| Abstract
| - 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.
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