Identification of the α ₂ -δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin

TLDR

Neuropathic pain, a debilitating condition caused by nervous system lesions, is difficult to treat, yet pregabalin and gabapentin have proven clinical efficacy despite lacking anti‑inflammatory or physiological pain effects, and their mechanism remained unclear until recently. The study aimed to determine whether pregabalin’s analgesic effect depends on the α2‑δ‑1 subunit of voltage‑dependent calcium channels. Using a mutant mouse with a single‑point mutation in the α2‑δ‑1 subunit gene, the authors examined pregabalin binding and analgesic responses. The mutation markedly reduced pregabalin binding in brain and spinal cord and abolished its analgesic efficacy, confirming the α2‑δ‑1 subunit as the therapeutic target for pain control.

Abstract

Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (α 2 -δ-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the α 2 -δ-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.