Chlorimipramine increases B-endorphin in the hypothalamus, induces analgesia and potentiates morphine

CHLORIMIPRAMINE INCREASES B-ENDORPHIN IN THE HYPOTHALAMUS, FFjFr* INDUCES ANALGESIA AND POTENTIATES MORPHINE. P.Sacerdote", A.MartiniO, G.C.Monza', P.Mantegazza' and A.E.Panerai, Dept. Cascade 42 of Pharmacology, University of Milano, Milano, 20129,Italy. Aim of Investigation: Antidepressants and within these chlorimip~amine are increasingly used in pain therapy, however it is not known their mechanism of action. For this reason we evaluated B-endorphin (BE) concentrations in the hypothalamus of rats after the administration of antidepressants or 5-hydroxytryptophan (5HTP). Methods: Analgesic thresholds were measured after acute or whronic treatment with graded doses of antidepressants or the serotonin precursor. BEhypothalamic concentrationswere measured after each treatment alone or pretreatment with the serotonin antagonist metergoline. The effects of acute or chronic treatment with the same drugs on morphine-elicited analgesia was also evaluated. Results: Chlorimipramine, amitryptiline and 5HlP induced an increase in pain thresholds after acute treatments, but not evident after chronic treatment. Both acute and chronic treatments with all drugs induced an increase in morphine-induced analgesia. Moreover, all drugs and treatment regimens induced an increase in hypothalamic BE concentrations that was reversed by metergoline. Conclusions: Chlorimipramine and amitryptiline mimick the effect of the serotonin precursor 5HTP and their effect is abolished by the serotonin antagonist metergoline. The bulk of these data indicates that both the analgesic effect of antidepressants and the enhancement of morphine analgesia is mediated by an increase in the serotoninergic tone.

ANALGESIC AND OTHER EFFECTS OF ALKYLAMIDES.

N-SUBSTITUTED MET-ENKEPHALIN

Research Institute, Lucknow, India. Aim of Investigation: The structural requirements for improving the morphinomimetic activity of met-enkephalin have been investigated by intr ducing hydrophobic characteristics around C-terminus, substitution of Gly? by D-aminoacid and conversion of Phe4 to MePhe. Methods: Eighteen analogs were synthesized by solution-phase method of synm and evaluated for their morphinomimetic activity in vitro on guinea-pig ileum (GPI) and & vivo analgesia was measured inditing Eddy's hotplate (56+0.5'%) met= after intracerebral (ICI, and systemic administration. Results: All the compounds were active in both the test systems but there was no correlation between in vivo and in vitro results. The presence of C-terminal isopropylamide residueoffered iiiZx?iiZl-enhancement in analgesia. A further, 3 and 8-fold increase in analgesia was obtained by successive introduction of D-Ala and MePhe at 2 and 4 positions D-Ala2 MePhe4, Met5-enk-isopropylamidewas, on molar basis, about 61 000 and 706 time more potent than met-enkephalin and morphine respectiveli. The introduction of Gly5 residue in this compound further improved the analgesic activity even by systemic routes. Analgesia as well as inhibitory effect on GPI was antagonised by naloxone. Conculsion: Introduction of iso ropylamide at C-terminus replacement of GUY* by D-Ala, N-methylation of Phe! and substitution of Met4 by glycine lead to Potent, orally active enkephalin analogs with marked analgesia.