Hypothalamic but not pituitary immunoreactive beta-endorphin (beta-E) was significantly reduced (37%) in mice 24 hr following 30 daily doses of nicotine (1200 micrograms/kg, SC). Hypothalamic beta-E returned towards normal levels within 7 days and was observed to rise 50% above normal 14 days after the cessation of nicotine treatment. None of the other neuropeptides measure, substance P, neurotensin, or [met5]-enkephalin was altered by nicotine treatment. The data suggest that the hypothalamic beta-E containing neurons were unable to adapt to nicotine's repeated effects on this system.