Morphine-3-glucuronide: hyperglycemic and neuroendocrine potentiating effects.
The greater potency of morphine-6-glucuronide (M6G) as well as the inactivity of morphine-3-glucuronide (M3G) with respect to the antinociceptive effects of the parent molecule, morphine (MOR), have been well established. It has been suggested that M3G is an antagonist of MOR's antinociceptive and respiratory depressive effects. The present study addressed the central nervous system (CNS) interaction of these opiate metabolites on their metabolic and hormonal effects. Whole body glucose kinetics were assessed on conscious, chronically catheterized, unrestrained rats. M3G (5 microg) or H2O (5 microl) was injected intracerebroventricularly (i.c.v.) 15 min prior to the bolus administration of H2O (5 microl), M6G (1 microg), or MOR (80 microg). i.c.v. M3G (5 microg) resulted in behavioral excitation, hyperglycemia (+50%), stimulation of glucose rate of appearance (Ra; +100%), glucose rate of disappearance (Rd; +70%), and metabolic clearance rate (MCR; +33%) within 30 min after injection with no alterations in hormone concentrations. i.c.v. M6G and MOR produced progressive hyperglycemia with significantly high catecholamine and corticosterone levels. M3G pretreatment resulted in enhanced elevations in plasma glucose levels (+52% and + 18%), plasma lactate (+138% and +108%), norepinephrine (+96% and +30%), and epinephrine (+62% and +67%) in response to both i.c.v. MOR and M6G administration. These findings suggest a non-opiate and non-hormonal mechanism for M3G-induced hyperglycemia. In contrast, the metabolic and hormonal responses to i.c.v. M6G and MOR are associated with elevations in catecholamine and corticosterone levels. which are remarkably enhanced by M3G pretreatment, most likely through accelerated catecholamine release. Our findings suggest a modulatory role for MOR glucuronidation, not only by rendering it inactive, as in the case of M3G, but by an interplay of the metabolic effects of the parent molecule and its metabolite.
Hashiguchi
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Y
Department of Surgery, SUNY at Stony Brook 11794-8191, USA.
Molina
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PE
Abumrad
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NN
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D006728:Hormones / Q000097:blood; D006943:Hyperglycemia / Q000139:chemically induced*; D007700:Kinetics; D008297:Male; D009022:Morphine Derivatives / Q000494:pharmacology*; D009490:Neurosecretory Systems / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D006728:Hormones; D009022:Morphine Derivatives; C018108:morphine-3-glucuronide