F11 cells are a dorsal root ganglion (DRG) cell line used to model the function of authentic type C, peptidergic, nociceptive neurons. The cellular events underlying the antinociceptive effects of (+/-)-epibatidine, a nicotinic acetylcholine receptor (nAChR) ligand that is 200-fold more potent than morphine, is unknown. The present study investigated the ability of cholinergic channel activators (ChCAs) to effect nAChR-gated ion flux and modulate the release of substance P (SP), a neuropeptide identified to play a critical role in nociception. The prototypical agonists (-)-nicotine and (-)-cytisine, the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium, the novel ChCA ABT-418 [(S)-3-methyl-5-(-1-methyl-2-pyrrolidinyl)isoxazole], and (+/-)-epibatidine evoked a concentration-dependent stimulation of rubidium (86Rb+) efflux with EC50 values of 14.2 +/- 1.6, 63.4 +/- 24, 3.8 +/- 2.0, 29.8 +/- 2.6, and 0.019 +/- 0.001 microM as well as maximal intrinsic activities of 100, 97, 69, 75, and 102%, respectively. The noncompetitive nAChR antagonist mecamylamine potently antagonized (-)-nicotine-evoked ion flux, whereas the competitive antagonist dihydro-beta-erythroidine was a weak antagonist, giving support to an alpha3beta4 nAChR subtype. In addition, concentrations of (+/-)-epibatidine, similar to those necessary to induce maximal 86Rb+ efflux, evoked spontaneous release of SP from these cells, which was blocked by mecamylamine. Furthermore, prolonged exposure to (+/-)-epibatidine desensitized the functional response of the nAChR in this cell line (IC50 = 12 +/- 9 nM). These findings in F11 cells provide a model to investigate the role nAChRs play in modulating DRG cell function, and may lead to insights into the role these receptors have in modulating nociceptive transmission.