Characterization of supraspinal antinociceptive actions of opiod delta agonists in the rat

Supraspinally mediated antinociception has been clearly established for agonists acting via both μ- and δ-opioid receptors. The present experiments were undertaken to further characterize the role of supraspinal opioid δ receptors in the mediation of antinociception in rats and to examine the possible role of putative δ₁- and δ₂-opioid receptors in the antinociceptive effect. Cannulae directed at the right lateral ventricle, the periaqueductal gray (PAG), or the medullary reticular formation (MRF) were implanted in adult male, Sprague-Dawley rats for the microinjection of [d-Ala², Glu⁴]deltorphin (δ₂ agonist), [d-Pen²,d-Pen⁵]enkephalin (DPDPE, δ₁ agonist), [d-Ser²,Leu⁵,Thr⁶]enkephalin (DSLET, mixed δ μ agonist) or morphine (reference μ-opioid). Pretreatments (24 h prior to agonist microinjection) were made with the putative δ₁ and δ₂ antagonists, [d-Ala²,Leu⁵,Cys⁶]enkephalin (DALCE) and [d-Ala²,Cys⁴]deltorphin (Cys-DELT) and antinociception was measured in the 55°C hot plate (HP) and 52°C and 55°C (low and high intensity) warm-water tail-flick (TF) tests. Data were converted to percent maximal possible effect (%MPE). Intracerebroventricular (i.c.v.) administration of DPDPE produced less than a 50% MPE in the HP test whereas [d-Ala²,Glu⁴]deltorphin produced Cys-DELT sensitive antinociception of up to 92% MPE. Neither i.c.v. agonist was effective in the TF assays, and both agonists were without effect in the PAG. [d-Ala²,Glu⁴]deltorphin microinjected into the MRF produced Cys-DELT sensitive antinociception of 60 and 47% MPE in the HP and low-intensity TF tests, respectively, but was not effective in the 55°C TF test; DPDPE did not produce antinociception when microinjected at this site. Microinjection of DSLET in the MRF produced significant antinociception in all three assays. Morphine produced antinociception following i.c.v. administration or microinjection into the PAG in all tests. Microinjection of morphine into the MRF produced antinociception in the HP and 52°C, but not 55°C, TF tests. Morphine antinociception was not antagonized by either DALCE or Cys-DELT. These data demonstrate that supraspinal δ-opioid receptors can be activated to elicit antinociception in the rat and that opioid δ₂ receptors predominate in this effect. Further, these effects may occur predominately via ibhibition of supraspinally organized behavior without activation of descending systems such as those mediating the TF response in the rat.