Enkephalin antinociception in mice is mediated by δ₁- and δ₂-opioid receptors in the brain and spinal cord, respectively

Pharmacological evidence for the existence of δ-opioid receptor subtypes has been reported. This study was conducted to determine which type of δ-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 δ₁-opioid receptor antagonist but not by naltriben, a selective δ₂-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. β-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 δ-opioid receptor subtypes appeared to be involved in supraspinal (δ₁) and spinal (δ₂) antinociception induced by endogenous δ-opioid receptor agonists, [Leu⁵] and [Met⁵]enkephalin. The antinociception produced by i.c.v. administered β-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 δ₂-opioid receptors in the spinal cord to mediate antinociception. β-Endorphin may be interacting at receptors other than δ₁-or δ₂-opioid receptors in the brain, perhaps the putative ε receptors, to mediate their effects because neither i.c.v. administered BNTX nor naltriben inhibited its activity.