Understanding neuromuscular transmission failure in organophosphorus pesticide toxicity

About the project

Intermediate syndrome in organophosphorus toxicity is debilitating condition whereby people experience delayed muscle paralysis including of the respiratory muscle. Failure of neuromuscular junction (NMJ) transmission appears to cause the muscle paralysis.

Our goal is to understand the mechanisms of NMJ transmission failure in organophosphorus toxicity, not only to help treat those affected, but also as a platform to investigate other diseases related to NMJ transmission failure. Utilising electrophysiological techniques (e.g. tension measurements, intracellular recordings and patch clamp recordings) along with morphological approaches (calcium imaging, immunocytochemistry) we have been able to differentiate some of the key components of NMJ transmission failure.

Our major findings include: (i) omethoate, a pesticide anti-AChE metabolite, shows prolongs endplate depolarization and induces NMJ hypercontraction with impaired transmission; and (ii) cyclohexanol, an agricultural pesticide solvent metabolite, causes depression and prolongation of endplate potentials, thus myasthenic muscle contractions. Cyclohexanol can also bind to the nicotinic acetylcholine receptor and impair its gating mechanisms. Hypothermia and magnesium infusion seem to mitigate NMJ transmission failure, demonstrating their potential value as a treatment in humans.



Medical Research Council, Wellcome Trust


Dissanayake KN, Redman RR, Mackenzie H, Eddleston M, Ribchester RR
“Calcium bombs" as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions
Frontiers in Molecular Neuroscience
2022 Jul 26
Dissanayake KN, Margetiny F, Whitmore CL, Chou RC, Roesl C, Patel V, McArdle JJ, Webster R, Beeson D, Tattersall JEH, Wyllie DJA, Eddleston M, Ribchester RR
Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function
Journal of Physiology
2021 Nov 08
Dissanayake KN, Chou RC, Thompson A, Margetiny F, Davie C, McKinnon S, Patel V, Sultatos L, McArdle JJ, Clutton RE, Eddleston M, Ribchester RR
Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure
Clinical Toxicology
2021 May 14

Primary location


Principal Investigator

Other people involved

Richard Ribchester (Co-PI)

Michael Eddleston (Co-PI)

Tom Gillingwater (Collaborator)

Tom Wishart (Collaborator)