Antinociceptive and Hernodynarnic Eflects of a Novel cu,-Adrenergic Agonist, MPV-2426; in Sheep

Backgground: a,-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. clonidine is approved for epidural use in the treatment of neuropathic pain, but its wider application is limited by hemodynamic side effects. This study determined the antinociceptive and hemodynamic effects of a novel a,adrenergic agonist, M W 2 4 2 6 , in sheep. Methods: Forty sheep of mixed Western breeds with indwelling catheters were studied. In separate studies, antinociception to a mechanical stimulus, hemodynamic effects, arterial blood gas tensions, cerebrospinal fluid pharmacokinetics, and spinal cord blood flow was determined after epidural, intrathecal, and intravenous injection of M P V 2 4 2 6 . Results: M P V 2 4 2 6 produced antinociception with greater potency intrathecally (ED,, = 49 pg) than epidurally (ED,, = 2 0 2 pg), whereas intravenous administration had no effect. Intrathecal injection, in doses up to three times the ED,,, failed to decrease systemic or central arterial blood pressures or heart rate, whereas larger doses, regardless of route, increased systemic arterial pressure. Bioavailability in cerebrospinal fluid was 7% after epidural administration and 0.17% after intrave-