Vol. 281, Issue 2, 868-875, 1997

M₁ Receptor Agonist Activity Is Not a Requirement for Muscarinic Antinociception

Malcolm J. Sheardown, Harlan E. Shannon, Michael D. B. Swedberg, Peter D. Suzdak, Frank P. Bymaster, Preben H. Olesen, Charles H. Mitch, John S. Ward and Per Sauerberg

Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760, Måløv, Denmark (M.J.S., M.D.B.S., P.D.S., P.H.O., P.S.) and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (H.E.S., F.P.B., C.H.M., J.S.W.)

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 m₁ clone 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.