Molecular Pharmacology, Vol 16, 970-980, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Narcotics and Rat Testicular Metabolism

¹ Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1W5

The effect of various narcotic analgesics on protein and nucleic acid synthesis in rat testicular cell suspensions and on testosterone production in rat testis was studied. Racemic methadone (dl-Me), 1- and d-Me, 1--acetyl-methadol (LAM), and dl-Me metabolites, 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP) and 2-ethyl-1,5-dimethyl-3,3-diphenyl-pyrrolinium (EDDP), at 100 and 10 µM had a dose-related, significant effect on L-[1-¹⁴C]leucine and [2-¹⁴C]uridine incorporation into protein and RNA, respectively. LAM metabolites, methadol (MOL), acetylnormethadol (ANMOL) and normethadol (NMOL), were also inhibitory. Under the same conditions, morphine (Mo), heroin (He) and codeine (Co) had only minor effects on protein and RNA synthesis in comparison with dl-Me. The effect of narcotic analgesics on DNA synthesis was less than on RNA. The order of potency in inhibiting these biosynthetic process is: LAM dl-Me l-Me [unknown] d-Me — EMDP > EDDP > MOL [unknown] ANMOL [unknown] NMOL [unknown] He > Co > Mo. Furthermore at 1 mM dl-Me, l-Me and LAM caused about a 50% inhibition of testosterone (T) production and release from rat testes stimulated by hCG or dibutyryl-cAMP. In comparable experiments He or Mo were far less inhibitory. Further, the T production by dibutyryl-cAMP stimulated testicular Leydig cell preparations was also reduced by dl-Me and the ID₅₀ was about 9 µM. The results suggest that some narcotic analgesics such as dl-Me, LAM and their metabolites may reduce testicular T synthesis by virtue of their direct inhibitory effects on RNA and/or protein synthesis. However, He and Mo may decrease T levels primarily through the hypothalamic-pituitary-gonadal axis. A combination of central and peripheral action of some narcotics cannot be excluded.

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ACKNOWLEDGMENT We thank L. Rowe at RIA Laboratory, St. Paul’s Hospital, for technical assistance.