IntroductionOrganophosphate (OP) agents are used globally as insecticides and related compounds have been weaponized as nerve agents. Intentional exposures are responsible for a tremendous burden to the health care system in many developing countries [1][2][3][4]. OP agents exert their clinical effects largely by binding to peripheral and central acetylcholinesterase, resulting in a rise in the level of post-synaptic acetylcholine (ACh). The increased levels of postsynaptic ACh induce a range of central effects including seizure, apnea and long-term cognitive deficits [5][6][7].OP-induced central apnea is well documented in animal models of OP-toxicity and is postulated to be an important cause of fatality following human exposure [5]. The neural substrate underlying normal automatic respiratory rhythm generation (i.e, the central respiratory oscillator or CRO) is a topic of investigation and debate [8,9]. There is substantial evidence pointing to the importance of specific neuronal groups within the ventral medulla. The pre-Bötzinger complex (preBötC) contains cholinergic neurons [10] and is integral to normal respiratory function [11]. Other sites in the ventral region of the medulla are involved in respiratory control and contain cholinergic synapses, including the ventral surface of the medulla [12], the nucleus ambiguus [13] and the retrotrapezoid nucleus [14]. These and other brainstem sites may be involved in OP-induced central apnea, for example by affecting chemo-responsive or rhythm generating respiratory neurons or by inhibiting inspiratory drive through pontine cholinergic circuits [15].The hypothesized role of the brainstem in OP-induced central apnea has not been tested directly using validated models of OP poisoning, but the idea is supported indirectly by observations that perturbations of synaptic ACh in circuits involved in breathing cause changes in the pattern of respiratory activity. Some regions of the brainstem demonstrate increased respiratory activity when exposed to elevated ACh levels [10,16], while others demonstrate respiratory depression but not apnea [17]. However, it is unclear how these findings relate to OP poisoning as they stem from studies designed to mimic the cholinergic perturbations that occur during normal circuit function. Toxic levels of synaptic ACh Corresponding Author: Romolo J Gaspari, MD, Department of Emergency Medicine, 55 Lake Ave North, Worcester, MA 01655, Romolo.gaspari@umassmemorial.org, Office -508-334-7943, Fax -508-421-1410. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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