Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat.
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.
Hammond
D L
DL
Department of Anesthesia and Critical Care, University of Chicago, IL 60637, USA. dh15@midway.uchicago.edu
Nelson
V
V
Thomas
D A
DA
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D006930:Hyperalgesia; D007278:Injections, Spinal; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D008784:Methysergide / Q000008:administration & dosage / Q000494:pharmacology*; D008845:Microinjections; D010146:Pain; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D000700:Analgesics; D058788:GABA-B Receptor Antagonists; D001418:Baclofen; D008784:Methysergide