Clostridium difficile toxin A excites enteric neurones and suppresses sympathetic neurotransmission in the guinea pig

Background and aims-Evidence suggests that the intestinal actions of Clostr idium difficile toxin A-stimulation of secretion and motility, and an acute inflammatory response-have a neurally mediated component. Methods-Direct intracellular electrophysiological recording of electrical a nd synaptic behaviour in enteric neurones was performed in the submucous pl exus of guinea pig small intestine during exposure to the toxin. Results-Application of toxin A affected both the electrical behaviour of th e neuronal cell bodies and inhibitory noradrenergic neurotransmission to th e cell bodies. Altered electrical behaviour included depolarisation and inc reased excitability, Tetrodotoxin or a histamine H-2 receptor antagonist di d not affect the depolarisation evoked by toxin A. Failure of the histamine antagonist to suppress the actions of toxin A is evidence that its actions were not mediated by degranulation of intramural mast cells. The action of toxin A on neurotransmission was suppression of inhibitory postsynaptic po tentials evoked in the neuronal cell bodies by stimulation of sympathetic n erve fibres that synapsed with the cell bodies. The inhibitory postsynaptic potentials were mediated by norepinephrine (noradrenaline) acting at posts ynaptic alpha adrenoceptors on the cell bodies. Hyperpolarising responses e voked in the cell bodies by micropressure application of norepinephrine wer e unaffected by toxin A. This fulfils criteria for a presynaptic inhibitory action of toxin A to suppress release of norepinephrine from sympathetic p ostganglionic axons. Conclusions-Results suggest that the neural component of the action of toxi n A involves both direct excitation of enteric neurones and suppression of norepinephrine release from postganglionic sympathetic nerve fibres in the enteric nervous system.