Evidence for a selective role of the delta-opioid agonist [8R-(4bS*,8aalpha,8abeta, 12bbeta)]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.
The specific involvement of the delta-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant delta-opioid agonist. [8R-(4bS*,8aalpha,8abeta,12bbeta)]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 delta-opioid receptor, full agonist activity, and binding selectivity versus the mu- and kappa-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 delta-opioid antagonist naltrindole (3 mg/kg s.c.), but selective mu- and kappa-opioid antagonists were ineffective. Naltrindole (1 microg i.c.v.) also blocked the activity of 10 mg/kg (p.o.) SB-235863, showing that the compound activates delta-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 delta-opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects of mu- and kappa-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 delta-opioid receptors in the modulation of nociception.
Petrillo
Paola
P
Department of Neurobiology Research, GlaxoSmithKline Chemicals, Milano, Italy.
Angelici
Ornella
O
Bingham
Sharon
S
Ficalora
Giovanna
G
Garnier
Martine
M
Zaratin
Paola F
PF
Petrone
Giuseppe
G
Pozzi
Ottorino
O
Sbacchi
Massimo
M
Stean
Tania O
TO
Upton
Neil
N
Dondio
Guillio M
GM
Scheideler
Mark A
MA
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002351:Carrageenan; D002478:Cells, Cultured; D003292:Convulsants; D000242:Cyclic AMP / Q000378:metabolism; D004597:Electroshock; D004798:Enzymes / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006930:Hyperalgesia / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D007276:Injections, Intraventricular; D008156:Luciferases / Q000235:genetics; D008297:Male; D009022:Morphine Derivatives / Q000378:metabolism / Q000627:therapeutic use*; D009294:Narcotics / Q000378:metabolism / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000150:complications / Q000473:pathology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D014162:Transfection
D003292:Convulsants; D004798:Enzymes; D009022:Morphine Derivatives; D009294:Narcotics; D017465:Receptors, Opioid, delta; C445160:SB 235863A; D002351:Carrageenan; D000242:Cyclic AMP; D008156:Luciferases; D010433:Pentylenetetrazole