Chronic very low dose naltrexone administration attenuates opioid withdrawal expression.
BACKGROUND
Different regimens of agonist and antagonist drugs have been used in opioid withdrawal management, with variable results. We examined whether administering extremely small quantities of opiate antagonists in the presence of opiate agonist drugs reduces withdrawal expression.


METHODS
Forty-one male Sprague-Dawley rats were implanted with morphine or placebo pellets for eight days. Starting on day 3, some rats received naltrexone in their drinking water (5 mg/L), or unadulterated water. On day 8, rats were injected with saline or naltrexone (100 mg/kg) and evaluated for behavioral signs of withdrawal. Next, sections through the locus coeruleus (LC) and nucleus of the solitary tract (NTS), brainstem areas exhibiting cellular activation following opiate withdrawal, were processed for c-Fos to detect early gene expression. Finally, the same nuclei were examined for protein kinase A regulatory subunit II (PKA) and phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), using Western blot analysis.


RESULTS
Withdrawal was attenuated and c-Fos, PKA, and pCREB expression was decreased in the NTS and LC of rats receiving chronic very low doses of naltrexone.


CONCLUSIONS
Reduction of withdrawal upon chronic very low naltrexone administration may be due in part to decreased activation of brainstem noradrenergic neurons in morphine dependent rats.
Department of Psychiatry and Human Behavior, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Paolo
P
Mannelli
Edward
E
Gottheil
James F
JF
Peoples
Veronica C
VC
Oropeza
Elisabeth J
EJ
Van Bockstaele
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004334:Drug Administration Schedule; D007150:Immunohistochemistry / Q000379:methods; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D009294:Narcotics / Q000009:adverse effects*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
D017362:Cyclic AMP Response Element-Binding Protein; D009292:Narcotic Antagonists; D009294:Narcotics; D016760:Proto-Oncogene Proteins c-fos; D009271:Naltrexone; D017868:Cyclic AMP-Dependent Protein Kinases