Excitatory nicotinic and desensitizing muscarinic (M2) effects on C-nociceptors in isolated rat skin

The actions of different cholinergic agonists and antagonists were investig ated on nociceptive afferents using the rat skin-saphenous nerve preparatio n, in vitro. Nicotine was able to weakly excite C-nociceptors and to induce a mild sensitization to heat stimulation (in 77% of tested fibers) in a do se-dependent manner (10(-6) to 10(-5) M), but it caused no alteration in me chanical responsiveness tested with von Frey hairs. Muscarine did not induc e a significant nociceptor excitation, but almost all fibers exhibited a ma rked desensitization to mechanical and heat stimuli in a dose-dependent man ner (from 10(-6) to 10(-5) M). The muscarinic effects could be prevented by the general muscarinic antagonist scopolamine (10(-5) M), by the M3 antago nist 1,1-dimethyl-4-diphenylacetoxypiperidium oxide (10(-6) M) co-applied w ith the M2 antagonist gallamine (10(-5) M), and by gallamine alone. As posi tive control we used the relatively M2-selective agonist arecaidine (10(-6) to 10(-5) M), obtaining a similar desensitizing effect as with muscarine. Finally, we performed an immunocytochemical study that demonstrated the pre sence of M2 but not M3 receptors in thin epidermal nerve fibers of the rat hairy skin. Altogether, these data demonstrate opposite effects of nicotini c and muscarinic receptor stimulation on cutaneous nociceptors. M2 receptor -mediated depression of nociceptive responsiveness may convey a therapeutic , i.e., analgesic or antinociceptive, potential.