An insulin-independent mechanism of intrathecal morphine-induced hypoglycemia in mice: mediation through a central alpha-2 adrenergic pathway.
Studies on the mechanism of the hypoglycemia caused by the i.t. administration of morphine (40 micrograms) to nonfasted, unanesthetized mice included assessment of effects of i.t. morphine on circulating levels of immunoreactive insulin and glucagon, on body temperature, as well as testing the effects of i.p. pretreatment with antagonists of cholinergic, beta adrenergic, alpha-1 adrenergic, alpha-2 adrenergic, serotonergic and opioid receptors. Serum levels of insulin were not significantly affected at 30 and 60 min after i.t. morphine, but plasma glucagon levels were significantly increased at both time points. Rectal temperature decreased significantly in mice given either saline or morphine i.t., but there was no significant difference between the two groups over time. Atropine (2 mg/kg), propranolol (10 mg/kg), prazosin (2 mg/kg) and methysergide (2 mg/kg) did not affect morphine-induced hypoglycemia. Naloxone (20 mg/kg) antagonized i.t. morphine. Mecamylamine (2 mg/kg) produced a moderate hypoglycemia in control mice, which appeared to be additive to that caused by i.t. morphine. Yohimbine (1-4 mg/kg i.p.) also produced a moderate hypoglycemia in control mice, but caused a dose-related antagonism of i.t. morphine. The centrally active alpha-2 antagonist, L-657,743 (2S-trans)-1,3,4,5',6,6',7,12b-octahydro-1',3'-dimethylspiro -(2H-benzofuro- (2,3-a)quinolizine-2,4'(1'H)pyrimidin)-2-(3'H)-one hydrochloride) (4-20 mg/kg i.p.), but not the peripherally selective alpha-2 antagonist, L-659,066 (2R-trans)-N-(2-(1,3,4,6,7,12b-he xahydro-2'- oxospiro(2H-benzofuro(2,3-a) quinolizine-2,4-imidazolidin)-3'-yl)ethyl)methanesulfonamide hydrochloride) (4-20 mg/kg i.p.), caused a dose-related antagonism of i.t. morphine. The i.t. coadministration of yohimbine (2 or 10 micrograms) or L-659,066 (10 micrograms) with morphine exhibited no antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond.
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D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001831:Body Temperature / Q000187:drug effects; D004347:Drug Interactions; D005934:Glucagon / Q000097:blood; D007003:Hypoglycemia / Q000139:chemically induced* / Q000378:metabolism; D007278:Injections, Spinal; D007328:Insulin / Q000097:blood*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D007328:Insulin; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D009020:Morphine; D005934:Glucagon