α-1-Adrenergic Receptor Agonist Activity of Clinical α-Adrenergic Receptor Agonists Interferes with α-2-Mediated Analgesia

Background: The use of α-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects. Methods: Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, α-2A, and α-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays. Results: Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not α-2A knockout mice. In α-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated α-1 and α-2 receptors with similar potencies, whereas brimonidine was selective for α-2 receptors. In α-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's α-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the α-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold. Conclusions: α-1A receptor agonist activity can counterbalance α-2 receptor agonist-induced analgesia. Greater α-2 selectivity may enhance the therapeutic window of α-2 agonists in the treatment of pain.