The Mechanism of Allodynia and the Role of Opioids as Regulating Factors

异常性疼痛的机制和阿片类药物作为调节因素的作用

• 批准号: 11671843
• 负责人: IMAI Yasuo
• 金额: $ 2.18万
• 依托单位: University of Tokushima (2000)Hiroshima University (1999)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671843/
• 关键词: allodynia; prostaglandin; ATP receptor; α, β-methylene ATP; suramin; morphine; nociceptin; NMDA; α,β-methyleneATP; 痛覚過敏; マウス; オピオイド; P2プリン受容体

Prolonged tissue damage or injury often leads to a chronic state in which innocuous tactile stimuli evoked pain ; allodynia. However the underlying mechanisms for development of allodynia are not elucidated and the effective treatment for pain including drug therapy are yet established. Recently, intrathecal administration of a number of agonists and antagonists of neurotransmitter receptors have been shown to induce allodynia in mice and rats. The present study was performed to investigate the mechanism of allodynia by intrathecal administration of various drugs including antagonists and agonists of purinocetors or opioid and its related compounds in mice and found that ATP and its receptor are involved in the development of allodynia.Suramin (5, 10μg) and pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid (PPADS), antagonists of P2X receptor, inhibited prostaglandin (PG) E_2-induced allodynia. PPADS did not block glutamate-induced allodynia. α, β-Methylene ATP, an agonist of P2X receptor, elicited allodynia. α, β-Methylene ATP-induced allodynia was blocked by co-administration of PPADS, Mk 801 an antagonist of NMDA receptor or N^ω-nitro-L-arginin methyl ester (L-NAME), an inhibitor of nitric monoxide synthetase. Suramin at higher doses (20〜40μg) induced allodynia and hyperalgesia, which was inhibited by MK 801 and L-NAME.Nociceptin 1〜500 pg with maximal effect at 50 pg produced allodynia. Nociceptin-induced allodynia was inhibited by 10 ng of morphine and the inhibitory effect of morphine was reversed by naloxon. Nociceptin-induced allodynia was not blocked by PPADS.These results suggest that ATP P2X receptors in the spinal cord are involved in the regulation of tactile allodynia. Glutamate receptor and nitric oxide systems play an important role in the development of allodynia produced by α, β-methylene ATP and suramin. ATP may mediate PGE_2 - but not nociceptin-induced allodynia.

长期的组织损伤或损伤通常导致慢性状态，其中无害的触觉刺激诱发疼痛;异常性疼痛。然而，异常性疼痛发生的潜在机制尚未阐明，包括药物治疗在内的有效疼痛治疗方法尚未建立。最近，鞘内给药的神经递质受体的激动剂和拮抗剂的数量已被证明诱导异常性疼痛的小鼠和大鼠。本研究通过鞘内注射嘌呤受体拮抗剂和激动剂、阿片类药物及其相关化合物等多种药物，探讨了小鼠痛觉超敏的发生机制，发现ATP及其受体参与痛觉超敏的发生，P2 X受体拮抗剂苏拉明（5，10μg）和磷酸吡哆醛-6-偶氮苯基-2 ′，4 ′-二磺酸（PPADS），抑制前列腺素E_2诱发的痛觉超敏反应。PPADS不阻断谷氨酸诱导的异常性疼痛。P2 X受体激动剂α，β-亚甲基ATP诱发痛觉超敏。PPADS、NMDA受体拮抗剂MK 801和一氧化氮合成酶抑制剂L-硝基-L-精氨酸甲酯（L-NAME）可阻断α，β-亚甲基ATP诱发的痛觉超敏反应。高剂量苏拉明（20 ~ 40μg）可引起触诱发痛和痛觉过敏，MK 801和L-NAME可抑制该作用，孤啡肽1 ~ 500 μ g可引起触诱发痛，50 μ g时作用最大。10 ng吗啡可抑制痛敏反应，纳洛酮可逆转吗啡的抑制作用。PPADS不能阻断痛敏反应，提示脊髓内ATP P2 X受体参与了触觉异常性疼痛的调节。谷氨酸受体和一氧化氮系统在α，β-亚甲基ATP和苏拉明引起的痛觉超敏中起重要作用。ATP可能介导PGE_2诱发的痛觉超敏反应，但不介导孤啡肽诱发的痛觉超敏反应。

项目成果

Nobuyoshi Fukuhara: "Regulation of the development of allodynia by intrathecally administered P2 purinoceptor agonists and antagonists in mice"Neuroscience Letters. 292. 25-28 (2000)

Nobuyoshi Fukuhara：“通过鞘内注射 P2 嘌呤受体激动剂和拮抗剂调节小鼠异常性疼痛的发生”《神经科学快报》。

Nobuyoshi Fukuhara: "Regulation of the development of allodynia by intrathecally administered P2 purinoceptor agonists and antagonists in mice"Neuroscience Letters. 292・1. 25-28 (2000)

Nobuyoshi Fukuhara：“鞘内注射 P2 嘌呤受体激动剂和拮抗剂对小鼠异常性疼痛的调节”《神经科学快报》292·1（2000 年）。

Nobuyoshi Fukuhara, Yasuo Imai et al: "Regulation of the development of allodynia by intrathecally administered P2 purinoceptor agonists and antagonists in mice"Neuroscience Letters. 292. 25-28 (2000)

Nobuyoshi Fukuhara、Yasuo Imai 等人：“通过鞘内给予小鼠 P2 嘌呤受体激动剂和拮抗剂调节异常性疼痛的发生”《神经科学快报》。