Neurobiology of opiates

Opiate receptors belong to the G family of protein-coupled receptors, and all inhibit adenylate cyclase and calcium channels. Two subtypes, p and K, increase potassium conductance. Although the precise mechanisms underlying the development of tolerance to (and dependence on) opiates is not yet clear, there do not appear to be any consistent changes in opiate receptor levels. One contributory mechanism that has been suggested is the downregulation and desensitization of the opiate p receptor. Acutely, opiates lead to the inhibition of adenylate cyclase with reduced conversion of ATP to cAMP, resulting in reduced firing at noradrenergic neurones located on the locus coeruleus. Following chronic opiate administration, there is compensatory upregulation of cAMP, returning levels towards baseline. On cessation of opiate use (or following opiate receptor antagonism) withdrawal ensues, characterized by a massive surge in unopposed noradrenergic activity (termed the 'noradrenergic storm') from the locus coeruleus. This noradrenergic hyperactivity is thought to underlie many symptoms of opiate withdrawal, and explains the efficacy of the presynaptic a2 agonists clonidine and lofexidine in the treatment of the symptoms of acute opiate withdrawal.

Although the changes in noradrenergic activity underlie many of the withdrawal symptoms from opiates, it is likely that other neuroadaptive mechanisms and receptor systems are at work in the development of tolerance and dependence, with recent studies indicating roles for both glutamate and g-aminobutyric acid ( GABA). For example, positive reinforcement is thought to be mediated via the dopaminergic mesolimbic system. In the ventral tegmental area, GABA inhibits dopaminergic neurones, which in turn are inhibited via p opiate receptor activation. Consequently, opiate administration leads to increased dopaminergic activity which is thought to mediate the drive to use and its positive reinforcement.(1)

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