Background and Objectives The relative contributions of α₁-, α₂-, and β-adrenergic receptors to adrenergic agonists’ prolongation of nerve block by tetrodotoxin (TTX) are unknown. We investigated which receptor agonists prolong TTX block, and whether delayed injection of antagonists can interrupt prolonged blocks after coinjection of TTX and agonists.

Methods Rats received percutaneous sciatic nerve block with 120 μmol/L TTX with and without adrenergic agonists and antagonists. Block duration was assessed by a modified hot-plate test. Functional deficits in the uninjected leg were used to assess systemic distribution of TTX. Data were expressed as medians with 25th and 75th percentiles.

Results Coinjection of 5.5 μmol/L phenylephrine (α₁-specific), 10 μmol/L clonidine (α₂-specific), and 1.1 μmol/L epinephrine (mixed α- and β-agonist) prolonged TTX nerve block, but 5.5 μmol/L isoproterenol (mixed β-agonist) did not. Yohimbine inhibited TTX block prolongation by clonidine (median inhibitory concentrations, IC₅₀ = 130 nmol/L); phentolamine similarly inhibited epinephrine (IC₅₀ = 45 nmol/L). Adrenergic antagonists did not inhibit the prolongation of TTX block by agonists when injected 3 or 6 hours after the initial block. Subcutaneous injection of adrenergic agonists at a remote site did not prolong TTX block, except for a modest prolongation by clonidine.

Conclusion TTX block can be prolonged by α₁- and α₂-, but not β-adrenergic agonists via locally mediated events of relatively brief duration. Delayed injection of adrenergic antagonists does not interrupt the prolonged blocks produced by coinjection of TTX and adrenergic agonists unless administered soon after block is established.