YTHDF1-TRAF6 pathway regulated neuroinflammation response contributed morphine tolerance and hyperalgesia in periaqueductal gray

Abstract

Opioids like morphine have negative side effects such analgesia tolerance and morphine induced hyperalgesia (MIH), which is why their usage is restricted. Raising the dosage of morphine counteracts analgesic tolerance and MIH. Here, we discover that YTHDF1 and TNF receptor-associated factor 6 (TRAF6) expression, which are crucial for morphine analgesic tolerance and MIH. The m6A reader YTHDF1 positively controls the translation of TRAF6 mRNA, and chronic morphine treatments can enhance the m6A modification of TRAF6 mRNA. TRAF6 protein is drastically reduced by YTHDF1 knockdown, although TRAF6 mRNA level is unaffected. By reducing inflammatory markers such TNFα, IL-6, IL-1β and NF-κB, targeted reduction of YTHDF1 or suppression of TRAF6 activity in ventrolateral periaqueductal gray (vlPAG) slows the development of morphine analgesia tolerance and MIH. Our findings provide new insights into the mechanism by which YTHDF1 participates in morphine analgesia tolerance and MIH by regulating the inflammatory response involved in the expression of TRAF6 protein.