Naltrexone modulation of nicotinic acetylcholine receptor activity

AC Le Dain, BW Madsen and RO Edeson

Department of Pharmacology, University of Western Australia.

The narcotic antagonist naltrexone (NTX) has both depressant and excitatory effects on nicotinic acetylcholine receptor activity, and the present study was primarily concerned with mechanisms involved in the latter modulatory action. Single channel data were recorded in cell- attached mode from cultured embryonic chick skeletal muscle myotubes at 10 degrees C under control conditions (0.15 or 0.3 microM acetylcholine, ACh) or in the presence of NTX (0.15 microM ACh plus 0.1- 5 microM NTX). Distributions of open and closed times indicated that there were at least two open and four closed channel states in all cases, and evidence for at least two gateways between the open and closed classes was provided by autocorrelation data. In the absence of NTX the proportion of long (greater than 2 msec) openings increased with increasing ACh concentration, suggesting that the channel in both the mono- and biliganded forms of the receptor could open. Three possible six-state models of channel kinetics which were compatible with these findings could not be distinguished on the basis of conventional Markov modeling of open and closed times; however when account was taken of burst distributions, one model was clearly superior. Estimated transition rates in this model showed that enhanced receptor activity in the presence of NTX was due mainly to increased cooperativity of ACh binding. The results suggest that in the chick nicotinic ACh receptor, low micromolar concentrations of NTX may cause enhancement and blockade of activity by binding to a site which is allosterically coupled to several activation and gating processes.

Volume 258, Issue 2, pp. 551-558, 08/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics