title: Antinociception produced by systemic R(+)-baclofen hydrochloride is attenuated by CGP 35348 administered to the spinal cord or ventromedial medulla of rats.
abstract: This study examined the sites in the central nervous system at which subcutaneously-administered R(+)-baclofen hydrochloride (baclofen), the most active isomer of this prototypic gamma-aminobutyric acid (GABA)B receptor agonist, acts to produce antinociception in the rat. To determine whether baclofen acts in the spinal cord, either saline or the GABAB receptor antagonist CGP 35348 was injected intrathecally in rats pretreated 24 min earlier with 1 or 3 mg/kg s.c. baclofen. Intrathecal (i.t.) injection of 3 or 10 micrograms of CGP 35348 antagonized the increase in tail-flick and hot-plate latency produced by either dose of baclofen. To determine whether baclofen acts at sites in the ventromedial medulla (VMM), either saline or CGP 35348 was microinjected in the nucleus raphe magnus or nucleus reticularis gigantocellularis pars alpha of rats pretreated 24 min earlier with 1 or 3 mg/kg s.c. baclofen. Microinjection of 0.5 or 3 micrograms of CGP 35348 at sites in the VMM produced at best only a very modest attenuation of the antinociceptive effects of baclofen. These data suggest that systemically-administered baclofen acts at sites in both the spinal cord and the VMM, but that its antinociceptive effects are likely to be mediated to a greater extent by a spinal, rather than medullary site of action. However, a definitive comparison of the relative contribution of GABAB receptors in these two regions is precluded by differences in the diffusion and concentrations of the antagonist in the spinal cord and brainstem. Finally, microinjection of 0.5 or 3.0 micrograms of CGP 35348 in the nucleus raphe magnus or nucleus reticularis gigantocellularis pars alpha of saline-pretreated rats did not alter tail-flick or hot-plate latency. This finding suggests that, unlike GABAA receptors, GABAB receptors do not mediate the tonic GABAergic input to neurons in these nuclei.
authors.affiliation: Department of Anesthesia and Critical Care, University of Chicago, IL 60637, USA. p4
authors.forename: D A
authors.initials: DA
authors.lastname: Thomas
authors.forename: I M
authors.initials: IM
authors.lastname: Navarrete
authors.forename: B A
authors.initials: BA
authors.lastname: Graham
authors.forename: M K
authors.initials: MK
authors.lastname: McGowan
authors.forename: D L
authors.initials: DL
authors.lastname: Hammond
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects; D002404:Catheterization; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D008845:Microinjections; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000502:physiology*; D013237:Stereoisomerism
chemical_list: D018712:Analgesics, Non-Narcotic; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; C066430:CGP 35348; D001418:Baclofen