ACTIVATION OF BRAIN ACETYLCHOLINE-RECEPTORS BY NEUROMUSCULAR BLOCKING-DRUGS - A POSSIBLE MECHANISM OF NEUROTOXICITY

Background: Neuromuscular blocking drugs cause excitement and seizures when introduced into the central nervous system. We examined the poss ibility that these drugs produce paradoxical activation of acetylcholi ne or glutamate receptors, the chief types of brain receptors involved in excitatory neurotransmission. Methods: Because activation of centr al glutamate or acetylcholine receptors causes calcium influx into pos tsynaptic neurons, we measured intracellular calcium concentration ([C a2+](i)) as an index of receptor activation. Changes in [Ca2+](i) were compared in brain slices exposed to neuromuscular blocking drugs or a cetylcholine and glutamate receptor agonists. [Ca2+](i) was measured w ith the fluorescent dye fura-2. Results: Pancuronium and vecuronium ca used sustained increases in [Ca2+](i) in approximately the same potenc y ratio as for seizure activity in vivo (concentrations at which the i ncrease in [Ca2+](i) was 95% of maximal: 100 and 400 mu M, respectivel y). Atracurium and laudanosine did not increase [Ca2+](i) in cortical slices. Increases in [Ca2+](i) caused by both pancuronium and vecuroni um were prevented by the non-subtype-specific nicotinic acetylcholine receptor antagonist D-tubocurarine and were reduced 44-73% by atropine . Blockade of glutamate receptors or voltage-gated calcium or sodium c hannels had no effect on calcium influx. Conclusions: The results sugg est that the acute excitement and seizures caused by introduction of p ancuronium and ve curonium into the central nervous system is due to a ccumulation of cytosolic calcium caused by sustained activation of ace tylcholine receptor ion channels.