Chronic morphine-induced plasticity among signalling molecules.

Abstract

Most formulations of the consequences of the persistent activation of opioid receptors have centred on the diminution or loss of opioid receptor-coupled signalling mechanisms. Activation of opposing compensatory circuits remains another of the adaptations proposed to underlie the extreme loss of the antinociceptive potency of narcotics following their chronic administration. Recent research has revealed that adaptations to chronic morphine involve not only the impairment of opioid receptor functionality but also the altered consequences of its G protein coupling. Pre-eminent among the biochemical perturbations that underlie the chronic morphine-induced emergence of new signalling strategies are enhanced phosphorylation and altered expression of key signalling molecules. These molecular changes include the up-regulation and augmented phosphorylation of adenylyl cyclase type II isoforms, which underlies the ability of morphine to shift opioid receptor G protein signalling from predominantly Gialpha inhibitory to Gbetagamma stimulatory. Persistent morphine exposure also enhances the concomitant phosphorylation of G protein receptor kinase, beta arrestin and the G protein Gbeta subunit, one consequence of which is to further enhance G protein receptor signalling via the Gbetagamma subunit. This review will focus on our increasing understanding of the importance of qualitative changes among components of opioid receptor-coupled signalling pathways, as opposed to the interruption of such signalling, as the predominant mode of adapting to the presence of opioids.