Activation of TRPV1 contributes to morphine tolerance: Involvement of the mitogen-activated protein kinase signaling pathway
Activation of TRPV1 contributes to morphine tolerance: Involvement of the mitogen-activated protein kinase signaling pathway
复制标题
DOI：
10.1523/jneurosci.4170-07.2008
复制
发表时间：
2008-05-28
影响因子：
5.3
通讯作者：
Sommer, Claudia
中科院分区：
文献类型：
--
作者：
Chen, Yong;Geis, Christian;Sommer, Claudia
对阿片类药物镇痛作用的耐受性发生在慢性给药后，这是一种与异常疼痛敏感性（如痛觉过敏）的发展相关的药理学现象。在本研究中，我们研究了TRPV1在吗啡耐受性和耐受性相关的热痛觉过敏中的作用，TRPV1是有害化学和热刺激转导的关键。慢性吗啡治疗后，大鼠L4背根神经节（DRG）神经元、脊髓背角和坐骨神经中TRPV1免疫反应性（IR）明显升高。实时反转录（RT -PCR）结果显示，TRPV1 mRNA在脊髓和坐骨神经中表达上调，而在DRG中表达上调。选择性TRPV1拮抗剂SB366791 [N-（3-甲氧基苯基）- 4-氯氰胺]鞘内预处理可减轻吗啡耐受性和相关的热痛觉过敏。慢性吗啡暴露诱导L4 DRG神经元中丝裂原活化蛋白激酶（MAPKs）磷酸化增加，包括p38 MAPK-IR、细胞外信号调节蛋白激酶(ERK)-IR和c-Jun n-末端激酶(JNK)-IR。鞘内给予选择性p38、ERK或JNK抑制剂不仅降低吗啡耐受性和相关的热痛觉过敏，还抑制吗啡诱导的DRG神经元、脊髓和坐骨神经中TRPV1-IR的升高以及脊髓和坐骨神经中mRNA水平的升高。总之，我们已经确定了一种新机制，通过持续的吗啡治疗，通过以mapk依赖的方式调节TRPV1的表达，导致耐受性和耐受性相关的热痛觉过敏。因此，阻断TRPV1可能是降低吗啡耐受性的一种方法。
Tolerance to the analgesic effects of opioids occurs after their chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we investigated the role of TRPV1, which is crucial for the transduction of noxious chemical and thermal stimuli, in morphine tolerance and tolerance-associated thermal hyperalgesia. After chronic morphine treatment, a marked increase in TRPV1 immunoreactivity (IR) was detected in L4 dorsal root ganglion (DRG) neurons, spinal cord dorsal horn, and sciatic nerve. Real-time reverse transcription (RT)-PCR demonstrated that TRPV1 mRNA was upregulated in spinal cord and sciatic nerve but not in the DRG. Intrathecal pretreatment with SB366791 [ N-(3-methoxyphenyl)- 4-chlorocinnamide], a selective antagonist of TRPV1, attenuated both morphine tolerance and associated thermal hyperalgesia. Chronic morphine exposure induced increases in phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPK-IR, extracellular signal-regulated protein kinase (ERK)-IR, and c-Jun N-terminal kinase (JNK)-IR, in L4 DRG neurons. Intrathecal administration of the selective p38, ERK, or JNK inhibitors not only reduced morphine tolerance and associated thermal hyperalgesia but also suppressed the morphine-induced increase of TRPV1-IR in DRG neurons, spinal cord, and sciatic nerve and of mRNA levels in spinal cord and sciatic nerve. Together, we have identified a novel mechanism by which sustained morphine treatment results in tolerance and tolerance-associated thermal hyperalgesia, by regulating TRPV1 expression, in a MAPK-dependent manner. Thus, blocking TRPV1 might be a way to reduce morphine tolerance.