Intrathecal carbachol and clonidine produce a synergistic antiallodynic effect in rats with a nerve ligation injury.

Abstract

Antiallodynic effects have been demonstrated after intrathecal administration of alpha-2 adrenoceptor agonists and cholinesterase inhibitors in rats. Intrathecal carbachol also increases the activity of cholinergic receptor system at the spinal level. However, there is no study regarding the antagonism of carbachol on touch-evoked allodynia and the interaction with clonidine. This study examines the intrathecal interaction between two drugs in a rat model of nerve ligation injury. Rats were prepared with tight ligation of the left L5-6 spinal nerves and chronic intrathecal catheter implantation. Tactile allodynia was measured by using application of von Frey filaments to the lesioned hindpaw. Carbachol (0.3-10 microg) and clonidine (1-30 microg) were administered to obtain the dose-response curves and the 50% effective dose (ED(50)) for each drug. Fractions of ED(50) values (1/2, 1/4, 1/8, and 1/16) were administered intrathecally to establish the ED(50) of the carbachol-clonidine combination. Isobolographic and fractional analyses of drug interaction were performed. Intrathecal carbachol and clonidine alone produced a dose-dependent reduction of tactile allodynia without severe motor weakness or sedation. A carbachol-clonidine combination produced a dose-dependent increase in withdrawal threshold of the lesioned hindpaw with a reduced incidence and magnitude of side effects. Both analyses revealed a synergistic interaction after the coadministration of carbachol and clonidine. This study indicates that carbachol, like clonidine, provides a moderate antagonism on touch-evoked allodynia at the spinal level. The results suggest that intrathecally administered carbachol is synergistic when combined with clonidine.