Spiradoline, a kappa opioid receptor agonist, produces tonic- and use-dependent block of sodium channels expressed in Xenopus oocytes

Spiradoline, an arylacetamide kappa (κ) opioid receptor agonist, produced a potent tonic block of rat neuronal (EC₅₀=34±5 μM) and heart (EC₅₀=183±13 μM) sodium channels and also blocked IFMQ3 mutant neuronal sodium channels (EC₅₀=130±34 μM) that lack fast inactivation when expressed in Xenopus oocytes. Spiradoline produced a hyperpolarizing shift in the voltage-dependence of sodium channel inactivation and exhibited a marked frequency-dependent component to blockade of sodium channels. The onset of open channel block of the IFMQ3 channel by spiradoline was best fit with a first-order blocking scheme, yielding an affinity constant of 116±33 μM. Thus, spiradoline blocks sodium channels by interacting with the major states of the channel which could result in local anesthetic action in nerves and antiarrhythmic action in the heart.