Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat.
Alpha2-adrenergic agonists given intrathecally result in antinociception and intracerebroventricularly (ICV) in sedation. To examine whether different alpha2-adrenergic receptor subtypes differentially mediate antinociception and sedation, we measured the relative potency of three alpha2-adrenergic agonists, dexmedetomidine (DMET), clonidine (CLON) and UK-14.304 (UK), after spinal and ICV administration. Each agonist was given either alone or in the presence of systemically administered yohimbine, which acts as a competitive alpha2-antagonist in unanaesthetized rats. Intrathecal delivery of the agonists alone resulted in a dose-dependent antinociceptive effect (ED50 (nmol): DMET = 1.2, UK = 1.7, CLON = 5.6) with little sedative effect at the lower doses. Yohimbine pretreatment resulted in a rightward shift of the dose-response curves (DMET > CLON > UK). ICV alpha2-adrenergic agonists produced a dose-dependent sedation (ED50 (nmol): DMET = 10.5; UK = 28.7; CLON = 126), with little antinociceptive action. Again, yohimbine pretreatment produced a right shift of the ICV sedation dose-response curves (UK > DMET > CLON). Thus, we conclude that the spinal analgesic effects of DMET, CLON and UK appear to be mediated by two sites. After ICV delivery, DMET, CLON and UK appear to act at a common supra-spinal site to produce sedation and this site resembles that acted upon by UK in the spinal cord.
Buerkle
H
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Department of Anesthesiology, University of California, San Diego, USA.
Yaksh
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D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000698:Analgesia; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000494:pharmacology; D016292:Procedural Sedation; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D020926:Medetomidine; D017288:Pain Threshold / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018712:Analgesics, Non-Narcotic; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D000068438:Brimonidine Tartrate; D003000:Clonidine; D020926:Medetomidine