Heroin, like morphine, given intracerebroventricularly produces analgesia by acting on mu opioid receptors in most mice. In contrast, in Swiss Webster mice, heroin has the unusual property of acting on brain delta opioid receptors whereas morphine still acts on mu receptors. The literature indicates that in diabetic mice and rats, the mu agonist potency of morphine is diminished while that to a delta receptor agonist is enhanced. The purpose of the present study was to determine if the response to heroin occurred through a delta receptor in the brain of streptozotocin-induced diabetic Sprague-Dawley rats. One week after a cannula was surgically implanted in the lateral ventricle, diabetes was induced by intravenous administration of 55 mg/kg of streptozotocin. Three days later the receptor selectivity of intraventricular heroin in the tail flick test was determined by coadministration of opioid antagonists. In nondiabetic rats, a rightward shift in the dose response curve for heroin was produced by naloxone. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, a more mu receptor selective antagonist given in a single dose experiment, also inhibited heroin action. Thus, heroin acted on mu receptors. In diabetic rats, intracerebroventricular naltrindole, but not naloxone nor CTOP, inhibited the heroin response and indicated a delta agonist action for heroin. Inhibition by intrathecal yohimbine of the mu (nondiabetic) and bicuculline of the delta response (diabetic) suggested spinal alpha2-adrenergic and GABA(A) receptor mediation, respectively, for the descending systems. In conclusion, the response to heroin was changed from mu in nondiabetic rats to a delta receptor action in diabetic rats. Understanding the basis for this change in receptor selectivity of heroin could provide an important avenue for investigating determinants of opioid receptor function.