Microinjection of
baclofen, a gamma-aminobutyric acidB (
GABA[B]) receptor agonist, in the nucleus raphe magnus (NRM) or nucleus reticularis gigantocellularis pars alpha (NGCpalpha) of the rat produces antinociception at doses of 0.1-1.0 ng and
hyperalgesia at doses of 30-150 ng in the tail-flick test. The antinociception is proposed to result from disinhibition of spinally-projecting neurons in this region that contain
serotonin. The
hyperalgesia is proposed to result either from inhibition of these neurons or from disinhibition of a serotonergic
pain facilitatory pathway that also originates in this area of the ventromedial medulla. To determine the involvement of bulbospinal serotonergic pathways in the biphasic effects of
baclofen, rats were pretreated intrathecally with either 30 microg of
methysergide or saline. Ten minutes later, either saline, 0.5 ng or 150 ng of
baclofen was microinjected in the NRM and NGCpalpha, and alterations in nociceptive threshold were assessed by the tail-flick and hot-plate tests. Intrathecal pretreatment with
methysergide prevented the increase in tail-flick latency produced by 0.5 ng of
baclofen, but did not prevent the decrease in tail-flick latency produced by 150 ng of
baclofen. Neither dose of
baclofen altered hot-plate latency and this lack of effect was unchanged by
methysergide. These data support the idea that the antinociceptive effect of low doses of
baclofen in the tail-flick test is mediated by disinhibition of a bulbospinal serotonergic projection and release of
serotonin in the spinal cord. These data also suggest that the
hyperalgesia produced by high doses of
baclofen does not result from disinhibition of a serotonergic
pain facilitatory pathway, but rather from direct inhibition of tonically-active
pain inhibitory neurons in the NRM and NGCpalpha.