Pharmacological characterization of orphanin FQ/nociceptin and its fragments.
Pharmacological characterization of orphanin FQ/nociceptin and its fragments.
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发表时间：
1997-08
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通讯作者：
G. Rossi;L. Leventhal;E. Bolan;G. Pasternak
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作者：
G. Rossi;L. Leventhal;E. Bolan;G. Pasternak
阿片受体家族第四个成员的克隆导致了一种新的神经肽的发现，称为孤啡肽FQ或伤害素(OFQ/N)。在CD-1小鼠身上的研究证实，OFQ/N能够在15分钟内迅速诱导对阿片类拮抗剂不敏感的痛敏。在接下来的30分钟内，痛觉过敏消失，在甩尾试验中出现止痛，这很容易被阿片类拮抗剂逆转。然而，OFQ/N对所有传统阿片受体的亲和力很差，并且OFQ/N的镇痛作用对分别选择性阻断Mu、Delta或kappa1的反义寡核苷酸不敏感，这使得OFQ/N的镇痛作用不太可能是通过典型的阿片受体介导的。氟哌啶醇阻断抗阿片Sigma系统可使OFQ/N的镇痛效力提高100倍以上。这种效应在BALB-C和瑞士韦氏小鼠身上表现明显。虽然OFQ/N单独在这些小鼠中几乎没有止痛活性，但用氟哌啶醇阻断sigma系统在两个品系中都发现了强大的止痛反应。两个较短的OFQ/N片段，OFQ/N(1-7)和OFQ/N(1-11)，在CD-1小鼠体内也是镇痛的，它们的作用可被阿片拮抗剂异丙诺啡逆转，尽管这两个肽对[125I]OFQ/N结合和所有阿片受体的亲和力很差。在反义研究中，针对KOR-3第一个编码外显子的探针可以消除OFQ/N痛觉过敏，但不能消除OFQ/N镇痛。相反，基于第二和第三编码外显子的反义探针对OFQ/N痛觉过敏无效，但容易逆转kappa3阿片类药物的镇痛作用。这些结果表明，OFQ/N通过不同于传统阿片受体的药理上不同的受体而引起镇痛和痛觉过敏。
The cloning of a fourth member of the opioid receptor family has led to the discovery of a new neuropeptide termed orphanin FQ or nociceptin (OFQ/N). Studies in CD-1 mice confirm the ability of OFQ/N to rapidly induce hyperalgesia within 15 min which is insensitive to opioid antagonists. This is followed in the next 30 min by loss of hyperalgesia and the appearance of analgesia in the tailflick assay which is readily reversed by opioid antagonists. However, the very poor affinity of OFQ/N for all the traditional opioid receptors and the insensitivity of OFQ/N analgesia to antisense oligodeoxynucleotides active against MOR-1, DOR-1 or KOR-1 sequences that selectively block mu, delta or kappa1 analgesia, respectively, make it unlikely that OFQ/N analgesia is mediated through typical opioid receptors. Blockade of the antiopioid sigma system by haloperidol enhances the analgesic potency of OFQ/N of more than 100-fold. This effect is pronounced in BALB-C and Swiss-Webster mice. Although OFQ/N alone has little analgesic activity in these mice, the blockade of sigma systems with haloperidol uncovers a robust analgesic response in both strains. Two shorter OFQ/N fragments, OFQ/N(1-7) and OFQ/N(1-11), also are analgesic in CD-1 mice and their actions are reversed by the opioid antagonist diprenorphine despite very poor affinities of both peptides against [125I]OFQ/N binding and all the opioid receptors. In antisense studies, a probe targeting the first coding exon of KOR-3 eliminates OFQ/N hyperalgesia, but not OFQ/N analgesia. Conversely, antisense probes based on the second and third coding exons are inactive against OFQ/N hyperalgesia but readily reverse kappa3 opioid analgesia. These results suggest that OFQ/N elicits both analgesia and hyperalgesia through pharmacologically distinct receptors that do not correspond to traditional opioid receptors.