title: Modulation of GABA release during morphine withdrawal in midbrain neurons in vitro.
abstract: Chronic treatment with opioids induces adaptations in neurons leading to tolerance and dependence. Studies have implicated the midbrain periaqueductal gray (PAG) in the expression of many signs of withdrawal. Patch-clamp recording techniques were used to examine whether augmentation of adenylyl cyclase signalling produces hyperexcitation in GABAergic nerve terminals within the mouse PAG. Both the rate of mIPSCs and the amplitude of evoked IPSCs during naloxone-precipitated withdrawal was profoundly enhanced in chronically morphine treated mice, compared to vehicle treated controls, in the presence but not the absence an adenosine A(1) receptor antagonist DPCPX. Enhanced GABAergic transmission in the presence of DPCPX was abolished by blocking protein kinase A. Inhibitors of cAMP transport, phosphodiesterase and nucleotide transport mimicked the effect of DPCPX. Coupling efficacy of micro-receptors to presynaptic inhibition of GABA release was increased in dependent mice in the presence of DPCPX. The increased coupling efficacy was abolished by blocking protein kinase A, which unmasked an underlying micro-receptor tolerance. These findings indicate that enhanced adenylyl cyclase signalling following chronic morphine treatment produces (1) GABAergic terminal hyperexcitability during withdrawal that is retarded by a concomitant increase in endogenous adenosine, and (2) enhanced micro-receptor coupling to presynaptic inhibition that overcomes an underlying tolerance.
authors.affiliation: Department of Pharmacology and Pain Management Research Institute, University of Sydney and Royal North Shore Hospital, St Leonards, NSW 2006, Australia. steveh@med.usyd.edu.au
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hack
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Vaughan
authors.forename: MacDonald J
authors.initials: MJ
authors.lastname: Christie
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000345:Affinity Labels / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004745:Enkephalins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000378:metabolism*; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D009294:Narcotics / Q000008:administration & dosage; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013449:Sulfonamides; D009435:Synaptic Transmission / Q000187:drug effects; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014528:Uricosuric Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000345:Affinity Labels; D004745:Enkephalins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009292:Narcotic Antagonists; D009294:Narcotics; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D013449:Sulfonamides; D014528:Uricosuric Agents; D014665:Vasodilator Agents; D014970:Xanthines; C074155:8-chloroadenosine-3',5'-cyclic monophosphorothioate; D005576:Colforsin; D009270:Naloxone; C048599:N(6)-cyclopentyladenosine; D013868:Thioinosine; D005680:gamma-Aminobutyric Acid; D004176:Dipyridamole; D009020:Morphine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; C001789:4-nitrobenzylthioinosine; D000241:Adenosine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D011339:Probenecid