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Involvement of Brain Serotonin in the Prolactin- Releasing Effect of Opioid Peptides^*

Departments of Pharmacology and Pharmacognosy, University of Catania and Cagliari, and the Department of Pharmacology, University of Milan, Milan, Italy; and the Research Institute for Pharmaceutical Chemistry Budapest, Hungary

Address requests for reprints to: Eugenio E. Miiller, M.D., % Department of Pharmacology, University of Milan, Via Vanvitelli, 32– 20129 Milan, Italy.

Abstract

The role played by brain serotonin (5-HT) neurotransmission in mediating the PRL-releasing effect of enkephalins was investigated in the rat. Both MetG-enkephalin (Metenk) and (D-Met², Pro⁵)-enkephalinamide (EKNH₂), an analog with long lasting analgesic activity, were used in freely moving rats bearing a cannula chronically implanted into the jugular vein. Met-enk injected intracerebroventricularly (IVT; 200 and 400 µg/rat) induced a marked and dose-related increase in plasma PRL; EKNH₂ (0.2 mg/kg, iv) induced a rise in plasma PRL similar to that evoked by Met-enk (400µg/rat). Metergoline (1 mg/kg, iv), a 5-HT receptor blocker, significantly reduced the PRL-releasing effect of Met-enk (200 µg/rat); these results were duplicated by using another 5-HT receptor blocker, i.e. methysergide (2.5 mg/kg, iv). Metergoline and methysergide also significantly reduced the increase in plasma PRL due to EKNH₂. 5,6-Dihydroxytryptamine (50 µg, IVT), a neurotoxic drug which destroys 5-HT nerve terminals, almost completely abolished the rise in plasma PRL induced by EKNH₂ (1.0 mg/kg, ip). However, blockade of 5-HT biosynthesis by p-chlorophenylalanine (100 mg/kg, sc, twice) potentiated the rise in plasma PRL induced by EKNH₂, an effect possibly resulting from the development of supersensitive 5-HT receptors. Pretreatment with quipazine (15 mg/kg, iv), a direct stimulant of 5-HT receptors, almost completely suppressed the PRL-releasing effect of Met-enk (400 µg/ rat), EKNH₂, and IVT injected 5-HT (2 µg/rat). Blockade of catecholamine neurotransmission by a-methyl-p-tyrosine (200 mg/kg, ip) did not modify the PRL-releasing effect of EKNH₂. In all, these results suggest that enkephalins exert their PRLreleasing effect via mediation of the brain 5-HT system.

Footnotes

^* This work was supported by the Serpero Foundation, Milan, Italy, and C.N.R. Grant CT76.01543.04. A portion of these studies was presented at the International Symposium on Central Nervous System Effects of Hypothalamic Hormones and Other Peptides, Montreal, Quebec, Canada, 1978.

Received September 12, 1978.

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