Brain Research, 607 (1993) 39-46 0 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00 39 BRES 18641 Intrathecal GABA, antagonists attenuate the antinociception produced by microinjection of L-glutamate into the ventromedia! medulla of the rat Malcolm K. McGowan and Donna L. Hammond Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL 60637 (USA) (Accepted 20 October 19921 Key words: GABA, receptor; Antinociception; Nucleus raphe magnus; Spinal cord; L-Glutamate; CGP 35348; Phaclofen; Methysergide This study examined whether the antinociception produced by glutaminergic stimulation of neurons in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars (Y(NGCpal is mediated by an action of GABA at GABA, receptors in the spinal cord. Rats were pretreated with intrathecal (i.t.1 administration of the selective GABA, receptor antagonists phaclofen (100 kg) or CGP 35348 (30 rg), the serotonin receptor antagonist methysergide (30 pgl, or vehicle. Fifteen min later, 30 nmol L-glutamate was microinjected into the NRM, NGCpcq or sites in the medulla outside these two regions. Microinjection of L-glutamate into the NRM or NGCpo in vehicle-pretreated rats significantly increased tail flick latency. This increase was antagonized, but not abolished, by i.t pretreatment with 30 Fg CGP 35348 or 100 pg phaclofen. Pretreatment with 30 pg methysergide completely antagonized the antinociception produced by L-glutamate. Microinjection of L-glutamate at medullary sites outside the NRM or NGCpa did not produce antinociception. In an ancillary experiment, the possibility that the ability of methysergide, phaclofen or CGP 35348 to antagonize glutamate-induced antinociception was related to non-specific increases in tail skin temperature was explored. Although phaclofen or methysergide increased tail skin temperature, the magnitude and time course of this increase were not consistent with the antagonism of glutamate-induced antinociception. Moreover, administration of CGP 35348 resulted in a modest decrease in tail skin temperature. Thus, antagonism of glutamate-induced antinociception does not appear to result from non-specific alterations in tail skin temperature. Taken together, these results indicate that the antinociception produced by activation of neurons in the NRM and NGCpa is at least partially mediated by GABA, receptors in the spinal cord. INTRODUCTION At least two subtypes of the y-aminobutyric acid (GABA) receptor, GABA, and GABA,, are currently recognized12,13,‘7@. I n the spinal cord, the densities of these receptors are generally highest in the superficial laminae of the dorsal horn in the rat14,36,39 and the human4’, suggesting that they may be involved in the modulation of nociceptive sensitivity. This postulate is supported by the finding that intrathecal (i.t.1 adminis- tration of GABA-ergic agents alters nociceptive sensi- tivity in a variety of species. For example, the GABA, receptor agonist muscimol increases nociceptive threshold when injected intrathecally in the rat21s4’ or the mouse’. Conversely, i.t. injection of GABA, recep- tor antagonists, such as picrotoxin or bicuculline, de- creases nociceptive threshold in the rat4’ and induces caudally-directed biting and scratching behavior in the mouse’. Nociceptive threshold is also increased follow- ing i.t. injection of the GABA, receptor agonist ba- clofen in the rat21,42,48, mouse24 or primate5’. Taken together, these data implicate both GABA, and GABA, receptors in the spinal cord in the regulation of nociceptive sensitivity. The dorsal horn contains high densities of GABA, which is thought to originate predominantly from GABAergic interneurons6~15,29,32,33~35~37~46,47. However, more recent studies indicate that GABA in the spinal cord also derives from supraspinal neurons. Several investigators have identified GABAergic neurons in the medulla that project to the spinal cord of the rat 27*30,38 and the rabbit’ l. Many of these neurons are situated in the ventromedial and ventrolateral medulla, including the nucleus raphe magnus (NRM) and nu- Correspondence: D.L. Hammond, Department of Anesthesia and Critical Care, The University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA. Fax: (1) (312) 702-3535.