Hypoglycemia induced by intrathecal opioids in mice: stereospecificity, drug specificity and effect of fasting.
The specificity of the hypoglycemic response to the intrathecal (i.t.) administration of the naturally occurring (-)-enantiomer of morphine previously reported from our laboratory was studied in mice. (+)-Morphine HBr (50 micrograms) caused a behavioral syndrome (scratching, biting, seizures) comparable to that produced by (-)-morphine sulfate (50 micrograms), but did not cause hypoglycemia. Many opioids, at a dose of 50 micrograms i.t. in nonfasted mice, showed either a saline-like hyperglycemic response or no significant effect on blood glucose. (+)-Morphine, ketocyclazocine, U-50,488, (-)- and (+)-N-allyl-normetazocine, beta-endorphin, (-)- and (+)-naloxone and naltrexone caused hyperglycemia. Significant changes from basal blood glucose were not produced by [D-Pen2, L-Pen5]-enkephalin, [D-Ser2]-Leu-enkephalin-Thr or sufentanil in 50-micrograms doses, or by codeine (300 micrograms), levorphanol (400 micrograms) or methadone (200-400 micrograms). Agonists which produced both hypoglycemic and behavioral effects were, in order of decreasing potency, hydromorphone greater than normorphine greater than morphine greater than 6-acetylmorphine greater than oxymorphone much greater than heroin. Morphine-induced hypoglycemia was partially antagonized by the i.t. coadministration of naloxone methobromide (10 micrograms). Fasting for 24 hr increased the sensitivity to hypoglycemic and lethal effects of morphine. D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin (5-50 micrograms i.t.) tended to decrease blood glucose in both nonfasted and fasted mice, but these effects were moderate and appeared to be unrelated to dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Brase
D A
DA
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond.
Singha
A K
AK
Estrada
U
U
Lux
F
F
Dewey
W L
WL
D000818:Animals; D001786:Blood Glucose; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000494:pharmacology*; D013237:Stereoisomerism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009022:Morphine Derivatives; D009020:Morphine