Role of ascending and descending noradrenergic pathways in the antinociceptive effect of baclofen and clonidine

Abstract

Baclofen and clonidine interact with central noradrenaline (NA) pathways by a variety of mechanisms. The specific role of ascending and descending pathways in antinociception produced by these agents was examined by lesioning the dorsal bundle (DB), locus coeruleus (LC) and descending NA pathways by the microinjection of the neurotoxin 6-hydroxydopamine (6-OHDA). Lesions were verified using high-performance liquid chromatography analysis of NA. Both baclofen and clonidine were injected intraperitoneally in all experiments. The antinociceptive effect of baclofen in the tail-flick test was inhibited 7–21 days after DB lesions. This manipulation decreased NA levels in cortex, hippocampus and hypothalamus but did not alter spinal cord levels. Lesions of the LC potentiated the effect of baclofen 12–16 days postlesion. NA levels were reduced in all the regions just mentioned. DB lesions produced a transient decrease in the effect of clonidine, being observed 7 but not 12–16 days postlesion. Neither acute depletion of NA levels with α-methyl-p-tyrosine (α-MPT), nor LC lesions significantly affected antinociception produced by clonidine. Intraspinal 6-OHDA potentiated the antinociceptive action of clonidine in the tail-flick test. This treatment markedly reduced spinal cord NA levels, but had minimal effects on brain NA. The results of this and previous studies in this laboratory suggest that the antinociceptive effect of baclofen is mediated by interactions with both ascending and descending NA pathways. These pathways appear to interact in a complex manner. Interpretation of data for clonidine is complicated because lesions can both deplete endogenous NA as well as inducing postsynaptic supersensitivity of α 2-receptors . Clonidine does not depend on endogenous NA pathways for producing antinociception because acute depletion of NA with α-MPT does not alter its action. Spinal sites of action are of importance following systemic clonidine because intraspinal 6-OHDA produces supersensitivity. Altering NA activity in ascending pathways alone produces a transient inhibition of the effect of clonidine, but supersensitivity is not apparent. Simultaneous lesions of both ascending and descending pathways do not produce supersensitivity, again suggesting important interactions between such pathways can occur.