Reversal of pertussis toxin-induced thermal allodynia by muscarinic cholinergic agonists in mice

The intrathecal administration of pertussis toxin (PTX) not only blocks the antinociceptive effects of the muscarinic cholinergic receptor agonist oxo tremorine administered systemically, but also produces a long-lasting therm al allodynia in mice. The purpose of the present studies was to determine b oth the antinociceptive effects in normal mice and the antiallodynic effect s in PTX-treated mice of systemically administered muscarinic cholinergic r eceptor agonists and cholinesterase inhibitors. In normal, mice, antinocice ptive effects were tested using a 55 degrees C water-bath tail-flick test. In mice treated 7 days previously with PTX (0.3 mu g i.t.), antiallodynic e ffects were tested using a 45 degrees C water-bath tail-flick test. The non selective high-efficacy muscarinic agonists oxotremorine, H-TZTP (3-(1,2,5- thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate), and methylth io[3.2.1], (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 rece ptor partial agonist and M-1/M-3/M-5 muscarinic receptor antagonist, the no nselective partial agonists RS86 and pilocarpine, and the cholinesterase in hibitors physostigmine and tacrine all produced dose-related antinociceptio n. Oxotremorine, H-TZTP and methylthio[2.2.1] produced dose-related reversa ls of PTX-induced thermal allodynia whereas vedaclidine produced a partial reversal and RS86 and pilocarpine, as well as physostigmine and tacrine, fa iled to reverse the allodynia. The present results provide further evidence that decrements in PTX-sensitive G(i/o)-protein functioning may be involve d in initiating and/or maintaining some persistent or neuropathic pain stat es. Moreover, the present results suggest that muscarinic receptor agonists such as vedaclidine may be useful in the treatment of persistent pain stat es that are due at least in part to dysfunction of inhibitory second messen ger systems. (C) 2000 Elsevier Science Ltd. All rights reserved.