Evidence for the involvement of descending noradrenergic pathways in the antinociceptive effect of baclofen

The role of descending monoaminergic pathways in the antinociceptive effect of baclofen following intraperitoneal (i.p.) administration was investigated by determining the effect of intrathecal (i.t.) administration of neurotoxins [6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT)] and receptor antagonists (phentolamine and methysergide) on baclofen in the tail-flick and hot-plate tests. Pretreatment with 6-OHDA (20 and 50 μg) inhibited baclofen antinociception in both tests 4-13 days after treatment, but pretreatment with 5,6-DHT (20 and 100 μg) produced a slight increase in the tail-flick test. The higher doses of both neurotoxins produced hyperalgesia in the tail-flick test. In other experiments, baclofen was injected intraperitoneally followed by i.t. amine antagonists when a plateau level of antinociception was attained. Phentolamine (30-100 μg) reversed baclofen antinociception in both the tail-flick and hot-plate tests. Methysergide (30-100 μg) only reversed the effect of baclofen in doses ≥ 50 μg in the tail-flick test. Phentolamine (15 and 30 μg) and methysergide (50 μg) antagonized the antinociceptive effect of i.t. noradrenaline. Both phentolamine and methysergide produced hyperalgesia in the tail-flick test. However, hyperalgesia per se does not appear to be the only factor responsible for the reversal of baclofen antinociception because dose and agent dissociations between these effects were observed. These results suggest that a major mechanism of action of baclofen in producing antinociception is the activation of noradrenergic pathways descending to the spinal cord.