The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2‐induced allodynia, tactile pain associated with nerve injury
The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2‐induced allodynia, tactile pain associated with nerve injury
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DOI：
10.1111/j.1460-9568.2006.04623.x
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发表时间：
2006-02
影响因子：
3.4
通讯作者：
E. Okuda‐Ashitaka;T. Minami;S. Matsumura;H. Takeshima;R. Reinscheid;O. Civelli;S. Ito
中科院分区：
文献类型：
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作者：
E. Okuda‐Ashitaka;T. Minami;S. Matsumura;H. Takeshima;R. Reinscheid;O. Civelli;S. Ito
疼痛通常超过其作为警告和帮助伤口愈合的有用性，并且在组织损伤和神经损伤后变得慢性和顽固。许多分子被认为是持续性疼痛的介质和调节剂，如痛觉过敏和触觉疼痛（异常性疼痛）。我们以前的研究表明，鞘内（i.t.）注射前列腺素（PG）E2、PGF 2 α或神经肽痛敏素（Nociceptin，也称为N/OFQ），在清醒的小鼠中产生异常性疼痛。在本研究中，我们使用N/OFQ受体（NOP）拮抗剂N-（4-氨基-2-甲基喹啉-6-基）-2-（4-乙基苯氧基-甲基）苯甲酰胺单盐酸盐（JTC-801），以及缺乏N/OFQ前原肽（ppN/OFQ-/-）和NOP受体（NOP-/-）的小鼠，研究了PG和N/OFQ之间疼痛反应的关系。JTC-801剂量依赖性地阻断N/OFQ和PGE 2诱导的异常性疼痛，但不阻断PGF 2 α诱导的异常性疼痛。在NOP-/-小鼠中，N/OFQ和PGE 2均未诱导异常性疼痛。相比之下，N/OFQ诱导的异常性疼痛不受非甾体抗炎药吲哚美辛预处理60分钟抑制PG产生的影响。在PGE受体（EP）亚型选择性激动剂中，EP 4激动剂AE 1 - 329显著刺激脊髓切片中N/OFQ的释放并诱导异常性疼痛。AE 1 - 329还增加了荧光一氧化氮检测脊髓切片中的一氧化氮产生，这被JTC-801预处理阻断。相反，在ppN/OFQ-/-小鼠中未观察到PGE 2诱导的异常性疼痛。N/OFQ免疫反应点与EP 4共定位。总之，这些结果表明，PGE 2诱导异常性疼痛的刺激N/OFQ释放在脊髓中通过EP 4受体亚型。
Pain often outlasts its usefulness as warning and aid in wound healing, and becomes chronic and intractable after tissue damage and nerve injury. Many molecules have been implicated as mediators and modulators in persistent pain such as hyperalgesia and tactile pain (allodynia). We previously showed that prostaglandin (PG) E2, PGF2α or the neuropeptide nociceptin, also called orphanin FQ (N/OFQ) administered intrathecally (i.t.) produced allodynia in conscious mice. In the present study, we examined the relationship of pain responses between PGs and N/OFQ using the N/OFQ receptor (NOP) antagonist, N‐(4‐amino‐2‐methylquinolin‐6‐yl)‐2‐(4‐ethylphenoxy‐methyl)benzamide monohydrochloride (JTC‐801), and in mice lacking the N/OFQ prepropeptide (ppN/OFQ–/–) and the NOP receptor (NOP–/–). JTC‐801 dose‐dependently blocked the N/OFQ‐ and PGE2‐induced allodynia, but not the PGF2α‐induced one. Neither N/OFQ nor PGE2 induced allodynia in NOP–/– mice. By contrast, the N/OFQ‐induced allodynia was not affected by inhibition of PG production by a 60‐min pretreatment with the non‐steroidal anti‐inflammatory drug, indomethacin. Among PGE receptor (EP) subtype‐selective agonists, the EP4 agonist, AE1‐329, markedly stimulated the release of N/OFQ from spinal slices and induced allodynia. AE1‐329 also increased nitric oxide production in spinal slices using fluorescent nitric oxide detection, which was blocked by pretreatment with JTC‐801. Conversely, PGE2‐induced allodynia was not observed in ppN/OFQ–/– mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE2 induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.