Previous studies of the pharmacologic and physiologic mechanisms of antinociception have focused primarily on the involvement of opioid peptides and monoamines. Although several lines of evidence implicate GABA in the modulation of nociception, limitations in our understanding of the pharmacology of GABA receptors and a paucity of drugs with which to manipulate these receptors have severely hampered studies of the role of GABA to date. However, recent advances in the pharmacology of both GABAA and GABAB receptors now provide the tools with which to more thoroughly characterize the role of GABA in antinociception. This proposal will systematically characterize involvement of GABAA and GABAB receptors in the modulation of nociception by neurons in three regions of the CNS for which the pharmacologic and physiologic mechanisms of antinociception have been best characterized: the spinal cord, n. raphe magnus and n. reticularis gigantocullaris pars alpha. These studies will first assess the effects of GABAA and GABAB agonists and antagonists on nociceptive sensitivity and motor function following intracerebral microinjection and intrathecal injection. The pharmacologic specificity of these effects will then be determined. With respect to the GABAA receptor, these studies will determine whether benzodiazepine agonists in a manner consonant with GABAA receptor pharmacology. Of particular interest will be the determination of (1) whether GABAA receptors involved in nociception are linked to a benzodiazepine modulatory site as it now appears that not all GABAA sites are linked to benzodiazepine sites and (2) whether a specific subtype of the GABAA receptor mediates antinociception. With respect to the GABAB receptor, these studies will determine, using the newly introduced GABAB antagonists, whether the antinociception produce by baclofen is truly mediated by a GABAB receptor or by a """"""""baclofen"""""""" receptor. Finally, this proposal will also examine the pharmacology of the neuronal pathways that mediate the effects of GABAA and GABAB receptor agonists and antagonists on nociception. Using a multidisciplinary approach, these studies will determine whether GABAergic modulation of nociception is mediated by activation or inhibition of a bulbospinal serotonergic projection originating in the n. raphe magnus. The results of these studies will provide new insights into non-opioid mechanisms of antinociception.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011423-09
Application #
2749348
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1990-06-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Hammond, D L (2001) J.J. Bonica Lecture--2001: role of spinal GABA in acute and persistent nociception. Reg Anesth Pain Med 26:551-7
Ugarte, S D; Homanics, G E; Hammond, D L (2001) Effect of embryonic knock-down of GABAA receptors on the levels of monoamines and their metabolites in the CNS of the mouse. Brain Res 904:290-7
Ugarte, S D; Homanics, G E; Firestone, L L et al. (2000) Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor. Neuroscience 95:795-806
Hammond, D L; Nelson, V; Thomas, D A (1998) Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat. Neurosci Lett 244:93-6
John, J M; Kaneko, M; Hammond, D L (1998) Intrathecal bicuculline does not increase formalin-induced inflammation. Brain Res 794:320-4
Hama, A T; Fritschy, J M; Hammond, D L (1997) Differential distribution of (GABA)A receptor subunits on bulbospinal serotonergic and nonserotonergic neurons of the ventromedial medulla of the rat. J Comp Neurol 384:337-48
Kaneko, M; Hammond, D L (1997) Role of spinal gamma-aminobutyric acidA receptors in formalin-induced nociception in the rat. J Pharmacol Exp Ther 282:928-38
Mason, P; Owens, C A; Hammond, D L (1996) Antagonism of the antinocifensive action of halothane by intrathecal administration of GABAA receptor antagonists. Anesthesiology 84:1205-14
Thomas, D A; Navarrete, I M; Graham, B A et al. (1996) Antinociception produced by systemic R(+)-baclofen hydrochloride is attenuated by CGP 35348 administered to the spinal cord or ventromedial medulla of rats. Brain Res 718:129-37
Thomas, D A; McGowan, M K; Hammond, D L (1995) Microinjection of baclofen in the ventromedial medulla of rats: antinociception at low doses and hyperalgesia at high doses. J Pharmacol Exp Ther 275:274-84