Neuromuscular dysfunction induced by acetylcholinesterase inhibition

The organophosphate cholinesterase inhibitor paraoxon produces a dose-dependent necrosis in rat skeletal muscle fibers after a single administration. The pathology, which is initiated at the motor end-plate region, is evident as early as 30 minutes after paraoxon administration and is characterized by dilated mitochondria, expanded sarcoplasmic reticulum, fused and widened subsynaptic folds, and coated cleft vesicles. By 24 hours, a generalized breakdown of muscle fiber architecture is evident with an accompanying infiltration of phagocytes. Electrophysiological studies have shown that paraoxon increases neurotransmitter release and causes spontaneous and impulse-related antidromic nerve activity, both of which can be reduced significantly by reactivation of inhibited acetylcholinesterase (AChE) with pyridine-2-aldoxime methiodide. The severity of the myopathy has been found to be positively correlated to the degree and duration of AChE inhibition. It appears that 2 hours of inhibition, with a critical loss in activity, viz., 85%, is necessary to initiate severe muscle fiber necrosis. Prior nerve transection prevents myopathic development and current data support the hypothesis that the induction of skeletal muscle fiber necrosis is triggered by inhibition of a neurally regulated fraction of AChE.