title: The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla.
abstract: Electrophysiological data suggest an involvement of rostral ventromedial medulla (RVM) GABA and glutamate (GLU) neurons in morphine analgesia. Direct evidence that extracellular concentrations of GABA or GLU are altered in response to mu opioid receptor (MOP-R) activation is, however, lacking. We used in vivo microdialysis to investigate this issue. Basal GABA overflow increased in response to intra-RVM perfusion of KCl (60 mmol/L). Reverse microdialysis of the MOP-R agonist D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) (20-500 micromol/L) produced a concentration-dependent decrease of RVM GABA overflow. Behavioral testing revealed that concentrations that decreased GABA levels increased thermal withdrawal thresholds. A lower agonist concentration that did not increase GABA failed to alter thermal thresholds. DAMGO did not alter GLU concentrations. However, KCl also failed to modify GLU release. Since rapid, transporter-mediated uptake may mask the detection of changes in GLU release, the selective excitatory amino acid transporter inhibitor pyrrolidine-2,4-dicarboxylic acid (tPDC, 0.6 mmol/L) was added to the perfusion medium for subsequent studies. tPDC increased GLU concentrations, confirming transport inhibition. KCl increased GLU dialysate levels in the presence of tPDC, demonstrating that transport inhibition permits detection of depolarization-evoked GLU overflow. In the presence of tPDC, DAMGO increased GLU overflow in a concentration-dependent manner. These data demonstrate that MOP-R activation decreases GABA and increases GLU release in the RVM. We hypothesize that the opposing effects of MOP-R on GLU and GABA transmission contribute to opiate antinociception.
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Raf Jan-Filip
authors.initials: RJ
authors.lastname: Schepers
authors.forename: Janet Lynn
authors.initials: JL
authors.lastname: Mahoney
authors.forename: Agustin
authors.initials: A
authors.lastname: Zapata
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chefer
authors.forename: Toni Shaun
authors.initials: TS
authors.lastname: Shippenberg
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D045604:Extracellular Fluid / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects*; D017551:Microdialysis / Q000379:methods; D009292:Narcotic Antagonists / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D003998:Dicarboxylic Acids; D009292:Narcotic Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D010455:Peptides; D011759:Pyrrolidines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; C009862:connective tissue-activating peptide; C083486:pyrrolidine-2,4-dicarboxylic acid