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

Abstract

Long-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.

Tsc22d3 promotes morphine tolerance in mice through the GPX4 ferroptosis pathway

“…The pharmacological effects of morphine are related to the interaction between neurons and immune cells, and this interaction may result in the occurrence of inflammation. Chronic inflammation may be associated with the development of morphine tolerance, causing a gradual reduction in the patient’s response to morphine [ 26 ].…”

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

“…Its widespread utilization in pain management for conditions such as cancer is attributed to its rapid onset and prompt relief ( Badshah et al, 2023 ). However, the chronic administration of morphine inevitably leads to various undesirable effects such as morphine tolerance (MT) and dependence, respiratory depression, nausea, vomiting, and sedation, which pose challenges to its clinical application ( Ouyang et al, 2022 ). The development of morphine tolerance is a complex and multifaceted process, encompassing various factors such as the desensitization and internalization of opioid receptors ( Narita et al, 2006 ), the formation of heterodimers between G protein-coupled receptors ( Szentirmay et al, 2013 ), activation of glial cells, modifications in glutamate receptor function ( Wang et al, 2021 ), stimulation of the cyclic adenosine monophosphate (cAMP) pathway ( Coffey et al, 2022 ) and mitogen-activated protein kinase (MAPK) pathway ( Fu and Zhang, 2023 ), among others.…”

No significant change of N6‐methyladenosine modification landscape in mouse brain after morphine exposure

“…The regulatory effects of FTO and YTHDF1 on addictive drugs suggest that m 6 A might play functional roles in drug induced reward‐related behaviors. For example, dysregulation of m 6 A epitranscriptomic and FTO expression in the hippocampus following cocaine‐induced CPP (Xue et al., 2021 ), FTO is present in dopamine neurons and controls cocaine responses (Hess et al., 2013 ), YTHDF1‐TRAF6 pathway regulates the neuroinflammatory response and contributes to morphine tolerance (Ouyang et al., 2022 ). These findings warrant further investigation to better understand the molecular mechanisms underlying morphine exposure and to explore potential therapeutic targets.…”