Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal

Abstract 

Rationale: Nitric oxide (NO) has been postulated to contribute significantly to analgesic effects of opiates as well as to the development of tolerance and physical dependence to morphine. Objective: The present study was undertaken to determine the effect of chronic morphine treatment and abstinence on the expression of neuronal NO synthase (neuronal NOS, nNOS) in several brain regions of mice. Methods: Seven days after the implantation of a 75 mg morphine pellet, adult male CD1 mice received a SC dose of 1 mg/kg naloxone. Fifteen minutes after the naloxone injection, brains were removed and nNOS expression was studied by using immunohistochemical methods. Results: Morphine-dependence produced an increase in the number of nNOS-positive cells in the main and accessory olfactory bulb, olfactory nuclei, cerebellum, locus coeruleus, medulla oblongata (nucleus of the solitary tract and prepositus hypoglossal nucleus), and a decrease in nNOS immunoreactivity in hypothalamus. The administration of naloxone to morphine-dependent mice to induce abstinence increased nNOS immunoreactivity in the hypothalamus and locus coeruleus. Conclusions: These results indicate that the chronic treatment with morphine leads to alterations in nNOS expression in important regions implicated in the physical tolerance and dependence to opiates and suggest the use of specific inhibitors of this isoform in these conditions.