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

Spiradoline, an arylacetamide kappa (kappa) opioid receptor agonist, produc ed a potent tonic block of rat neuronal (EC50 = 34 +/-5 muM) and heart (EC5 0 = 183 +/- 13 muM) sodium channels and also blocked IFMQ3 mutant neuronal sodium channels (EC50 = 130 +/- 34 muM) that lack fast inactivation when ex pressed in Xenopus oocytes. Spiradoline produced a hyperpolarizing shift in the voltage-dependence of sodium channel inactivation and exhibited a mark ed 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 muM. Thus, spiradoline blocks sodium channels by interacting with the majo r states of the channel which could result in local anesthetic action in ne rves and antiarrhythmic action in the heart. (C) 2001 Elsevier Science Inc. All rights reserved.