Increased antinociception by alpha-adrenoceptor drugs after spinal cord noradrenaline depletion

Animals depleted of the bulbospinal NA fiber tracts have been reported to be supersensitive to antinociceptive effects of intrathecally administered noradrenaline (NA) in vivo. In the present investigation, the antinociceptive effects were determined after systemic or intrathecal injections of noradrenergic agents. NA and the selective alpha 2-adrenoceptor agonists guanfacine and clonidine were used. NA depletion was performed by treatment neonatally with 6-hydroxydopamine (6-OHDA), or in adult animals by intrathecal 6-OHDA administration or systemic N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4). The neurotoxins were found to cause a severe depletion of spinal NA without affecting dopamine (DA) or 5-hydroxytryptamine (5-HT) levels. The antinociceptive effects of intrathecal injection of NA, clonidine and guanfacine were more strongly enhanced in the depleted than in the control rats. It was also found that clonidine and guanfacine given systemically had a stronger effect in depleted than in control animals. In conclusion, depletion of descending NA pathways induces functional supersensitivity both to intrathecally administered NA and to the selective alpha 2-adrenoceptor agonists clonidine and guanfacine. It was also found that systemically administered clonidine and guanfacine had a stronger effect in NA-depleted than in control animals.