Antinociceptive Effects of Spinal Cholinesterase Inhibition and Isobolographic Analysis of the Interaction with μ and α2 Receptor Systems

BackgroundSpinal chollnergic receptors have been shown to have a potent antinociceptive action, an effect that can be mimicked by spinal cholinesterase inhibitors. We (1) characterized the cholinergic receptor system through which in-trathecally applied cholinesterase inhibitors produce their antinociceptive effect and (2) examined their interaction with spinal μ opioid and α2-adrenergic receptors. MethodsRats were prepared with chronic intrathecal catheters and the nociceptive threshold was assessed by the use of the radiant heat-evoked hind paw withdrawal. ResultsSpinal administration of neostlgmine, edrophonium, carbachol, clonidine, and morphine produced a dose-dependent increase on the thermally evoked hind paw withdrawal latency. The order of potency (dose producing a 50% effect, in nanomoles) was morphine (1.1) = neostlgmine (1.2) > clonidine (4.4) > carbachol (15) > edrophonium (112). Spinal pretreatment with atropine (35 nmol) attenuated the antinociceptive effect of intrathecal carbachol (55 nmol), neo-stigmine (15 nmol), and edrophonium (500 nmol) but did not affect the potency of intrathecal morphine (15 nmol) or clonidine (435 nmol). In addition, intrathecal pretreatment with naloxone (31 nmol) and yohimbine (28 nmol) attenuated the effects of intrathecally administered morphine and clonidine, respectively, but did not significantly affect the potency of carbachol, neostigmine, or edrophonium. The nicotinic receptor antagonist mecamylamine (60 nmol) did not affect thermal nociception. Isobolographic analysis revealed a syn-ergistlc interaction after the coadminlstratlon of neostlgmlne-clonidine (P > < 0.001), edrophonium-clonldine (P < 0.0001), and edrophonlutn-morphine (P < 0.01) mixtures. Neostlgmine-morphine exhibited simple additivity. ConclusionsThese data indicate that analgesia after spinal cholinesterase inhibition is mediated through muscarinic, but not nlcotlnic cholinerglc, opioid, or α2-adrenergic receptor systems, and that these spinal effects of cholinesterase inhibition interact synergistically with the antinociceptive effects of intrathecal μ and α2 agonists.