IL-1 beta and IL-6 excite neurons and suppress nicotinic and noradrenergicneurotransmission in guinea pig enteric nervous system

Conventional intracellular microelectrodes and injection of biocytin were u sed to study the actions of IL-1 beta and IL-6 on electrical and synaptic b ehavior in morphologically identified guinea pig small intestinal submucous neurons. Exposure to nanomolar concentrations of either IL-1 beta or IL-6 stimulated neuronal excitability. The excitatory action consisted of depola rization of the membrane potential, decreased membrane conductance, and inc reased discharge of action potentials. Excitatory action of IL-1 beta was s uppressed by the natural IL-1 beta human receptor antagonist. Electrical st imulation of sympathetic postganglionic axons evoked inhibitory postsynapti c potentials (IPSPs), and stimulation of cholinergic axons evoked nicotinic fast excitatory postsynaptic potentials (EPSPs). Both kinds of synaptic po tentials occurred in neurons with uniaxonal morphology believed to be secre tomotor neurons. Either IL-1 beta or IL-6 suppressed the noradrenergic IPSP s and the fast EPSPs, and the two acted synergistically when applied in com bination. Suppression of the IPSP resulted from presynaptic inhibition of t he release of norepinephrine from sympathetic nerves. The results suggest t hat the presence of either or both inflammatory cytokines will release the sympathetic brake from secretomotor neurons to the intestinal crypts and fr om nicotinic synapses in the integrative microcircuits, where norepinephrin e is known to have a presynaptic inhibitory action. This, in concert with e xcitation of secretomotor neurons, may lead to neurogenic secretory diarrhe a.