Muscarinic M2 receptors on peripheral nerve endings: a molecular target of antinociception.
We recently described a novel endogenous mechanism of peripheral antinociception, possibly involving activation of muscarinic M2 acetylcholine receptors that are expressed on nociceptive nerve endings and decrease their sensitivity. In the present study, this mechanism was scrutinized in skin taken from mice with targeted deletions of the muscarinic M2 receptor gene and, for control purposes, of the M4 receptor gene. Two different approaches were taken. Electrophysiologically the effects of muscarine on nociceptive afferents were investigated using the mouse skin-saphenous nerve preparation, in vitro. Muscarine did not excite nociceptors in the wild-type littermates (WT) and M4 knock-out (M4 KO) mice, but almost all fibers exhibited marked desensitization to mechanical and heat stimuli. Surprisingly, in the M2 KO mice, muscarine was able to excite C-nociceptors and to induce a mild sensitization to heat but caused no alteration in mechanical responsiveness tested with von Frey hairs. In the second, neurochemical approach, the heat-induced cutaneous release of calcitonin gene-related peptide (CGRP) was investigated to gain comparative data on the neurosecretory (vasodilatory) functions of the primary afferent neurons. The substantial increase of CGRP release evoked by noxious heat (47 degrees C) was diminished under muscarine by >50% in the WT and M4 KO animals but remained unaltered in the M2 KO mice. Together, these data provide direct evidence that M2 receptors on cutaneous nerve endings mediate effective depression of nociceptive responsiveness. This observation should be of interest for the development of novel classes of analgesic agents.
Bernardini
Nadia
N
Department of Physiology and Experimental Pathophysiology, University of Erlangen, D-91054 Erlangen, Germany.
Roza
Carolina
C
Sauer
Susanne K
SK
Gomeza
Jesus
J
Wess
Jürgen
J
Reeh
Peter W
PW
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D046508:Culture Techniques; D016503:Drug Delivery Systems; D004553:Electric Conductivity; D006358:Hot Temperature; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000378:metabolism*; D010525:Peripheral Nerves / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000294:innervation
D000700:Analgesics; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D009116:Muscarine; D015740:Calcitonin Gene-Related Peptide