β-Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release

β-Endorphin blocks release of luteinizing hormone (LH)-releasing hormone (LHRH) into the hypophyseal portal vessels by stimulating μ-opiate receptors, thereby inhibiting secretion of LH. LHRH release is controlled by release of nitric oxide from nitricoxidergic (NOergic) neurons in the basal tuberal hypothalamus. To determine whether β-endorphin exerts its inhibitory action on this NOergic pathway, medial basal hypothalami (MBH) from male rats were incubated with β-endorphin (10(−8) M). β-Endorphin decreased basal secretion of LHRH, and significantly inhibited the release of prostaglandin E(2) (PGE(2)), a known stimulant of LHRH release. Incubation of MBH with β-endorphin at various concentrations (10(−9)–10(−6) M) in vitro decreased the activity of NO synthase (NOS) (measured by the conversion of [(14)C]arginine to labeled citrulline). Conversely, the activity of NOS was increased by the μ-receptor antagonist, naltrexone (10(−8) M). Not only was the inhibitory action of β-endorphin on LHRH and PGE(2) release blocked by naltrexone (10(−8) M), but it increased NOS activity and LHRH and PGE(2) release. β-Endorphin also stimulated γ-aminobutyric acid (GABA) release. Because GABA inhibits both nitroprusside (NP-induced PGE(2) and LHRH release by blocking the activation of cyclooxygenase by NO, this is another mechanism by which β-endorphin inhibits NP-induced PGE(2) and LHRH release. The results indicate that β-endorphin stimulates μ-opioid receptors on NOergic neurons to inhibit the activation and consequent synthesis of NOS in the MBH. β-Endorphin also blocks the action of NO on PGE(2) release and, consequently, on LHRH release, by stimulating GABAergic inhibitory input to LHRH terminals that blocks NO-induced activation of cyclooxygenase and consequent PGE(2) secretion.