Chronic spinal infusion of dexmedetomidine, ST-91 and clonidine: spinal alpha 2 adrenoceptor subtypes and intrinsic activity.
The antinociceptive effect (hot plate test) and behavioral changes produced by the continuous 7-day i.t. infusion of alpha 2 adrenoceptor agonists dexmedetomidine (10 and 3 nmol/hr), clonidine (100 and 30 nmol/hr) and 2-(2,6-diethylphenylamino)-2-imidazoline (ST-91) (30 and 10 nmol/hr) were examined in rats. The highest doses of each agonist produced an equivalent increase in hot plate latency on day 1 of infusion. These effects diminished to near base line by 5 to 7 days. In separate groups, i.t. dose-response curves were obtained with dexmedetomidine, clonidine and ST-91 in groups of rats which had received a 7-day infusion of saline or the equianalgesic concentrations of dexmedetomidine (10 nmol/hr) or ST-91 (30 nmol/hr). Dose-response curves in drug-infused animals showed a right shift as compared to the vehicle-infused rats. Calculation of the ratio of the ED50 values (tolerance ratio: drug vs. control) in animals receiving the continuous infusion of dexmedetomidine vs. saline indicated: 8- (6-12), 36- (19-54) and 1.0- (0.6-1.5) (ratio with 95% Cl) fold rightward shifts of dexmedetomidine, clonidine and ST-91 dose-response curves, respectively. Chronic infusion of ST-91 resulted in 62- (36-127), 22- (13-46) and 0.9- (0.7-1.1) fold rightward shift of the ST-91, clonidine and dexmedetomidine dose-response curves, respectively. Previously, we have shown that dexmedetomidine and clonidine act upon spinal alpha 2 adrenoceptor, which appeared distinguishable from that acted upon by ST-91.(ABSTRACT TRUNCATED AT 250 WORDS)
Takano
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Y
Department of Anesthesiology, University of California, San Diego, La Jolla.
Yaksh
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D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002404:Catheterization; D003000:Clonidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D020926:Medetomidine; D008969:Molecular Sequence Data; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D013997:Time Factors
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; C011266:ST 91; D003000:Clonidine; D020926:Medetomidine