title: Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway.
abstract: Chronic morphine administration induces adaptations in neurons resulting in opioid tolerance and dependence. Functional studies have implicated a role for the periaqueductal gray area (PAG) in the expression of many signs of opioid withdrawal, but the cellular mechanisms are not fully understood. This study describes an increased efficacy, rather than tolerance, of opioid agonists at mu-receptors on GABAergic (but not glutamatergic) nerve terminals in PAG after chronic morphine treatment. Opioid withdrawal enhanced the amplitudes of electrically evoked inhibitory synaptic currents mediated by GABAA receptors and increased the frequency of spontaneous miniature GABAergic synaptic currents. These effects were not blocked by 4-aminopyridine or dendrotoxin, although both Kv channel blockers abolish acute opioid presynaptic inhibition of GABA release in PAG. Instead, the withdrawal-induced increases were blocked by protein kinase A inhibitors and occluded by metabolically stable cAMP analogs, which do not prevent acute opioid actions. These findings indicate that opioid dependence induces efficacious coupling of mu-receptors to presynaptic inhibition in GABAergic nerve terminals via adenylyl cyclase- and protein kinase A-dependent processes in PAG. The potential role of these adaptations in expression of withdrawal behavior was supported by inhibition of enhanced GABAergic synaptic transmission by the alpha2 adrenoceptor agonist clonidine. These findings provide a cellular mechanism that is consistent with other studies demonstrating attenuated opioid withdrawal behavior after injections of protein kinase A inhibitors into PAG and suggest a general mechanism whereby opioid withdrawal may enhance synaptic neurotransmission.
authors.affiliation: Department of Pharmacology and The Medical Foundation, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Ingram
authors.forename: C W
authors.initials: CW
authors.lastname: Vaughan
authors.forename: E E
authors.initials: EE
authors.lastname: Bagley
authors.forename: M
authors.initials: M
authors.lastname: Connor
authors.forename: M J
authors.initials: MJ
authors.lastname: Christie
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D004546:Elapid Venoms / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000378:metabolism* / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D004546:Elapid Venoms; D018755:GABA Agonists; D018756:GABA Antagonists; D009294:Narcotics; D009498:Neurotoxins; D015221:Potassium Channels; C042467:dendrotoxin receptor; D005680:gamma-Aminobutyric Acid; C020273:dendrotoxin; D015761:4-Aminopyridine; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D003000:Clonidine