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

J Neurosci. 2001 May 1;21(9):3295-302. doi: 10.1523/JNEUROSCI.21-09-03295.2001.

Abstract

The actions of different cholinergic agonists and antagonists were investigated on nociceptive afferents using the rat skin-saphenous nerve preparation, 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 dose-dependent manner (10(-)6 to 10(-)5 m), but it caused no alteration in mechanical responsiveness tested with von Frey hairs. Muscarine did not induce a significant nociceptor excitation, but almost all fibers exhibited a marked desensitization to mechanical and heat stimuli in a dose-dependent manner (from 10(-)6 to 10(-)4 m). The muscarinic effects could be prevented by the general muscarinic antagonist scopolamine (10(-)5 m), by the M3 antagonist 1,1-dimethyl-4-diphenylacetoxypiperidium oxide (10(-)6 m) co-applied with the M2 antagonist gallamine (10(-)5 m), and by gallamine alone. As positive 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 presence of M2 but not M3 receptors in thin epidermal nerve fibers of the rat hairy skin. Altogether, these data demonstrate opposite effects of nicotinic and muscarinic receptor stimulation on cutaneous nociceptors. M2 receptor-mediated depression of nociceptive responsiveness may convey a therapeutic, i.e., analgesic or antinociceptive, potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / antagonists & inhibitors
  • Acetylcholine / physiology
  • Animals
  • Cholinergic Agonists / pharmacology
  • Cholinergic Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Hot Temperature
  • Immunohistochemistry
  • In Vitro Techniques
  • Male
  • Muscarinic Agonists / pharmacology
  • Muscarinic Antagonists / pharmacology
  • Nerve Fibers / drug effects
  • Nerve Fibers / metabolism*
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / pharmacology
  • Nociceptors / cytology
  • Nociceptors / drug effects
  • Nociceptors / metabolism*
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Physical Stimulation
  • Rats
  • Rats, Wistar
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / metabolism*
  • Receptors, Nicotinic / metabolism*
  • Sensory Thresholds / drug effects
  • Sensory Thresholds / physiology
  • Skin / cytology
  • Skin / innervation*

Substances

  • Cholinergic Agonists
  • Cholinergic Antagonists
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • Receptors, Nicotinic
  • Acetylcholine