Breathing Research and Therapeutics Center, University of Florida, Gainesville, FL, USA.
Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
J Physiol. 2021 Aug;599(15):3771-3797. doi: 10.1113/JP281362. Epub 2021 Jul 6.
While respiratory complications following opioid use are mainly mediated via activation of mu opioid receptors, long-latency off-target signalling via innate immune toll-like receptor 4 (TLR4) may impair other essential elements of breathing control such as respiratory motor plasticity. In adult rats, pre-treatment with a single dose of morphine blocked long-term facilitation (LTF) of phrenic motor output via a long-latency TLR4-dependent mechanism. In the phrenic motor nucleus, morphine triggered TLR4-dependent activation of microglial p38 MAPK - a key enzyme that orchestrates inflammatory signalling and is known to undermine phrenic LTF. Morphine-induced LTF loss may destabilize breathing, potentially contributing to respiratory side effects. Therefore, we suggest minimizing TLR-4 signalling may improve breathing stability during opioid therapy.
Opioid-induced respiratory dysfunction is a significant public health burden. While respiratory effects are mediated via mu opioid receptors, long-latency off-target opioid signalling through innate immune toll-like receptor 4 (TLR4) may modulate essential elements of breathing control, particularly respiratory motor plasticity. Plasticity in respiratory motor circuits contributes to the preservation of breathing in the face of destabilizing influences. For example, respiratory long-term facilitation (LTF), a well-studied model of respiratory motor plasticity triggered by acute intermittent hypoxia, promotes breathing stability by increasing respiratory motor drive to breathing muscles. Some forms of respiratory LTF are exquisitely sensitive to inflammation and are abolished by even a mild inflammation triggered by TLR4 activation (e.g. via systemic lipopolysaccharides). Since opioids induce inflammation and TLR4 activation, we hypothesized that opioids would abolish LTF through a TLR4-dependent mechanism. In adult Sprague Dawley rats, pre-treatment with a single systemic injection of the prototypical opioid agonist morphine blocks LTF expression several hours later in the phrenic motor system - the motor pool driving diaphragm muscle contractions. Morphine blocked phrenic LTF via TLR4-dependent mechanisms because pre-treatment with (+)-naloxone - the opioid inactive stereoisomer and novel small molecule TLR4 inhibitor - prevented impairment of phrenic LTF in morphine-treated rats. Morphine triggered TLR4-dependent activation of microglial p38 MAPK within the phrenic motor system - a key enzyme that orchestrates inflammatory signalling and undermines phrenic LTF. Morphine-induced LTF loss may destabilize breathing, potentially contributing to respiratory side effects. We suggest minimizing TLR-4 signalling may improve breathing stability during opioid therapy by restoring endogenous mechanisms of plasticity within respiratory motor circuits.
虽然阿片类药物使用后的呼吸并发症主要是通过激活μ阿片受体来介导的,但长潜伏期的非靶点信号转导通过先天免疫 toll 样受体 4(TLR4)可能会损害呼吸控制的其他基本要素,如呼吸运动的可塑性。在成年大鼠中,单次给予吗啡预处理通过长潜伏期 TLR4 依赖性机制阻断膈神经运动输出的长期易化(LTF)。在膈神经运动核中,吗啡触发 TLR4 依赖性小胶质细胞 p38 MAPK 激活 - 一种协调炎症信号的关键酶,已知会破坏膈神经 LTF。吗啡诱导的 LTF 丧失可能会使呼吸不稳定,从而导致呼吸副作用。因此,我们建议最大限度地减少 TLR-4 信号可能会改善阿片类药物治疗期间的呼吸稳定性。
阿片类药物引起的呼吸功能障碍是一个重大的公共卫生负担。虽然呼吸效应是通过μ阿片受体介导的,但长潜伏期的非靶点阿片信号通过先天免疫 toll 样受体 4(TLR4)可能调节呼吸控制的基本要素,特别是呼吸运动的可塑性。呼吸运动回路的可塑性有助于在不稳定的影响下保持呼吸。例如,呼吸的长期易化(LTF),一种由急性间歇性低氧引发的研究得很好的呼吸运动可塑性模型,通过增加呼吸肌肉的呼吸运动驱动力来促进呼吸稳定性。一些形式的呼吸 LTF 对炎症非常敏感,甚至 TLR4 激活(例如,通过全身脂多糖)引发的轻度炎症也会消除。由于阿片类药物会引起炎症和 TLR4 激活,我们假设阿片类药物会通过 TLR4 依赖性机制消除 LTF。在成年 Sprague Dawley 大鼠中,单次系统给予原型阿片类激动剂吗啡预处理可在数小时后阻断膈神经运动系统中的 LTF 表达 - 膈神经运动池驱动膈肌收缩。吗啡通过 TLR4 依赖性机制阻断膈神经 LTF,因为预先给予(+)-naloxone - 阿片类药物无效的对映异构体和新型小分子 TLR4 抑制剂 - 可防止吗啡处理大鼠的膈神经 LTF 受损。吗啡触发 TLR4 依赖性小胶质细胞 p38 MAPK 在膈神经运动系统中的激活 - 一种协调炎症信号并破坏膈神经 LTF 的关键酶。吗啡诱导的 LTF 丧失可能会使呼吸不稳定,从而导致呼吸副作用。我们建议通过恢复呼吸运动回路中的内源性可塑性机制,最大限度地减少 TLR-4 信号可能会改善阿片类药物治疗期间的呼吸稳定性。