5-hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice.
5-hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice.
复制标题
5-羟色胺3型受体调节阿片类药物诱导的小鼠痛觉减退和耐受。
DOI：
10.1097/aln.0b013e31820efb19
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发表时间：
2011-05
期刊：
影响因子：
8.8
通讯作者：
Clark JD
中科院分区：
文献类型：
--
作者：
Liang DY;Li X;Clark JD
阿片类药物引起的痛觉过敏（OIH）和耐受性正在挑战与阿片类药物管理疼痛相关的适应不良。最近的遗传学研究和现有文献表明，5-羟色胺3型（5-HT3）受体参与了这些现象。然而，相关受体群体的位置以及5-HT3系统与控制OIH和耐受性的其他系统之间的相互作用尚未被探索。我们假设5-HT3受体调节OIH和耐受性，并且这种调节涉及多个神经递质和受体系统的表达控制。C57BL/6小鼠给予标准化的4天吗啡给药方案。5-HT3拮抗剂昂丹司琼在吗啡给药期间或结束后给药。机械测试用于量化OIH，热甩尾反应用于测量吗啡耐受性。在其他实验中，采集脊髓和背根神经节组织，通过实时聚合酶链反应或免疫化学分析信使RNA水平。结果表明：1)全身或鞘内注射昂丹司琼可显著预防和逆转OIH，但足底局部注射对OIH无显著作用。2)全身或鞘内注射昂丹司琼可预防和逆转吗啡耐受，3)昂丹司琼可阻断吗啡诱导的背根神经节和脊髓与OIH和耐受相关的多个基因的增加。吗啡通过5-HT3依赖机制支持对吗啡慢性给药的多重适应不良。此外，使用5-HT3受体拮抗剂可能为预防或逆转OIH和与慢性阿片类药物使用相关的耐受性提供新的途径。
Opioid-induced hyperalgesia (OIH) and tolerance are challenging maladaptations associated with opioids in managing pain. Recent genetic studies and the existing literature suggest the 5-hydroxy tryptamine type 3 (5-HT3) receptor participates in these phenomena. The location of the relevant receptor populations and the interactions between the 5-HT3 system and other systems controlling OIH and tolerance have not been explored, however. We hypothesized that 5-HT3 receptors modulate OIH and tolerance, and that this modulation involves the control of expression of multiple neurotransmitter and receptor systems. C57BL/6 mice were exposed to a standardized 4-day morphine administration protocol. The 5-HT3 antagonist ondansetron was administered either during or after the conclusion of morphine administration. Mechanical testing was used to quantify OIH, and thermal tail flick responses were used to measure morphine tolerance. In other experiments spinal cord and dorsal root ganglion tissues were harvested for analysis of messenger RNA levels by real-time polymerase chain reaction or immunochemistry analysis. The results showed 1) Systemic or intrathecal injection of ondansetron significantly prevented and reversed OIH, but not local intraplantar injection. 2) Systemic or intrathecal injection of ondansetron prevented and reversed tolerance, and 3) Ondansetron blocked morphine induced increases of multiple genes -relevant to OIH and tolerance in dorsal root ganglion and spinal cord. Morphine acts via a 5-HT3 dependent mechanism to support multiple maladaptations to the chronic administration of morphine. Furthermore, the use of 5-HT3 receptor antagonists may provide a new avenue to prevent or reverse OIH and tolerance associated with chronic opioid use.