GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal.
Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms.
Bagley
Elena E
EE
Pain Management Research Institute at Royal North Shore Hospital, The University of Sydney, NSW 2006, Australia. bagleye@med.usyd.edu.au
Gerke
Michelle B
MB
Vaughan
Christopher W
CW
Hack
Stephen P
SP
Christie
MacDonald J
MJ
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018118:Chloride Channels; D004791:Enzyme Inhibitors; D050485:GABA Plasma Membrane Transport Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C493414:Slc6a1 protein, mouse; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases