Influence of glutethimide on rat brain mononucleotides by sub-chronic codeine treatment.
It was investigated the in vivo effect of glutethimide on the intracellular neuroadaptation characteristic for m-opioid receptor tolerance induced by chronic codeine treatment and reflected by increased levels of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). AC activity was appreciated by cyclic-AMP (cAMP) formation, the levels of adenine and guanine nucleotides in brain extracts being assayed using a high performance liquid chromatographic method. The concomitant chronic administration of codeine and glutethimide resulted in a pronounced and long-lasting energetic depletion of the neurons, consistent with the high risk of overdose, and increase of cAMP's stable metabolite, 5'-AMP. This increase is persistent even after withdrawal and suggests an interference with the adenylyl cyclase system involved in the development of tolerance of opioid receptor and in relapse and provides a possible explanation of addiction and fast increase of doses observed in humans abusing this combination.
Loghin
F
F
Department of Toxicology, University of Medicine and Pharmacy Iuliu Hatieganu, 13, Emil Isac, 3400 Cluj-Napoca, Romania. felicialoghin@yahoo.com
Popa
D S
DS
Socaciu
C
C
D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003061:Codeine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology; D005984:Glutethimide / Q000494:pharmacology*; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000701:Analgesics, Opioid; D006150:Guanine Nucleotides; D006993:Hypnotics and Sedatives; D005984:Glutethimide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D003061:Codeine