Okuda-Ashitaka Emiko, Minami Toshiaki, Matsumura Shinji, Takeshima Hiroshi, Reinscheid Rainer K, Civelli Olivier, Ito Seiji
Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizono, Moriguchi 570-8506, Japan.
Eur J Neurosci. 2006 Feb;23(4):995-1004. doi: 10.1111/j.1460-9568.2006.04623.x.
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) E(2), PGF(2alpha) 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 PGE(2)-induced allodynia, but not the PGF(2alpha)-induced one. Neither N/OFQ nor PGE(2) 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, PGE(2)-induced allodynia was not observed in ppN/OFQ(-/-) mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE(2) induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.
疼痛常常在其作为伤口愈合的警示和辅助作用消失后仍持续存在，并在组织损伤和神经损伤后变得慢性且难以治疗。许多分子被认为是持续性疼痛（如痛觉过敏和触觉疼痛，即异常性疼痛）的介质和调节因子。我们之前表明，鞘内注射前列腺素（PG）E₂、PGF₂α或神经肽孤啡肽（也称为孤啡肽FQ，N/OFQ）会在清醒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），并在缺乏N/OFQ前体肽（ppN/OFQ⁻/⁻）和NOP受体（NOP⁻/⁻）的小鼠中，研究了PGs与N/OFQ之间的疼痛反应关系。JTC-801剂量依赖性地阻断了N/OFQ和PGE₂诱导的异常性疼痛，但不阻断PGF₂α诱导的异常性疼痛。N/OFQ和PGE₂在NOP⁻/⁻小鼠中均未诱导出异常性疼痛。相比之下，非甾体抗炎药吲哚美辛预处理60分钟抑制PG生成，并不影响N/OFQ诱导的异常性疼痛。在PGE受体（EP）亚型选择性激动剂中，EP4激动剂AE1-329显著刺激脊髓切片中N/OFQ的释放并诱导异常性疼痛。使用荧光一氧化氮检测，AE1-329还增加了脊髓切片中一氧化氮的生成，这被JTC-801预处理所阻断。相反，在ppN/OFQ⁻/⁻小鼠中未观察到PGE₂诱导的异常性疼痛。N/OFQ免疫反应性小点与EP4共定位。综上所述，这些结果表明，PGE₂通过EP4受体亚型刺激脊髓中N/OFQ的释放而诱导异常性疼痛。
