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

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‐ami‐notetralin (TL‐99) strongly inhibited synaptosomal K+‐in‐duced [3H]NA release (EC50= 5–10 nM) by activating α2‐adrenoceptors. Release was also inhibited (maximally by 40–50%) by morphine (EC50= 5–10 nM), [Leu5]enkephalin (EC50=∼300 nM), [d‐Ala2,d‐Leu5]enkephalin (DADLE), and Tyr‐d‐Ala‐Gly‐(NMe)Phe‐Gly‐ol (DAGO) (EC50 values =∼30 nM). In contrast to the μ‐selective opioid receptoragonists morphine and DAGO, the highly δ‐selective agon ist [d‐Pen2, dPen5]enkephalin (1 μM) did not affect [3H]‐NA release. Furthermore, the inhibitory effect of DADLE, an agonist with affinity for both δ‐and μ‐opioid receptors, was antagonized by low concentrations of naloxone. The findings strongly support the view that, like α2‐adrenocep‐tors, μ‐opioid receptors mediating inhibition of NA release in the rat cerebral cortex are localized on noradrenergic nerve terminals.