Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, United States; Medical College of Yangzhou University, Yangzhou, China.
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, United States.
Brain Behav Immun. 2022 Mar;101:37-48. doi: 10.1016/j.bbi.2021.12.014. Epub 2021 Dec 24.
Opioid addiction remains a severe health problem. While substantial insights underlying opioid addiction have been yielded from neuron-centric studies, the contribution of non-neuronal mechanisms to opioid-related behavioral adaptations has begun to be recognized. Toll-like receptor 4 (TLR4), a pattern recognition receptor, has been widely suggested in opioid-related behaviors. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase essential for TLR4 responses, However, the potential role of IRAK4 in opioid-related responses has not been examined. Here, we explored the role of IRAK4 in cue-induced opioid-seeking behavior in male rats. We found that morphine self-administration increased the phosphorylation level of IRAK4 in the nucleus accumbens (NAc) in rats; the IRAK4 signaling remained activated after morphine extinction and cue-induced reinstatement test. Both systemic and local inhibition of IRAK4 in the NAc core attenuated cue-induced morphine-seeking behavior without affecting the locomotor activity and cue-induced sucrose-seeking. In addition, inhibition of IRAK4 also reduced the cue-induced reinstatement of fentanyl-seeking. Our findings suggest an important role of IRAK4 in opioid relapse-like behaviors and provide novel evidence in the association between innate immunity and drug addiction.
阿片成瘾仍是严重的健康问题。尽管神经中枢研究为阿片成瘾提供了大量的见解，但非神经机制在阿片类药物相关行为适应中的贡献开始得到认可。Toll 样受体 4（TLR4）是一种模式识别受体，已广泛应用于阿片类药物相关行为的研究中。白细胞介素 1 受体相关激酶 4（IRAK4）是 TLR4 反应所必需的激酶。然而，IRAK4 在阿片类药物相关反应中的潜在作用尚未得到检验。在这里，我们研究了 IRAK4 在雄性大鼠线索诱导的阿片类药物觅药行为中的作用。我们发现，吗啡自我给药增加了大鼠伏隔核（NAc）中 IRAK4 的磷酸化水平；吗啡消退和线索诱导的复吸测试后，IRAK4 信号仍保持激活。NAc 核心区的 IRAK4 全身和局部抑制均减弱了线索诱导的吗啡觅药行为，而不影响运动活性和线索诱导的蔗糖觅药。此外，抑制 IRAK4 还减少了芬太尼觅药的线索诱导复吸。我们的研究结果表明 IRAK4 在阿片类药物复发性行为中具有重要作用，并为先天免疫与药物成瘾之间的关联提供了新的证据。
