated calcium channels. These data establish pregabalin as a member of a novel class of analgesic agents.