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

A multiplicative antinociceptive interaction of morphine activity at supras pinal and spinal sites has been clearly established and is thought to be re sponsible, in part, for the clinical utility of this compound in normal dos e-ranges. While synergistic actions of mu-opioid receptor agonists have bee n shown, it is unclear whether a similar interaction exists for opioid agon ists acting via delta-opioid receptors. Responses to acute nociception were determined with the 52 degrees C hot plate, 52 degrees C warm-water tail-f lick and the Hargreaves paw-withdrawal tests. The peptidic opioid delta(1) agonist [D-Pen(2),D-Pen(5)]enkephalin (DPDPE) or delta(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 delta agonists produced dose-dependent ant inociception in all tests. With the exception of DPDPE in the hot plate tes t, isobolographic analysis revealed that the supraspinal/spinal antinocicep tive interaction for both DPDPE and DELT were synergistic in all nociceptiv e tests. These data suggest that opioid delta agonists exert a multiplicati ve antinociceptive interaction between supraspinal and spinal sites to acut e noxious stimuli and suggest possibility that compounds acting through del ta-opioid receptors may have sufficient potency for eventual clinical appli cation. (C) 1999 Elsevier Science B.V. All rights reserved.