The intrathecal administration of
pertussis toxin (PTX) not only blocks the antinociceptive effects of the
muscarinic cholinergic receptor agonist
oxotremorine administered systemically, but also produces a long-lasting
thermal allodynia in mice. The purpose of the present studies was to determine both the antinociceptive effects in normal mice and the antiallodynic effects in PTX-treated mice of systemically administered
muscarinic cholinergic receptor agonists and
cholinesterase inhibitors. In normal mice, antinociceptive effects were tested using a 55 degrees C water-bath tail-flick test. In mice treated 7 days previously with PTX (0.3 microg i.t.), antiallodynic effects were tested using a 45 degrees C water-bath tail-flick test. The nonselective high-efficacy
muscarinic agonists oxotremorine, H-TZTP (3-(1,2, 5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate), and methylthio[2.2.1], (exo (+)3-(3-methylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]
heptane oxalate), as well as
vedaclidine, a mixed M(2)/M(4)
muscarinic receptor partial agonist and M(1)/M(3)/M(5)
muscarinic receptor antagonist, the nonselective partial agonists RS86 and
pilocarpine, and the
cholinesterase inhibitors physostigmine and
tacrine all produced dose-related antinociception.
Oxotremorine, H-TZTP and methylthio[2.2.1] produced dose-related reversals of PTX-induced
thermal allodynia whereas
vedaclidine produced a partial reversal and RS86 and
pilocarpine, as well as
physostigmine and
tacrine, failed to reverse the
allodynia. The present results provide further evidence that decrements in PTX-sensitive G(i/o)-
protein functioning may be involved in initiating and/or maintaining some persistent or
neuropathic pain states. Moreover, the present results suggest that
muscarinic receptor agonists such as
vedaclidine may be useful in the treatment of persistent
pain states that are due at least in part to dysfunction of inhibitory second messenger systems.