Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States.
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
J Neurophysiol. 2024 Sep 1;132(3):968-978. doi: 10.1152/jn.00265.2024. Epub 2024 Aug 7.
How cellular adaptations give rise to opioid analgesic tolerance to opioids like morphine is not well understood. For one, pain is a complex phenomenon comprising both sensory and affective components, largely mediated through separate circuits. Glutamatergic projections from the medial thalamus (MThal) to the anterior cingulate cortex (ACC) are implicated in processing of affective pain, a relatively understudied component of the pain experience. The goal of this study was to determine the effects of chronic morphine exposure on mu-opioid receptor (MOR) signaling on MThal-ACC synaptic transmission within the excitatory and feedforward inhibitory pathways. Using whole cell patch-clamp electrophysiology and optogenetics to selectively target these projections, we measured morphine-mediated inhibition of optically evoked postsynaptic currents in ACC layer V pyramidal neurons in drug-naïve and chronically morphine-treated mice. We found that morphine perfusion inhibited the excitatory and feedforward inhibitory pathways similarly in females but caused greater inhibition of the inhibitory pathway in males. Chronic morphine treatment robustly attenuated morphine presynaptic inhibition within the inhibitory pathway in males, but not females, and mildly attenuated presynaptic inhibition within the excitatory pathway in both sexes. These effects were not observed in MOR phosphorylation-deficient mice. This study indicates that chronic morphine treatment induces cellular tolerance to morphine within a thalamo-cortical circuit relevant to pain and opioid analgesia. Furthermore, it suggests this tolerance may be driven by MOR phosphorylation. Overall, these findings improve our understanding of how chronic opioid exposure alters cellular signaling in ways that may contribute to opioid analgesic tolerance. Opioid signaling within the anterior cingulate cortex (ACC) is important for opioid modulation of affective pain. Glutamatergic medial thalamus (MThal) neurons synapse in the ACC and opioids, acting through mu opioid receptors (MORs), acutely inhibit synaptic transmission from MThal synapses. However, the effect of chronic opioid exposure on MThal-ACC synaptic transmission is not known. Here, we demonstrate that chronic morphine treatment induces cellular tolerance at these synapses in a sex-specific and phosphorylation-dependent manner.
细胞适应如何导致阿片类药物（如吗啡）的镇痛耐受，目前还不完全清楚。首先，疼痛是一种复杂的现象，包括感觉和情感成分，主要通过单独的回路介导。内侧丘脑（MThal）到前扣带皮层（ACC）的谷氨酸能投射与情感疼痛的处理有关，这是疼痛体验中一个相对研究较少的部分。本研究的目的是确定慢性吗啡暴露对兴奋性和前馈抑制通路中 MThal-ACC 突触传递的 μ 阿片受体（MOR）信号的影响。我们使用全细胞膜片钳电生理学和光遗传学来选择性地靶向这些投射，测量了在药物-naive 和慢性吗啡处理的小鼠中，MOR 信号对光诱发的 ACC 层 V 锥体神经元突触后电流的吗啡介导抑制。我们发现，吗啡灌流在雌性中同样抑制兴奋性和前馈抑制通路，但在雄性中引起抑制性通路的抑制更大。慢性吗啡处理在雄性中强烈减弱抑制性通路中的吗啡突触前抑制，但在雌性中没有，并且在两性中轻度减弱兴奋性通路中的突触前抑制。在 MOR 磷酸化缺陷型小鼠中未观察到这些效应。这项研究表明，慢性吗啡处理在与疼痛和阿片类药物镇痛相关的丘脑皮质回路中诱导细胞对吗啡的耐受。此外，它表明这种耐受可能是由 MOR 磷酸化驱动的。总的来说，这些发现提高了我们对慢性阿片类药物暴露如何改变细胞信号传导方式以导致阿片类药物镇痛耐受的理解。ACC 中的阿片信号对于阿片类药物对情感疼痛的调节很重要。谷氨酸能内侧丘脑（MThal）神经元在前扣带皮层（ACC）中突触，阿片类药物通过 μ 阿片受体（MOR）作用，急性抑制来自 MThal 突触的突触传递。然而，慢性阿片类药物暴露对 MThal-ACC 突触传递的影响尚不清楚。在这里，我们以性别特异性和磷酸化依赖性的方式证明，慢性吗啡处理在这些突触诱导细胞耐受。
