Chronic naltrexone infusion: effects on innervation of rat neurointermediate lobe

The rat pituitary neurointermediate lobe contains nerve fibers which are sensitive to the neurotoxic effects of 6-hydroxydopamine and to acute injections of the opiate antagonist, naltrexone. In the present study, naltrexone hydrochloride was administered to adult male Sprague-Dawley rats in a chronic infusion over a period of one week, using Alza osmotic pumps to determine whether a low (10(-5)M) dose could, over a longer period, also induce toxic effects on pituitary innervation. Electron microscopy of pituitary intermediate lobe fibers revealed swollen neurovesicles and membranous structures in nerve terminals, and significantly fewer normal-appearing nerve terminals, after drug infusion. Light microscopic immunostaining of paraffin sections of pituitary glands illustrated some diminution of serotonin (5-HT)-immunofluorescence in the intermediate lobe after naltrexone treatment. Immunostaining of sections from the same animals for tyrosine hydroxylase (TH) revealed intensified fiber staining in the intermediate lobe, with some regions of terminals having a swollen appearance. High pressure liquid chromatographic-electrochemical detection (HPLC-EC) analysis of neurotransmitters in selected brain areas and pituitary indicated a significant increase in norepinephrine levels in the hypothalamus. The observations suggest that intermediate lobe innervation is sensitive to low, continuously infused doses of naltrexone, which acts as a neurotoxin to produce degenerative changes in nerve terminals. The changes appear to be reflected in alterations in staining patterns of neurotransmitters, and may also affect transmitter uptake in damaged terminals.