Characterization of supraspinal antinociceptive actions of opioid delta agonists in the rat.
Supraspinally mediated antinociception has been clearly established for agonists acting via both micro- and delta-opioid receptors. The present experiments were undertaken to further characterize the role of supraspinal opioid delta receptors in the mediation of antinociception in rats and to examine the possible role of putative delta1- and delta2-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 (delta2 agonist), [D-Pen2,D-Pen5]enkephalin (DPDPE, delta1 agonist), [D-Ser2,Leu5,Thr6]enkephalin (DSLET, mixed delta/micro agonist) or morphine (reference micro-opioid). Pretreatments (24 h prior to agonist microinjection) were made with the putative delta1 and delta2 antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) and [D-Ala2,Cys4]deltorphin (Cys-DELT) and antinociception was measured in the 55 degrees C hot plate (HP) and 52 degrees C and 55 degrees 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 degrees 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 degrees C, but not 55 degrees C, TF tests. Morphine anticociception was not antagonized by either DALCE or Cys-DELT. These data demonstrate that supraspinal delta-opioid receptors can be activated to elicit antinociception in the rat and that opioid delta2 receptors predominate in this effect. Further, these effects may occur predominately via inhibition of supraspinally organized behavior without activation of descending systems such as those mediating the TF response in the rat.
Ossipov
Michael H
MH
Departments of Pharmacology and Chemistry, University of Arizona Health Sciences Center, Tucson, AZ 85724 USA.
Kovelowski
Carl J
CJ
Nichols
Michael L
ML
Hruby
Victor J
VJ
Porreca
Frank
F
D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects*; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D006358:Hot Temperature; D007276:Injections, Intraventricular; D008297:Male; D008526:Medulla Oblongata; D009020:Morphine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D012154:Reticular Formation / Q000187:drug effects*
D004745:Enkephalins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; C082680:deltorphin, Ala(2)-Cys(4)-; C053821:enkephalin-Leu, Ala(2)-Cys(6)-; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-