Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase

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• 作者：David J. Marcus ; Michael Zee ; Alex Hughes ; Matthew B. Yuill…
• 关键词：Morphine ; Fentanyl ; JNK ; GPCR ; GRK ; Cisplatin ; Desensitization ; Tolerance ; Mu opioid receptor ; Chemotherapy
• 刊名：Molecular Pain
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：11
• 期：1
• 全文大小：1,873 KB
• 刊物主题：Pain Medicine; Molecular Medicine;
• 出版者：BioMed Central
• ISSN：1744-8069

文摘

Background Morphine and fentanyl are opioid analgesics in wide clinical use that act through the μ-opioid receptor (MOR). However, one limitation of their long-term effectiveness is the development of tolerance. Receptor desensitization has been proposed as a putative mechanism driving tolerance to G protein-coupled receptor (GPCR) agonists. Recent studies have found that tolerance to morphine is mediated by the c-Jun N-terminal Kinase (JNK) signaling pathway. The goal of the present study was to test the hypotheses that: 1) JNK inhibition will be antinociceptive on its own; 2) JNK inhibition will augment morphine antinociception and; 3) JNK mediates chronic tolerance for the antinociceptive effects of morphine using acute (hotplate and tail-flick), inflammatory (10 μl of formalin 2.5 %) and chemotherapy (cisplatin 5 mg/kg ip once weekly)-induced neuropathic pain assays.