Enkephalin antinociception in mice is mediated by delta 1- and delta 2-opioid receptors in the brain and spinal cord, respectively.

Pharmacological evidence for the existence of delta-opioid receptor subtypes has been reported. This study was conducted to determine which type of delta-opioid receptors was involved supraspinally and spinally when antinociception was induced by the natural enkephalins, [Leu5]enkephalin and [Met5]enkephalin. In the mouse tail flick assay, the antinociceptive ED50 values of both intracerebroventricularly (i.c.v.) administered [Leu5]enkephalin and [Met5]enkephalin (together with the peptidase inhibitors, bestatin and thiorphan) were significantly increased by 7-benzylidenenaltrexone (BNTX), a selective delta 1-opioid receptor antagonist but not by naltriben, a selective delta 2-opioid receptor antagonist. On the other hand, when the enkephalins were administered intrathecally (i.t.), the antinociceptive ED50 values of both enkephalins were significantly raised by naltriben but not by BNTX. beta-Endorphin-induced (i.c.v.) antinociception was antagonized by naltriben administered i.t. or s.c. but not by BNTX administered i.t. or s.c. Different delta-opioid receptor subtypes appeared to be involved in supraspinal (delta 1) and spinal (delta 2) antinociception induced by endogenous delta-opioid receptor agonists, [Leu5] and [Met5]enkephalin. The antinociception produced by i.c.v. administered beta-endorphin has been attributed to the release of [Met5]enkephalin in the spinal cord and its antagonism by naltriben support the finding that enkephalins interact with delta 2-opioid receptors in the spinal cord to mediate antinociception. beta-Endorphin may be interacting at receptors other than delta 1- or delta 2-opioid receptors in the brain, perhaps the putative epsilon receptors, to mediate their effects because neither i.c.v. administered BNTX nor naltriben inhibited its activity.