Mu and kappa opioids inhibit transmitter release by different mechanisms.

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Abstract
The actions of various opioids were examined on Cal action potentials in the cell somata of guinea pig myenteric neurons 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 K conductance; opioids that are more selective agonists for the .kappa. receptor subtype (dynorphin, tifluadom, U50488H) [trans-(.+-.)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate] did not. Cal 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. 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 Ba. Presynaptic inhibition caused by .mu. receptor activation probably results from an increase in K conductance, whereas .kappa.-receptor agonists may depress the release of acetylcholine by directly reducing Ca entry into the nerve terminals.