Targeting the GABAB receptor for the treatment of pain

Abstract

Pharmacological and neurobiological data indicate that γ-aminobutyric acid (GABA) is involved in pain processing and perception, with both basic and clinical studies demonstrating that selective activation of GABAergic transmission yields a nociceptive response. This is particularly true for agents that stimulate GABAB receptors. While these findings are in accord with the neuroanatomical localization of GABAB receptors on nociceptive pathways, such work has yet to yield a clinically useful analgesic. Some reasons for this failure are the side effects associated with GABAB agonists and the tolerance that develops to their therapeutic effects. Described in this chapter are the neuroanatomical localization and function of GABAergic neurons as they relate to nociception and to the antinociceptive responses to GABAB receptor agonists. Particular emphasis is placed on detailing possible reasons why GABAergic compounds, especially orthosteric receptor agonists, display limited clinical efficacy as analgesics. Among these are the variations in GABA receptor expression and function that occur with the persistent receptor activation associated with a painful stimulus and the chronic administration of orthosteric compounds. Strategies are described for developing GABAergic drugs, such as allosteric GABAB receptor modulators, that by selectively activating sites associated with pain pathways provoke fewer side effects and less tolerance than orthosteric agents.