title: Selective opioid delta agonists elicit antinociceptive supraspinal/spinal synergy in the rat.
abstract: 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 mu-opioid receptor agonists have been shown, it is unclear whether a similar interaction exists for opioid agonists acting via delta-opioid receptors. Responses to acute nociception were determined with the 52 degrees C hot plate, 52 degrees C warm-water tail-flick 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 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 delta agonists exert a multiplicative antinociceptive interaction between supraspinal and spinal sites to acute noxious stimuli and suggest possibility that compounds acting through delta-opioid receptors may have sufficient potency for eventual clinical application.
authors.affiliation: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kovelowski
authors.forename: D
authors.initials: D
authors.lastname: Bian
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: J
authors.initials: J
authors.lastname: Lai
authors.forename: M H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: F
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000008:administration & dosage / Q000494:pharmacology*; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D008845:Microinjections; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
chemical_list: D000700:Analgesics; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; C060209:deltorphin II, Ala(2)-; D020881:Enkephalin, D-Penicillamine (2,5)-