Pain, 35 (1988) 121-127 Elsevier PA1 01289 121 Clinical Section Human brain metabolism of morphine and naloxone zyxwvutsrqponmlkj Agneta Wahlstriim, Bengt Winblad ‘, Marie Bixo 2 and Anders Rane Division of Clinical Pharmacology, University Hospital, S-751 85 Uppsala (Sweden) (Received 4 January 1988, revision received 3 May 1988, accepted 16 May 1988) Summary The glucuronidation of morphine and naloxone was investigated in several regions of the human brain. Post-mortem brain tissue specimens were obtained from 19 patients 15 of whom had had cancer. With a few exceptions, all cancer patients had been treated with opiates during the terminal stage of their life. The glucuronide formation of morphine and naloxone was studied in vitro after incubation of the brain microsomal fraction with the substrate and uridine diphosphate glucuronic acid (UDPGA). The glucuronides were analyzed by high performance liquid chromatography. Glucuronidation of morphine and naloxone was catalyzed in 6 of the 19 investigated tissue specimens. The rate of formation of naloxone-3glucuronide (N3G) exceeded that of the morphine-3glucuronide (M3G). Morphine-6-glucuronide formation was found in only 2 specimens, in which the formation rate was 10% of the formation rate of M3G. When morphine and naloxone were present simultaneously at equal concentrations (3 mM), the N3G/M3G formation rate ratio increased compared to that when the 2 substrates were incubated one by one. Our findings are interesting from a clinical point of view since the pathways studied represent both bioactivation and inactivation steps in the metabolism of opioids. Key words: Human brain; Morphine; Naloxone; Metabolism; Glucuronidation zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML Introduction Ever since the active 6-glucuronide metabolite of morphine (M6G) was discovered [19], there has been interest in studying its formation and kinet- ics under normal and pathophysiological condi- t Present address: Department of Geriatric Medicine, Karo- linska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden. a Present address: Department of Pathology, Ume% Univer- sity, S-901 87 Urn&, Sweden. Correspondence to: Agneta Wahlstrom, Associate Prof., Div. of Clinical Pharmacology, University Hospital, S-751 85 Upp- sata. Sweden. tions [ll]. The potency of M6G is about 45 times higher than that of morphine when administered intracerebrally to the mouse [20]. Although M6G is a minor metabolite, systemically its possible local formation in the brain in close proximity of the opiate receptors may considerably potentiate the morphine effects. Naloxone, one of the first known pure antago- nists of morphine, seems to be a substrate of the same UDP-glucuronyl transferase (UDPGT) in the liver (unpublished results). Although the 6- OH-naloxA1 metabolite has been reported to be the major metabolite prior to glucuronidation in rabbit and chicken liver [14], this is not the case in man. Judging from urine metabolite excretion 0304-3959/88/$03.50 0 1988 Elsevier Science Publishers B.V. (Biomedical Division)