Mu and kappa opioids inhibit transmitter release by different mechanisms

The actions of various opioids were examined on calcium action potentials in the cell somata of guinea pig myenteric neurones and on the release of acetylcholine at synapses onto these cells. The opioids morphine, normorphine, and [D-Ala2, MePhe4, Met5(O)]enkephalin-ol caused membrane hyperpolarizations resulting from an increase in potassium conductance; opioids that are more selective agonists for the kappa receptor subtype (dynorphin, tifluadom, U50488H) did not. Conversely, calcium action potentials were depressed or abolished by the kappa opioids but were not affected by morphine and [D-Ala2, MePhe4, Met(O)5]enkephalin-ol. Both groups of opioids caused presynaptic inhibition of acetylcholine release in the myenteric plexus, depressing the amplitude of the fast excitatory postsynaptic potential. The presynaptic inhibition caused by [D-Ala2, MePhe4, Met(O)5]enkephalin-ol, morphine, and normorphine, but not that caused by the kappa opioids, was prevented by pretreatment with the selective mu site-directed irreversible antagonist beta-funaltrexamine. Furthermore, the presynaptic inhibitory action of morphine and [D-Ala2, MePhe4, Met(O)5]enkephalin-ol, but not that of the kappa-receptor agonists, was reversibly blocked by barium. The results suggest that presynaptic inhibition caused by mu receptor activation probably results from an increase in potassium conductance, whereas kappa-receptor agonists may depress the release of acetylcholine by directly reducing calcium entry into the nerve terminals.