RT Journal Article
SR Electronic
T1 Narcotics and Rat Testicular Metabolism
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 970
OP 980
VO 16
IS 3
A1 A. JAKUBOVIC
A1 E. G. MCGEER
YR 1979
UL http://molpharm.aspetjournals.org/content/16/3/970.abstract
AB 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-α-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. ACKNOWLEDGMENT We thank L. Rowe at RIA Laboratory, St. Paul’s Hospital, for technical assistance.