Research Article| Volume 163, ISSUE 2, P105-110, March 01, 1999

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Peripheral inflammation is associated with decreased veratridine-induced release of GABA in the rat ventrocaudal periaqueductal gray: microdialysis study


      Systemic administration of opiates or direct injection of opioid peptides into the periaqueductal gray (PAG) produces a profound antinociception which is thought to be associated with inhibition of neuronal activity in the PAG. This inhibitory effect has been postulated to result from opiate inhibition of GABAergic neurons in the PAG. Whether this opioid-GABAergic system is affected in acute pain state has not been investigated. The present study was thus designed to determine the effects of unilateral peripheral inflammation on ventrocaudal PAG γ-aminobutyric acid (GABA) release in the rat using in vivo microdialysis and subsequent high pressure liquid chromatography (HPLC) analysis. Microdialysis was chosen to perform direct and dynamic studies of amino acid concentrations in the PAG in control rats and in animals subjected to acute and prolonged inflammation caused by injection of 120 μl of Complete Freund’s Adjuvant (CFA) into the hind paw. GABA release was significantly decreased in the CFA treated groups both 24 h as well as 7 days post-treatment. GABA release decreased to approximately one-fourth that of the 24 h mineral oil control group. Likewise, veratridine-induced release of GABA was decreased in rats treated with CFA 7 days prior to dialysis. Systemic injection of naloxone (5 mg/kg i.p.) caused selective and significant block in the decrease of veratridine-induced release of GABA in the 24 h CFA-treated rats. Taken together with data from our previous studies, these results suggest that the decrease in veratridine-induced GABA release in this study may be due to an increase opiate inhibition of GABA resulting from the induction of acute or prolonged elevation of nociceptive input.


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        • Behbehani M.M.
        • Jiang M.
        • Chandler S.D.
        The effect of (met)enkephalin on the periaqueductal gray neurons of the rat: in vitro study.
        Neuroscience. 1990; 38: 373-380
        • Bennett G.K.
        • Kajander K.C.
        • Sahara Y.
        • Iadarola M.J.
        • Sugimoto T.
        Neurochemical and anatomical changes in the dorsal horn of rats with an experimental painful peripheral neuropathy.
        in: Cervero F. Processing of Sensory Information in the Superficial Dorsal Horn of the Spinal Cord. Plenum Press, New York1989: 463-472
        • Benveniste H.
        • Huttemeier P.C.
        Microdialysis: Theory and application.
        Prog Neurobiol. 1990; 35: 195-215
        • Depaulis A.
        • Morgan M.M.
        • Liebeskind J.C.
        GABAergic involvement in the antinociceptive effects of morphine at the level of the periaqueductal gray matter in the rat.
        Proc West Pharmacol Soc. 1985; 28: 143-145
        • Draisci G.
        • Iadarola M.G.
        Temporal analysis of increases in c-fos, preprodynorphin and preproenkephalin mRNAs in rat spinal cord.
        Mol Brain Res. 1989; 6: 31-37
        • Duggan A.W.
        Electrophysiology of opioid peptides and sensory systems.
        Br Med Bull. 1983; 39: 65-70
        • Fields H.L.
        • Heinricher M.M.
        Anatomy and physiology of a nociceptive modulatory system.
        Philos Trans R Soc Lond. 1985; 30: 361-381
        • Fields H.L.
        • Hienricher M.M.
        • Mason P.
        Neurotransmitters in nociceptive modulatory circuits.
        Annu Rev Neurosci. 1991; 14: 219-245
        • Iadarola M.J.
        • Brady L.S.
        • Draisci G.
        • Dubner R.
        Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: Stimulus specificity, behavioral parameters and opioid receptor binding.
        Pain. 1988; 35: 313-326
        • Kajender K.C.
        • Sahara Y.
        • Iadarola M.J.
        • Bennett G.J.
        Dynorphin increases in the dorsal spinal cord in rats with a painful peripheral neuropathy.
        Peptides. 1990; 11: 719-728
        • Kayser V.
        • Guilband G.
        Physiological relevance and time course of a tonic endogenous opioid modulation of nociceptive messages, based on the effects of naloxone in a rat model of localized hyperalgesic inflammation.
        Brain Res. 1991; 567: 197-203
        • Lindort O.
        • Mopper K.
        High performance liquid chromatographic determination in picomole amounts of amino acids by precolumn fluorescence derivatization with o-phthaldialdehyde.
        Anal Chem. 1974; 51: 1667-1674
        • Lipp J.
        Possible mechanisms of morphine analgesia.
        Clin Neuropharmacol. 1991; 14: 131-147
        • Lombard M.C.
        • Besson J.M.
        Electrophysiological evidence for a tonic activity of the spinal cord intrinsic opioid systems in a chronic pain model.
        Brain Res. 1989; 477: 48-56
        • Nahin R.L.
        • Hylden J.L.K.
        • Iadarola M.J.
        • Dubner R.
        Peripheral inflammation is associated with increased dynorphin immunoreactivity in both projection and local circuit neurons in the superficial dorsal horn of the rat lumbar spinal cord.
        Neurosci Lett. 1989; 96: 247-252
        • Paxinos G.
        • Watson C.
        The Rat Brain in Stereotaxic Coordinates. 2nd Ed. Academic Press, Sydney1986
        • Reichling D.B.
        • Basbaum A.I.
        Contribution of brainstem GABAergic circuitry to descending antinociceptive controls. II. Electron microscopic immunocytochemical evidence of GABAergic control over the projection from the periaqueductal gray to the nucleus raphe magnus in the rat.
        J Comp Neurol. 1990; 302: 378-393
        • Renno W.M.
        • Mullet M.A.
        • Beitz A.J.
        Systemic morphine reduces GABA release in the lateral but not the medial portion of the midbrain periaqueductal gray of the rat.
        Brian Res. 1992; 594: 221-232
        • Renno W.M.
        • Mullet M.A.
        • Williams F.G.
        • Beitz A.J.
        Construction of 1-mm microdialysis probe for amino acids dialysis in rats.
        J Neurosci Methods. 1998; 79: 217-228
        • Skilling S.R.
        • Smullin D.H.
        • Beitz A.J.
        • Larson A.A.
        Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation.
        J Neurochem. 1988; 51: 127-132
        • Stein C.
        • Millan J.J.
        • Herz A.
        Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: Alterations in behavior and nociceptive thresholds.
        Pharmacol Biochem Behav. 1988; 31: 445-451
        • Stiller C.O.
        • Linderoth B.
        • O’Connor W.T.
        • Franck J.
        • Falkenberg T.
        • Ungerstedt U.
        • Brodin E.
        Repeated spinal cord stimulation decreases the extracellular level of gamma-aminobutyric acid in the periaqueductal gray matter of freely moving rats.
        Brain Res. 1995; 699: 231-241
        • Ungerstedt U.
        Measurement f neurotransmitter release by intracranial dialysis.
        in: Marsden C.A. Measurement of Neurotransmitter Release in Vivo. Wiley, New York1984: 81-105
        • Williams F.G.
        • Beitz A.J.
        Ultrastructural morphometric analysis of enkephalin-immunoreactive terminals in the ventrocaudal periaqueductal gray: analysis of their relationship to periaqueductal gray-raphe magnus projection neurons.
        Neuroscience. 1990; 38: 381-394
        • Williams F.G.
        • Beitz A.J.
        Ultrastructural morphometric analysis of GABA-immunoreactive terminals in the ventrocaudal periaqueductal gray: analysis of the relationship of GABA terminals and the GABAa receptor of periaqueductal gray-raphe magnus projection neurons.
        J Neurocytol. 1990; 19: 686-696
        • Williams F.G.
        • Renno W.M.
        • Beitz A.J.
        Chronic nociception causes an increase in basal enkephalin in the periaqueductal gray: A microdialysis study. Society for Neuroscience Abstracts, Anaheim, CA1992
        • Williams F.G.
        • Mullet M.A.
        • Beitz A.J.
        Basal release of Met-enkephalin and neurotensin in the ventrolateral periaqueductal gray matter of the rat: a microdialysis study of antinociceptive circuits.
        Brain Res. 1995; 690: 207-216
        • Zambotti F.
        • Zonta M.
        • Parenti R.
        • Tommasi L.
        • Vicentini F.
        • Conci F.
        • Montezazza P.
        Periaqueductal gray matter involvement in the muscimol induced decrease of morphine antinociception.
        Naunyn-Schmeideberg’s Arch. Pharmacol. 1982; 318: 368-369