Radial distension of the large intestine produced a slow depolarization in a population of neurons in the inferior mesenteric ganglion of the guinea pig. The slow potentials often occurred simultaneously with cholinergic fast potentials [(excitatory postsynaptic potentials (EPSPs)] yet persisted in the presence of nicotinic and muscarinic cholinergic antagonists when all fast EPSPs were absent. The amplitude of the distension-induced noncholinergic slow depolarization increased with increasing distension pressure. For distensions of 1-min duration at pressures of 10-20 cm of water, the mean depolarization amplitude was 3.4 mV. The slow depolarization was associated with an increase in membrane resistance, and prolonged periods ofcolon distension resulted in a tachyphylaxis of the depolarization. Desensitization of ganglion cells to the peptide substance P attenuated the distension-induced slow potential by an average of 49% ± 17%. Thus, two colonic mechanosensory afferent pathways converge on principal ganglion cells in the inferior mesenteric ganglion: one was previously described to be mediated by acetylcholine, and the other is described here, whose transmitter remains to be determined but which preliminary evidence suggests is mediated in part by substance P. The noncholinergic afferent pathway may enhance the intestinal inhibitory reflex mediated by cholinergic mechanosensory afferent input to the abdominal prevertebral sympathetic ganglia.In the prevertebral sympathetic ganglia, two general types of postsynaptic potential are recorded intracellularly. These potentials can be differentiated by their time course and the transmitters that mediate them. Fast excitatory postsynaptic potentials (EPSPs) can be evoked with single nerve shocks and are mediated by acetylcholine acting at nicotinic receptors. Slow EPSPs, elicited by repetitive nerve stimulation, are not mediated by acetylcholine (1); rather, other putative neurotransmitters have been implicated for the slow EPSP, including serotonin (2), substance P (SP) (3)(4)(5), and vasopressin (6, 7). Both fast and slow potentials can be evoked by stimulation of preganglionic or postganglionic nerves. The fibers activated by stimulation of the latter could be of two kinds: (i) branches of primary sensory neurons that traverse the ganglia (8, 9) and (ii) afferent neurons located in the gastrointestinal tract that project to the ganglia (8,(10)(11)(12). A cholinergic mechanosensory pathway to the prevertebral ganglia from the colon of the guinea pig has been described (13-17). Activation ofthis pathway by distension of the colon results in an increase in the frequency and amplitude of cholinergic EPSPs in ganglionic neurons. This pathway has been shown to mediate the afferent limb of a mechanosensitive intestinal reflex (16), in which distension of a segment of colon inhibits motility in an adjacent segment (10). It is not known whether the gastrointestinal mechanosensory pathway also comprises noncholinergic fibers; indeed, it remains to be determined whet...