Identification of the α2-δ-1 subunit of voltage-calcium calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin

Mark J. Field, Peter J. Cox, Emma Stott, Heather Melrose, James Offord, Ti Zhi Su, Steve Bramwell, Laura Corradini, Steven England, Joanna Winks, Ross A. Kinloch, Jan Hendrich, Annette C. Dolphin, Tony Webbl, Dic Williams

Research output: Contribution to journalArticlepeer-review

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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 (α2-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 α2-8-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.

Original languageEnglish (US)
Pages (from-to)17537-17542
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - Nov 14 2006

ASJC Scopus subject areas

  • General


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