Respiratory failure triggered by cholinesterase inhibitors may involve activation of a reflex sensory pathway by acetylcholine spillover

Abstract Respiration failure during exposure by cholinesterase inhibitors has been widely assumed to be due to inhibition of cholinesterase in the brain. Using a double chamber plethysmograph to measure various respiratory parameters, we observed long “end inspiratory pauses” (EIP) during most exposure that depressed breathing. Surprisingly, Colq KO mice that have a normal level of acetylcholinesterase (AChE) in the brain but a severe deficit in muscles and other peripheral tissues do not pause the breathing by long EIP. In mice, long EIP can be triggered by a nasal irritant. Eucalyptol, an agonist of cold receptor (TRPM8) acting on afferent sensory neurons and known to reduce the EIP triggered by such irritants, strongly reduced the EIP induced by cholinesterase inhibitor. These results suggest that acetylcholine (ACh) spillover from the neuromuscular junction, which is unchanged in Colq KO mice, may activate afferent sensory systems and trigger sensory reflexes, as reversed by eucalyptol. Indeed, the role of AChE at the cholinergic synapses is not only to accurately control the synaptic transmission but also to prevent the spillover of ACh. In the peripheral tissues, the ACh flood induced by cholinesterase inhibition may be very toxic due to interaction with non-neuronal cells that use ACh at low levels to communicate with afferent sensory neurons.