Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia
Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia
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DOI：
10.1016/j.neuroscience.2007.12.038
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发表时间：
2008-04-09
期刊：
影响因子：
3.3
通讯作者：
Chen, J.
中科院分区：
文献类型：
--
作者：
Hao, J.;Liu, M. -G.;Chen, J.
蜂毒肽是蜂毒中的一种主要毒肽，在实验性蜜蜂蜇伤后的局部炎症反应、伤害感受和痛觉过敏中起着重要作用。然而，蜂毒肽诱导的多种疼痛相关行为的确切外周机制仍不太清楚。在本研究中，我们试图研究外周丝裂原活化蛋白激酶（MAPK）在蜂毒肽诱导的伤害性感受和痛觉过敏中的潜在作用，通过给予三种MAPK抑制剂，即U 0126，（1 μ g，10 μ g）用于细胞外信号调节激酶（ERK），SP 600125（10 μ g，100 μ g）和SB 239063（10 μ g，100 μ g）对p38 MAPK的作用。三种药物治疗前和治疗后均能显著抑制蜂毒肽诱发的持续性自发伤害性感受（PSN）和原发性热痛觉过敏的发生和维持，对机械性痛觉过敏的抗伤害性感受作用不大。在媒介物处理组中，同侧注射蜂毒素对另一后爪的热敏感性和机械敏感性没有产生影响，表明在蜂毒素测试中没有发生对侧热和机械痛觉过敏。此外，将每种抑制剂局部施用到对侧后爪中对在原发性损伤后爪中测试的PSN或热/机械痛觉过敏没有产生显著影响，排除了三种药物的全身药理学作用。此外，三种化合物分别在未处理动物中的局部给药没有改变对热或机械刺激的基础疼痛敏感性，表明在生理状态下三种MAPK亚家族成员在正常疼痛敏感性中缺乏外周功能作用。综上所述，我们得出结论，激活外周MAPK，包括ERK，JNK和p38，可能有助于诱导和维持持续进行性疼痛和原发性热痛觉过敏的蜂毒肽测试。然而，它们不太可能参与蜂毒肽诱导的原发性机械性痛觉过敏的处理，这暗示了外周机械性痛觉过敏和热痛觉过敏之间的机械分离。(c)2008由Elsevier Ltd代表IBRO出版。
Recently, we have reported that melittin, a major toxic peptide of the whole bee venom, plays a central role in production of local inflammation, nociception and hyperalgesia following the experimental honeybee's sting. However, the exact peripheral mechanisms underlying melittin-induced multiple pain-related behaviors are still less characterized. In the present study, we sought to investigate the potential roles of peripheral mitogen-activated protein kinases (MAPKs) in melittin-induced nociception and hyperalgesia by pre- and post-administration of three MAPK inhibitors, namely U0126 (1 mu g, 10 mu g) for extracellular signal-regulated kinase (ERK), SP600125 (10 mu g, 100 mu g) for c-Jun N-terminal kinase (JNK) and SB239063 (10 mu g, 100 mu g) for p38 MAPK, into the local inflamed area of one hind paw of rats. Both pre- and post-treatment with three drugs significantly suppressed the occurrence and maintenance of melittin-evoked persistent spontaneous nociception (PSN) and primary heat hyperalgesia, with little antinociceptive effect on mechanical hyperalgesia. In vehicle-treated group, ipsilateral injection of melittin produced no impact on thermal and mechanical sensitivity of the other hind paw, suggesting no occurrence of contralateral heat and mechanical hyperalgesia in the melittin test. In addition, local administration of each inhibitor into the contralateral hind paw exerted no significant influence on either PSN or heat/mechanical hyperalgesia tested in the primary injured hind paw, excluding the systemically pharmacological effects of the three drugs. Furthermore, local administration of the three compounds in naive animals, respectively, did not change the basal pain sensitivity to either thermal or mechanical stimuli, suggesting lack of peripherally functional roles of the three MAPK subfamily members in normal pain sensitivity under the physiological state. Taken together, we conclude that activation of peripheral MAPKs, including ERK, JNK and p38, might contribute to the induction and maintenance of persistent ongoing pain and primary heat hyperalgesia in the melittin test. However, they are not likely to be involved in the processing of melittin-induced primary mechanical hyperalgesia, implicating a mechanistic separation between mechanical and thermal hyperalgesia in the periphery. (c) 2008 Published by Elsevier Ltd on behalf of IBRO.