Pharmacological evidence for different alpha2-adrenergic receptor sites mediating analgesia and sedation in the rat

Alpha(2)-adrenergic agonists given intrathecally result in antinociception and intracerebroventricularly (ICV) in sedation. To examine whether different alpha(2)-adrenergic receptor subtypes differentially mediate antinociception and sedation, we measured the relative potency of three alpha(2)-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 alpha(2)-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 alpha(2)-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.