Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord

Background: Synergy between drugs manifests with increased potency and/or efficacy of the combination relative to either agonist given alone. Synergy is typically observed between drugs of different classes, as is the case with the α-adrenergic-opioid receptor synergy often observed in preclinical studies. However, rare studies report synergy between agonists of the same class. The current study examined the analgesic interaction between two intrathecally injected α 2 -adrenergic receptor (AR) agonists previously thought to act at the same receptor subtype when given spinally. Methods: Mice were given clonidine, dexmedetomidine, or the combination spinally to evaluate the interaction between these two agonists. The ED 50 values were calculated, and the interactions were tested by isobolographic analysis. The rotarod test was performed in the same mice after the completion of analgesic assessment to assess motor or sedative effects. These experiments were performed in outbred mice as well as in mice with mutant α 2A ARs, α 2C AR knockout mice, or wild-type controls. Finally, analgesic cross-tolerance between clonidine and dexmedetomidine was evaluated. Results: Clonidine and dexmedetomidine interacted synergistically in all lines except the α 2C AR knockout line, implicating α 2C ARs in the interaction. In addition, clonidine and dexmedetomidine did not show analgesic cross-tolerance in the outbred strain, suggesting that the two drugs have distinct mechanisms of action. Conclusions: The current study introduces a new synergistic agonist pair, clonidine-dexmedetomidine. These two drugs seem to require the α 2A AR for spinal analgesia when given separately; when delivered as a combination, the resultant synergistic interaction requires the α 2C AR as well.