Muscarinic antinociception

Ghelardini, C., Galeotti, N., Bartolini, A. Loss of muscarinic antinociception by antisense inhibition of M1 receptors, Br. J. Pharmacol. 2000, 129, 1633-1640. 

Iwamoto FT. (1989). Antinociception after nicotine administration into the mesopontine tegmentum of rats Evidence for muscarinic actions. J Pharmacol Exp Ther. 251 412-21. 

Iwamoto FJ, Marion L. (1993). Characterization of the antinociception produced by intrathecally administered muscarinic agonists in rats. J Pharmacol Exp Ther. 266 329-38. 

All five muscarinic receptor subtypes have been detected in the central nervous system. The roles of Mx through M3 have been analyzed by means of experiments in knockout mice. The Mx subtype is richly expressed in brain areas involved in cognition. Knockout of Mx receptors was associated with impaired neuronal plasticity in the forebrain, and pilocarpine did not induce seizures in Mx mutant mice. The central nervous system effects of the synthetic muscarinic agonist oxotremorine (tremor, hypothermia, and antinociception) were lacking in mice with homozygously mutated M2 receptors. Animals lacking M3 receptors, especially those in the hypothalamus, had reduced appetite and diminished body fat mass. 

Figure 3 Muscarinic agonists with antinociceptive properties.

Muscarinic antagonists and On the other hand, investigations on the antinociceptive... 

Bartolini, A., Ghelardini, C., Fantetti, L., Malcangio, M., Malmberg-Aiello, P., Giotti, A.. Role of muscarinic receptor subtypes in central antinociception, Br. J. Pharmacol. 1992, 105, 77-82. 

Naguib, M. and Yaksh, T.L. Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord, Anesth. Analg. 1997, 85, 847-853. 

Bemardini N, Roza C, Sauer SK, Gomeza J, Wess J, Reeh PW (2002) Muscarinic M2 receptors on peripheral nerve endings a molecular target of antinociception. J Neurosci 22 RC229 Bemardini N, Sauer SK, Haberberger R, Fischer MJM, Reeh PW (2001) Excitatory nicotinic and desensitizing muscarinic (M2) effects on C-nociceptors in isolated rat skin. J Neurosci 21 3295-3302... 

Welch SP, Huffman JW, Lowe J (1998) Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR14176A. J Pharmacol Exp Ther 286 1301-1308 Wen HL, Mehal ZD, Ong BH, Ho WKK, Wen DYK (1985) Intrathecal administration of beta-endorphin and dynorphin-(l-13) for the treatment of intractable pain. Life Sd 37 1213-1220 Wess J (1996) Molecular biology of muscarinic acetylcholine receptors. Grit Rev Neurobiol 10 69-99... 

Relief from pain. Selected cholinergic agents have been found that display antinociceptive (analgesic) effects grossly similar to those of morphine. Most of these are nicotinic receptor agonists, but a modest number of muscarinic agonists have been found that also display antinociceptive effects. 

In a series of oxotremorine and oxotremo-rine-M (196) analogs (197,198), all compounds studied (tertiary and quaternary amines) demonstrated analgesic effects in neurogenic and inflammatory pain models (233). It was concluded that these compounds were acting as muscarinic analgesics. The antinociceptive effects were blocked by atropine but not by naloxone or mecamylamine. Members of the series varied as to classic muscarinic agonist effects (e.g., salivation). 

Wess, J., Duttaroy, A., Gomeza, J., Zhang, W., Yamada, M., Felder, C. C., Bemardini, N and Reeh, P. W. (2003). Muscarinic receptor. subtypes mediating ceniral and periplterai antinociception studied with mascarinic receptor knockout mice A mview. Life Sci. 72, 2047-2054. 

Muscarinic agonist, partial agonist or antagonist effects estimated on the basis of these receptor binding studies were confirmed in experiments on isolated guineapig ileum. Effects on central muscarinic receptors and abilities of the compounds to penetrate the blood-brain barrier (BBB) were confirmed by the demonstration of central pharmacological (antinociceptive and anticonvulsant) effects after systemic administration to animals [21-23]. 

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