Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord

Abstract

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 alpha-adrenergic-opioid receptor synergy often observed in preclinical studies. However, rare studies report synergy between agonists of the same class. The present study examined the analgesic interaction between two intrathecally injected alpha-2 adrenergic receptor (AR) agonists previously thought to act at the same receptor subtype when given spinally. Methods Mice were administered clonidine, dexmedetomidine, or the combination spinally to evaluate the interaction between these two agonists. The ED50 values were calculated and the interactions tested by isobolographic analysis. The rotarod test was performed in the same mice following 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 alpha2A-ARs, alpha2C-AR-knock-out or wildtype controls. Finally, analgesic cross-tolerance between clonidine and dexmedetomidine was evaluated. Results Clonidine and dexmedetomidine interacted synergistically in all lines except the alpha2C-AR knockout line, implicating alpha2C-ARs in the interaction. Additionally, 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 present study introduces a new synergistic agonist pair, clonidine – dexmedetomidine. These two drugs appear to require the alpha2A-AR for spinal analgesia when given separately; when delivered as a combination, the resultant synergistic interaction requires the alpha2C-AR as well.

The influence of dexmedetomidine on remifentanil‑induced hyperalgesia and the sex differences

“…Its molecular mechanism has been investigated by animal models, Yuan et al (32) reported that dexmedetomidine could prevent RIH via regulating spinal NMDA receptor trafficking as well as protein kinase C and calmodulin-dependent protein kinase II pathway. This result was consistent with other animal studies that suggested combination of α2 adrenergic receptor agonist with an opioid can increase analgesic potency to some extent (33,34). Moreover, by effectively suppressing glial cell proliferation and activate the adjacent nerve cells involved in peripheral and central sensitization, dexmedetomidine has been shown effectively decreasing hyperalgesia by increasing acetylcholine levels in the spinal cord (35).…”

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

“…The kappa 1 and α 2 adrenergic drugs require their respective receptors for activity. Clonidine analgesia was markedly impaired in α 2A receptor knockout mice (24) and U50,488H analgesia was lost in a kappa opioid receptor knockout mouse (25,26). Furthermore, it is unlikely they directly label the 6TM target based on the poor affinity of both clonidine and U50,488H for the E11 binding site in brain labeled by 125 I-IBNtxA (10).…”

Effect of Dexmedetomidine on Dose Requirement of Propofol and Thiopentone Induction in Patients Under General Endotracheal Anesthesia

“…Dexmedetomidine has α2:α1 binding selectivity ratio of 1620:1 compared to 220:1 for clonidine [5], and more predictable pharmacokinetic properties compared to clonidine [9,10]. It also possesses selective α2-adrenoceptor agonism, especially for the 2A subtype of this receptor, which causes it to be a much more effective sedative and analgesic agent than clonidine [11,12].…”