Synergistic effects between intrathecal clonidine and neostigmine in the formalin test

Spinal alpha-2 adrenoceptors and cholinergic receptors are involved in the regulation of acute nociception and the facilitated processing. The aim of this study was to examine the pharmacological effect of an intrathecal alph a-2 agonist and a cholinesterase inhibitor on the facilitated pain model in duced by formalin injection and to determine the nature of drug interaction using an isobolographic analysis. Both intrathecal clonidine and neostigmi ne dose-dependently suppressed the flinching during phase 1 and phase 2. In trathecal pretreatment with atropine reversed the antinociceptive effects o f clonidine and neostigmine in both phases. Pretreatment with intrathecal y ohimbine attenuated the effect of clonidine. The antinociception of clonidi ne and neostigmine was not reversed by mecamylamine. Isobolographic analysi s showed that intrathecal clonidine and neostigmine acted synergistically i n both phase 1 and 2. Intrathecal pretreatment with atropine and yohimbine antagonized the effect of the mixture of clonidine and neostigmine in both phases, but no antagonism was observed with mecamylamine pretreatment. Thes e data indicate that spinal clonidine and neostigmine are effective to coun teract the facilitated state evoked formalin stimulus, and these two drugs interact in a synergistic fashion. In addition, the analgesic action of int rathecal clonidine is mediated by spinal muscarinic receptors as well as al pha-2 adrenoceptors.