Evidence for Nicotinic Receptors Potentially Modulating Nociceptive Transmission at the Level of the Primary Sensory Neuron: Studies with F11 Cells

• Published in: Journal of neurochemistry 1997-09, Vol.69 (3), p.930-938
• Main Authors: Puttfarcken, Pamela S., Manelli, Arlene M., Arneric, Stephen P., Donnelly‐Roberts, Diana L.
• Format: Article
• Language: English
• Subjects: Analgesics, Non-Narcotic - pharmacology; Analysis of Variance; Animals; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cytosine - pharmacology; Dimethylphenylpiperazinium Iodide - pharmacology; Dorsal root ganglia; Epibatidine; F11 cells; Fundamental and applied biological sciences. Psychology; Ganglia, Spinal; Hybrid Cells; Isoxazoles - pharmacology; Mice; Neuroblastoma; Neurons, Afferent - cytology; Neurons, Afferent - drug effects; Neurons, Afferent - physiology; Nicotine - pharmacology; Nicotinic acetylcholine receptors; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - pharmacology; Pain; Pyridines - pharmacology; Pyrrolidines - pharmacology; Rats; Receptors, Nicotinic - physiology; Rubidium - metabolism; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Substance P; Substance P - metabolism; Synaptic Transmission; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1997.69030930.x

: 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 µM 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‐β‐erythroidine was a weak antagonist, giving support to an α3β4 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.