Selective opioid δ agonists elicit antinociceptive supraspinal/spinal synergy in the rat

A multiplicative antinociceptive interaction of morphine activity at supraspinal and spinal sites has been clearly established and is thought to be responsible, in part, for the clinical utility of this compound in normal dose-ranges. While synergistic actions of μ-opioid receptor agonists have been shown, it is unclear whether a similar interaction exists for opioid agonists acting via δ-opioid receptors. Responses to acute nociception were determined with the 52°C hot plate, 52°C warm-water tail-flick and the Hargreaves paw-withdrawal tests. The peptidic opioid δ 1 agonist [ d-Pen 2, d-Pen 5]enkephalin (DPDPE) or δ 2 agonist [ d-Ala 2,Glu 4]deltorphin (DELT) were given into the rostral–ventral medulla (RVM), intrathecally (i.th.) or simultaneously into both the RVM and i.th. (1:1 fixed ratio). Both of the opioid δ agonists produced dose-dependent antinociception in all tests. With the exception of DPDPE in the hot plate test, isobolographic analysis revealed that the supraspinal/spinal antinociceptive interaction for both DPDPE and DELT were synergistic in all nociceptive tests. These data suggest that opioid δ agonists exert a multiplicative antinociceptive interaction between supraspinal and spinal sites to acute noxious stimuli and suggest possibility that compounds acting through δ-opioid receptors may have sufficient potency for eventual clinical application.