Elizabeth R Jaeckel, Erwin R Arias-Hervert, Alberto L Perez-Medina, Stefan Schulz, William T Birdsong
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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. 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引用次数: 0
摘要
细胞适应性如何导致对吗啡等阿片类镇痛药产生耐受性,目前尚不十分清楚。首先,疼痛是一种复杂的现象,由感觉和情感两部分组成,主要通过不同的回路介导。从内侧丘脑(MThal)到前扣带回皮层(ACC)的谷氨酸能投射与情感性疼痛的处理过程有关,而情感性疼痛是疼痛体验中一个相对未被充分研究的部分。本研究的目的是确定慢性吗啡暴露对μ-阿片受体(MOR)信号传导在兴奋和前馈抑制通路中对MThal-ACC突触传递的影响。利用全细胞膜片钳电生理学和光遗传学选择性地靶向这些投射,我们测量了吗啡介导的对未服药小鼠和长期吗啡治疗小鼠 ACC 第 V 层锥体神经元的光诱发突触后电流的抑制。我们发现,吗啡灌注对雌性小鼠兴奋和前馈抑制通路的抑制作用相似,但对雄性小鼠抑制通路的抑制作用更大。慢性吗啡治疗可显著减弱吗啡在雄性抑制通路中的突触前抑制作用,但在雌性中却没有这种作用,同时还可轻度减弱吗啡在雌雄兴奋通路中的突触前抑制作用。在 MOR 磷酸化缺陷的小鼠中没有观察到这些效应。这项研究表明,在与疼痛和阿片类镇痛相关的丘脑-皮层回路中,慢性吗啡治疗会诱导细胞对吗啡产生耐受性。此外,它还表明这种耐受性可能是由 MOR 磷酸化驱动的。总之,这些发现加深了我们对长期暴露于阿片类药物如何改变细胞信号传导方式从而导致阿片类药物镇痛耐受性的理解。
Chronic morphine treatment induces sex- and synapse-specific cellular tolerance on thalamo-cortical mu opioid receptor signaling.
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.NEW & NOTEWORTHY 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.
期刊介绍:
The Journal of Neurophysiology publishes original articles on the function of the nervous system. All levels of function are included, from the membrane and cell to systems and behavior. Experimental approaches include molecular neurobiology, cell culture and slice preparations, membrane physiology, developmental neurobiology, functional neuroanatomy, neurochemistry, neuropharmacology, systems electrophysiology, imaging and mapping techniques, and behavioral analysis. Experimental preparations may be invertebrate or vertebrate species, including humans. Theoretical studies are acceptable if they are tied closely to the interpretation of experimental data and elucidate principles of broad interest.