EVIDENCE FOR NICOTINIC RECEPTORS POTENTIALLY MODULATING NOCICEPTIVE TRANSMISSION AT THE LEVEL OF THE PRIMARY SENSORY NEURON - STUDIES WITH F11 CELLS

F11 cells are a dorsal root ganglion (DRG) cell line used to model the function of authentic type C, peptidergic, nociceptive neurons, The c ellular events underlying the antinociceptive effects of (+/-)-epibati dine, a nicotinic acetylcholine receptor (nAChR) ligand that is 200-fo ld more potent than morphine, is unknown, The present study investigat ed the ability of cholinergic channel activators (ChCAs) to effect nAC hR-gated ion flux and modulate the release of substance P (SP), a neur opeptide identified to play a critical role in nociception. The protot ypical agonists (-)-nicotine and (-)-cytisine, the ganglionic stimulan t 1,1-dimethyl-4-phenylpiperazinium, the novel ChCA ABT-418 [(S)-3-met hyl-5-(-1-methyl-2-pyrrolidinyl) isoxazole], and (+/-)-epibatidine evo ked a concentration-dependent stimulation of rubidium (Rb-86(+)) efflu x with EC50 values of 14.2 +/- 1.6, 63.4 +/- 24, 3.8 +/- 2.0, 29.8 +/- 2.6, and 0.019 +/- 0.001 mu M as well as maxima intrinsic activities of 100, 97, 69, 75, and 102%, respectively. The noncompetitive nAChR a ntagonist mecamylamine potently antagonized (-)-nicotine-evoked ion fl ux, whereas the competitive antagonist dihydro-beta-erythroidine was a weak antagonist, giving support to an alpha 3 beta 4 nAChR subtype, I n addition, concentrations of (+/-)-epibatidine, similar to those nece ssary to induce maximal Rb-86(+) efflux, evoked spontaneous release of SP from these cells, which was blocked by mecamylamine. Furthermore, prolonged exposure to (+/-)-epibatidine desensitized the functional re sponse of the nAChR in this cell line (IC50 = 12 +/- 9 nM). These find ings in F11 cells provide a model to investigate the role nAChRs play in modulating DRG cell function, and may lead to insights into the rol e these receptors have in modulating nociceptive transmission.