The YTHDF1–TRAF6 pathway regulates the neuroinflammatory response and contributes to morphine tolerance and hyperalgesia in the periaqueductal gray

• DOI: 10.1186/s12974-022-02672-y
• Publication Date: 2022-12-22T14:02:41Z
• Authors: Handong Ouyang; Jianxing Zhang; Dongmei Chi; Kun Zhang; Yongtian Huang; Jingxiu Huang; Wan Huang; Xiaohui Bai
• Keywords: Rats, Sprague-Dawley; 03 medical and health sciences; Animals; Humans; Periaqueductal Gray; RC346-429; TNF Receptor-Associated Factor 6; Inflammation; Analgesics; 0303 health sciences; Morphine-induced hyperalgesia; Morphine; Tumor Necrosis Factor-alpha; Interleukin-6; Research; NF-kappa B; RNA-Binding Proteins; Rats; 3. Good health; Morphine tolerance; YTHDF1; Hyperalgesia; Inflammatory factors; Neurology. Diseases of the nervous system; TRAF6

AbstractLong-term use of opioids such as morphine has negative side effects, such as morphine analgesic tolerance and morphine-induced hyperalgesia (MIH). These side effects limit the clinical use and analgesic efficacy of morphine. Elucidation of the mechanisms and identification of feasible and effective methods or treatment targets to solve this clinical phenomenon are important. Here, we discovered that YTHDF1 and TNF receptor-associated factor 6 (TRAF6) are crucial for morphine analgesic tolerance and MIH. The m6A reader YTHDF1 positively regulated the translation of TRAF6 mRNA, and chronic morphine treatments enhanced the m6A modification of TRAF6 mRNA. TRAF6 protein expression was drastically reduced by YTHDF1 knockdown, although TRAF6 mRNA levels were unaffected. By reducing inflammatory markers such as IL-1β, IL-6, TNF-α and NF-κB, targeted reduction of YTHDF1 or suppression of TRAF6 activity in ventrolateral periaqueductal gray (vlPAG) slows the development of morphine analgesic tolerance and MIH. Our findings provide new insights into the mechanism of morphine analgesic tolerance and MIH indicating that YTHDF1 regulates inflammatory factors such as IL-1β, IL-6, TNF-α and NF-κB by enhancing TRAF6 protein expression.