Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109.
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller University, D-07747 Jena, Germany.
J Neurosci. 2024 Jan 17;44(3):e0293232023. doi: 10.1523/JNEUROSCI.0293-23.2023.
Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) via activity at μ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in the DMS. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation) in male, but not female, mice. At MThal cell bodies, chronic morphine treatment decreased subsequent morphine activation of potassium conductance (morphine tolerance) in both male and female mice. In knock-in mice expressing phosphorylation-deficient MORs, chronic morphine treatment resulted in tolerance to, rather than facilitation of, subsequent morphine signaling at MThal-DMS terminals, suggesting phosphorylation deficiency unmasks adaptations that counter the facilitation observed at presynaptic terminals in wild-type mice. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry, and sex.
慢性阿片类药物暴露会导致对阿片类药物止痛效果的耐受，但会对其他一些效果产生敏感。虽然这些适应的发生是众所周知的，但潜在的细胞机制尚不清楚。本研究旨在确定慢性吗啡治疗（一种典型的阿片类激动剂）如何在不同的亚细胞环境中诱导对随后的吗啡信号的适应。阿片类药物通过μ-阿片受体（MORs）的活性，急性抑制来自内侧丘脑（MThal）输入到背侧纹状体（DMS）的谷氨酸能传递。MORs存在于终止于 DMS 的 MThal 神经元的体和突触前区室中。我们研究了慢性吗啡处理对雄性和雌性小鼠中 MThal-DMS 突触和 MThal 胞体中随后的吗啡信号的影响。令人惊讶的是，慢性吗啡处理增加了随后吗啡对 MThal-DMS 突触传递的抑制作用（吗啡促进）在雄性，但不是雌性，小鼠中。在表达磷酸化缺陷 MOR 的敲入小鼠中，慢性吗啡处理导致随后吗啡对钾电导的激活（吗啡耐受）在雄性和雌性小鼠中均降低。慢性吗啡处理导致 MThal-DMS 末梢随后的吗啡信号出现耐受，而不是促进，这表明磷酸化缺陷揭示了在野生型小鼠中观察到的突触前末梢促进的适应，这表明磷酸化缺陷揭示了适应。本研究的结果表明，慢性吗啡暴露的影响并非普遍存在；相反，MOR 功能的适应可能取决于多个因素，如亚细胞受体分布、局部回路的影响和性别。
