Abstract

The analgesic effects of a series of muscarinic agonists were investigated by use of the mouse acetic acid writhing, grid-shock, hot-plate and tail-flick tests. The compounds tested were oxotremorine, pilocarpine, arecoline, aceclidine, RS86 and four 3–3(substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methyl pyridines (substituted TZTP), these being propoxy-TZTP, 3-Cl-propylthio-TZTP, xanomeline (hexyloxy-TZTP) and hexylthio-TZTP. These agonists were also assayed for their ability to displace [³H]oxotremorine-M and [³H]pirenzepine binding and for their functional selectivity at pharmacologic M₁, M₂ and M₃ receptors. These compounds all produced dose-dependent antinociceptive effects in all of the mouse analgesia tests. The effects of oxotremorine in the writhing test were fully antagonized by the muscarinic antagonist scopolamine (0.1 mg/kg), but only partially antagonized by methscopolamine (10 mg/kg) and unaffected by the opioid antagonist naltrexone. 3-Cl-propylthio-TZTP and propoxy-TZTP had virtually no effect at the M₁ receptor subtype as measured by the human m₁clone expressed in baby hamster kidney cells or the rabbit vas deferens assay. These compounds, however, were more potent in the analgesia tests than the selective M₁ agonists xanomeline and hexylthio-TZTP. These data suggest that muscarinic analgesia is mediated by central muscarinic receptors. However, activity at the M₁ receptor subtype is not a requirement for antinociceptive activity.