PT - JOURNAL ARTICLE AU - Paola Petrillo AU - Ornella Angelici AU - Sharon Bingham AU - Giovanna Ficalora AU - Martine Garnier AU - Paola F. Zaratin AU - Giuseppe Petrone AU - Ottorino Pozzi AU - Massimo Sbacchi AU - Tania O. Stean AU - Neil Upton AU - Guillio M. Dondio AU - Mark A. Scheideler TI - Evidence for a Selective Role of the δ-Opioid Agonist [8<em>R</em>-(4b<em>S</em>*,8aα,8aβ,12bβ)]7,10-Dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9<em>H</em>)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline Hydrochloride (SB-235863) in Blocking Hyperalgesia Associated with Inflammatory and Neuropathic Pain Responses AID - 10.1124/jpet.103.055590 DP - 2003 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1079--1089 VI - 307 IP - 3 4099 - http://jpet.aspetjournals.org/content/307/3/1079.short 4100 - http://jpet.aspetjournals.org/content/307/3/1079.full SO - J Pharmacol Exp Ther2003 Dec 01; 307 AB - The specific involvement of the δ-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant δ-opioid agonist. [8R-(4bS*,8aα,8aβ,12bβ)]7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) is a new pyrrolomorphinan with high affinity (Ki = 4.81 ± 0.39 nM) for the δ-opioid receptor, full agonist activity, and binding selectivity versus the μ- and κ-opioid receptors of 189-fold and 52-fold, respectively. Perorally administered SB-236863 was inactive in the rat tail-flick and hot-plate tests of acute pain response, but potently reversed thermal hyperalgesia in rats resulting from a carrageenan-induced inflammatory response. This activity could be blocked by the δ-opioid antagonist naltrindole (3 mg/kg s.c.), but selective μ- and κ-opioid antagonists were ineffective. Naltrindole (1 μg i.c.v.) also blocked the activity of 10 mg/kg (p.o.) SB-235863, showing that the compound activates δ-opioid receptor sites in the central nervous system. SB-235863 was additionally effective at reversing chronic hyperalgesia in the Seltzer rat model of partial sciatic nerve ligation after peroral administration. These data show that the δ-opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects of μ- and κ-opioid receptor activation (slowing of gastrointestinal transit and motor incoordination, respectively) were not observed after administration of 70 mg/kg (p.o.) SB-235863, nor was evoked seizure activity affected. These results suggest a selective and limited role of δ-opioid receptors in the modulation of nociception. The American Society for Pharmacology and Experimental Therapeutics