Morphine and Enkephalins Potently Inhibit [3H]Noradrenaline Release from Rat Brain Cortex Synaptosomes: Further Evidence for a Presynaptic Localization of μ‐Opioid Receptors

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Abstract
Synaptosomes prepared from rat cerebral cortex and labeled with [3H]noradrenaline (NA) were superfused with calcium-free Krebs-Ringer-bicarbonate medium and exposed to 10 mM K+ plus 0.1 mM Ca2+ so that [3H]NA release was induced, 6,7-Dihydroxy-N,N-dimethyl-2-aminotetralin (TL-99) strongly inhibited synaptosomal K+-induced [3H]NA release (EC50 = 5-10 nM) by activating .alpha.2-adrenoceptors. Release was also inhibited (maximally by 40-50%) by morphine (EC50 = 5-10 nM), [Leu5]enkephalin (EC50 = .apprx. 300 nM), [D-Ala2,D-Leu5]enkephalin (DADLE), and Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) (EC50 values = .apprx. 30 nM). In contrast to the .mu.-selective opioid receptor agonists morphine and DAGO, the highly .delta.-selective agonist [D-Pen2,D-Pen5]enkephalin (1 .mu.M) did not affect [3H]-NA release. Furthermore, the inhibitory effect of DADLE, an agonist with affinity for both .delta.- and .mu.-opioid receptors, was antagonized by low concentrations of naloxone. The findings strongly support the view that, like .alpha.2-adrenoceptors, .mu.-opioid receptors mediating inhibition of NA release in the rat cerebral cortex are localized on noradrenergic nerve terminals.