Morphine withdrawal increases intrinsic excitability of oxytocin neurons in morphine-dependent rats.
To determine whether intrinsic mechanisms drive supraoptic nucleus oxytocin neuron excitation during morphine withdrawal, we calculated the probability of action potential (spike) firing with time after each spike for oxytocin neurons in morphine-naive and morphine-dependent rats in vivo and measured changes in intrinsic membrane properties in vitro. The opioid receptor antagonist, naloxone, increased oxytocin neuron post-spike excitability in morphine-dependent rats; this increase was greater for short interspike intervals (<0.1 s). Naloxone had similar, but smaller (P=0.04), effects in oxytocin neurons in morphine-naive rats. The increased post-spike excitability for short interspike intervals was specific to naloxone, because osmotic stimulation increased excitability without potentiating excitability at short interspike intervals. By contrast to oxytocin neurons, neither morphine dependence nor morphine withdrawal increased post-spike excitability in neighbouring vasopressin neurons. To determine whether increased post-spike excitability in oxytocin neurons during morphine withdrawal reflected altered intrinsic membrane properties, we measured the in vitro effects of naloxone on transient outward rectification (TOR) and after-hyperpolarization (AHP), properties mediated by K+ channels and that affect supraoptic nucleus neuron post-spike excitability. Naloxone reduced the TOR and AHP (by 20% and 60%, respectively) in supraoptic nucleus neurons from morphine-dependent, but not morphine-naive, rats. In vivo, spike frequency adaptation (caused by activity-dependent AHP activation) was reduced by naloxone (from 27% to 3%) in vasopressin neurons in morphine-dependent, but not morphine-naive, rats. Thus, multiple K+ channel inhibition increases post-spike excitability for short interspike intervals, contributing to the increased firing of oxytocin neurons during morphine withdrawal.
Brown
Colin H
CH
School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK. Colin.Brown@ed.ac.uk
Stern
Javier E
JE
Jackson
Keshia L M
KL
Bull
Philip M
PM
Leng
Gareth
G
Russell
John A
JA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004347:Drug Interactions; D005260:Female; D007031:Hypothalamus / Q000166:cytology; D066298:In Vitro Techniques; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009021:Morphine Dependence / Q000473:pathology*; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010082:Oxepins; D010121:Oxytocin / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013997:Time Factors
C461941:1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin; D009281:Naphthalenes; D009292:Narcotic Antagonists; D009294:Narcotics; D010082:Oxepins; D012462:Saline Solution, Hypertonic; D009270:Naloxone; D010121:Oxytocin; D009020:Morphine