Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway

Chronic morphine administration induces adaptations in neurons resulting in opioid tolerance and dependence. Functional studies have implicated a role for the periaqueductal gray area (PAG) in the expression of many signs of opioid withdrawal, but the cellular mechanisms are not fully understood. Th is study describes an increased efficacy, rather than tolerance, of opioid agonists at mu-receptors on GABAergic (but not glutamatergic) nerve termina ls in FAG after chronic morphine treatment. Opioid withdrawal enhanced the amplitudes of electrically evoked inhibitory synaptic currents mediated by GABA, receptors and increased the frequency of spontaneous miniature GABAer gic synaptic currents. These effects were not blocked by 4-aminopyridine or dendrotoxin, although both Ky channel blockers abolish acute opioid presyn aptic inhibition of GABA release in FAG. Instead, the withdrawal-induced in creases were blocked by protein kinase A inhibitors and occluded by metabol ically stable cAMP analogs, which do not prevent acute opioid actions. Thes e findings indicate that opioid dependence induces efficacious coupling of mu-receptors to presynaptic inhibition in GABAergic nerve terminals via ade nylyl cyclase- and protein kinase A-dependent processes in FAG. The potenti al role of these adaptations in expression of withdrawal behavior was suppo rted by inhibition of enhanced GABAergic synaptic transmission by the a, ad renoceptor agonist clonidine. These findings provide a cellular mechanism t hat is consistent with other studies demonstrating attenuated opioid withdr awal behavior after injections of protein kinase A inhibitors into FAG and suggest a general mechanism whereby opioid withdrawal may enhance synaptic neurotransmission.