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.