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 i
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 i
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δ-阿片受体激动剂 [8R-(4bS*,8aalpha,8abeta, 12bbeta)]7,10-二甲基-1-甲氧基-11-(2-甲基丙基)氧羰基 5,6,7,8 选择性作用的证据
DOI：
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发表时间：
2003
影响因子：
3.5
通讯作者：
M. Scheideler
中科院分区：
文献类型：
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作者：
P. Petrillo;O. Angelici;S. Bingham;Giovanna Ficalora;M. Garnier;P. Zaratin;G. Petrone;O. Pozzi;M. Sbacchi;T. Stean;N. Upton;Guillio M. Dondio;M. Scheideler
通过研究一种选择性、口服型和中枢渗透型的阿片受体激动剂的体内药理活性，探讨了阿片受体在伤害性感受控制中的具体作用。[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盐酸盐(SB-235863)是一种新的吡咯吗啡类药物，对β-阿片受体具有高亲和力(Ki=4.81+/-0.39 nM)，其全部激动剂活性和结合选择性分别是Mu和Kappa-阿片受体的189倍和52倍。口服SB-236863在大鼠甩尾法和热板法急性疼痛反应中无效，但能有效逆转角叉菜胶诱导的炎症反应引起的大鼠热痛敏。此作用可被阿片受体拮抗剂纳曲哚(3 mg/kg，S.C.)所阻断，但选择性阿片受体拮抗剂Mu和kappa-阿片受体拮抗剂无效。纳曲哚(1微克i.c.v)对10 mg/kg(P.O.)SB-235863，表明该化合物激活了中枢神经系统中的阿片受体。口服SB-235863还能逆转部分结扎坐骨神经的Seltzer大鼠模型的慢性痛敏反应。这些数据表明，β-阿片受体在调节伤害性疼痛信号的诱发和持久变化中起着选择性作用。灌胃70 mg/kg后，未观察到Mu和Kappa阿片受体激活的典型副作用(胃肠传输减慢和运动不协调)。SB-235863，诱发的惊厥活动也不受影响。这些结果表明，β-阿片受体在痛觉调制中的作用是选择性的和有限的。
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.