Morphine and heroin act on supraspinal mu-opioid receptors in ICR mice to activate descending noradrenergic and serotonergic systems to inhibit the tail flick response. Antinociception induced by supraspinal [D-Pen2,5]-enkephalin (DPDPE, delta agonist) involves a descending system mediated by spinal gamma-aminobutyric acid, GABAA and GABAB, receptors. Because in Swiss Webster mice the receptor selectivity of heroin changes to delta whereas morphine remains mu, the purpose of the present study was to determine whether this delta action of heroin was mediated spinally by GABAA and GABAB receptors. Bicuculline (GABAA receptor antagonist) and picrotoxin (chloride ion channel blocker) given intrathecally produced rightward shifts in the dose-response curves of DPDPE and heroin given intracerebroventricularly. Thus, spinal GABAA receptors were involved. Intrathecal administration of 2-hydroxysaclofen (GABAB receptor antagonist) also shifted the dose-response curves to the right. Thus, the antinociception produced by heroin, like DPDPE, by activation of delta receptors in the brain of Swiss Webster mice involved both GABAA and the GABAB receptors in the spinal cord.