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NEUROPHARMACOLOGY

Evidence for a Selective Role of the -Opioid Agonist [8R-(4bS*,8a,8a,12b)]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) in Blocking Hyperalgesia Associated with Inflammatory and Neuropathic Pain Responses

Departments of Neurobiology Research (P.P., O.A., G.F., M.G., P.F.Z., G.P., O.P., M.S., M.A.S.) and Medicinal Chemistry (G.M.D.), GlaxoSmithKline Pharmaceuticals, Milano, Italy; and Neurobehavioral Research, Neurology Centre of Excellence for Drug Discovery, Essex, United Kingdom (S.B., T.O.S., N.U.)

The specific involvement of the -opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant -opioid agonist. [8R-(4bS*,8a,8a,12b)]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 (K_i = 4.81 ± 0.39 nM) for the -opioid receptor, full agonist activity, and binding selectivity versus the µ- and -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 -opioid antagonist naltrindole (3 mg/kg s.c.), but selective µ- and -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 -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 -opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects of µ- and -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 -opioid receptors in the modulation of nociception.

Address correspondence to: Dr. Mark A. Scheideler, Box 16, 10325 Kensington Pkwy., Kensington, MD 20895. E-mail: mark.scheideler{at}att.net

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