Dexmedetomidine Prolongs Lidocaine Intravenous Regional Anesthesia in Rats by Blocking the Hyperpolarization-Activated Cation Current

Abstract

Purpose

Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine enhances lidocaine IVRA is unclear but may involve modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.

Materials and Methods

Lidocaine IVRA with varying dexmedetomidine concentrations was performed in the tails of Sprague-Dawley rats. Tail-flick and tail-clamping tests assessed IVRA analgesia and anesthesia efficacy and duration. Contributions of α₂ adrenergic receptors and HCN channels were evaluated by incorporating an α adrenergic receptor antagonist, the HCN channel inhibitor ZD7288, and the HCN channel agonist forskolin. Furthermore, whole-cell patch clamp electrophysiology quantified the effects of dexmedetomidine on HCN channels mediating hyperpolarization-activated cation current (I_h) in isolated dorsal root ganglion neurons.

Results

Dexmedetomidine dose-dependently extended lidocaine IVRA duration and analgesia, unaffected by α₂ receptor blockade. The HCN channel inhibitor ZD7288 also prolonged lidocaine IVRA effects, while the HCN channel activator forskolin shortened effects. In dorsal root ganglion neurons, dexmedetomidine concentration-dependently inhibited I_h amplitude and shifted the voltage-dependence of HCN channel activation.

Conclusion

Dexmedetomidine prolongs lidocaine IVRA duration by directly inhibiting HCN channel activity, independent of α₂ adrenergic receptor activation. This HCN channel inhibition represents a novel mechanism underlying the anesthetic and analgesic adjuvant effects of dexmedetomidine in IVRA.

Keywords:

• dexmedetomidine
• hyperpolarization-activated cyclic nucleotide-gated channel
• intravenous regional anesthesia
• lidocaine

Acknowledgments

This study was sponsored by Fujian provincial health technology project (No. 2022CXA007), Natural Science Foundation of Fujian Province (No. 2021J01378, 2023J011201), Fujian Medical University Student Innovation Training Program (No. S202310392022), and Joint Funds for the Innovation of Science and Technology, Fujian province (No. 2023Y9275).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.