Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States.
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States.
J Neurophysiol. 2024 Sep 1;132(3):1056-1073. doi: 10.1152/jn.00444.2023. Epub 2024 Aug 7.
Besides having high potency and efficacy at the µ-opioid (MOR) and other opioid receptor types, fentanyl has some affinity for some adrenergic receptor types, which may underlie its unique pathophysiological differences from typical opioids. To better understand the unique actions of fentanyl, we assessed the extent to which fentanyl alters striatal medium spiny neuron (MSN) activity via opioid receptors or α-adrenoceptors in dopamine type 1 or type 2 receptor (D1 or D2)-expressing MSNs. In neuronal and mixed-glial cocultures from the striatum, acute fentanyl (100 nM) exposure decreased the frequency of spontaneous action potentials. Overnight exposure of cocultures to 100 nM fentanyl severely reduced the proportion of MSNs with spontaneous action potentials, which was unaffected by coexposure to the opioid receptor antagonist naloxone (10 µM) but fully negated by coadministering the pan-α-adrenoceptor inverse agonist prazosin (100 nM) and partially reversed by the selective α-adrenoceptor antagonist RS 100329 (300 nM). Acute fentanyl (100 nM) exposure modestly reduced the frequency of action potentials and caused firing rate adaptations in D2, but not D1, MSNs. Prolonged (2-5 h) fentanyl (100 nM) application dramatically attenuated firing rates in both D1 and D2 MSNs. To identify possible cellular sites of α-adrenoceptor action, α-adrenoceptors were localized in subpopulations of striatal astroglia and neurons by immunocytochemistry and mRNA by in situ hybridization in astrocytes. Thus, sustained fentanyl exposure can inhibit striatal MSN activity via a nonopioid receptor-dependent pathway, which may be modulated via complex actions in α-adrenoceptor-expressing striatal neurons and/or glia. Acute fentanyl exposure attenuated the activity of striatal medium spiny neurons (MSNs) in vitro and in dopamine D2, but not D1, receptor-expressing MSNs in ex vivo slices. By contrast, sustained fentanyl exposure suppressed the spontaneous activity of MSNs cocultured with glia through a nonopioid receptor-dependent mechanism modulated, in part, by α-adrenoceptors. Fentanyl exposure can affect striatal function via a nonopioid receptor mechanism of action that appears mediated by α-adrenoreceptor-expressing striatal neurons and/or astroglia.
除了具有高效力和疗效在 µ-阿片受体（MOR）和其他阿片受体类型，芬太尼有一些亲和力为一些肾上腺素能受体类型，这可能是其独特的病理生理学差异的基础从典型的阿片类药物。为了更好地了解芬太尼的独特作用，我们评估了芬太尼通过阿片受体或α-肾上腺素受体改变纹状体中型多棘神经元（MSN）活性的程度在多巴胺 1 型或 2 型受体（D1 或 D2）表达的 MSN 中。在纹状体的神经元和混合神经胶质共培养物中，急性芬太尼（100 nM）暴露降低了自发动作电位的频率。共培养物 overnight 暴露于 100 nM 芬太尼严重降低了具有自发动作电位的 MSN 的比例，该比例不受共暴露于阿片受体拮抗剂纳洛酮（10 µM）的影响，但完全被泛α-肾上腺素受体反向激动剂普萘洛尔（100 nM）共同给药所否定，并部分被选择性α-肾上腺素受体拮抗剂 RS 100329（300 nM）逆转。急性芬太尼（100 nM）暴露轻微降低动作电位的频率，并导致 D2，但不是 D1，MSN 的放电率适应。延长（2-5 h）芬太尼（100 nM）应用显著减弱 D1 和 D2 MSN 的放电率。为了鉴定可能的α-肾上腺素受体作用的细胞部位，通过免疫细胞化学和原位杂交在星形胶质细胞中定位了纹状体星形胶质细胞和神经元中的α-肾上腺素受体亚群。因此，持续的芬太尼暴露可以通过非阿片受体依赖性途径抑制纹状体 MSN 活性，该途径可能通过在表达α-肾上腺素受体的纹状体神经元和/或神经胶质细胞中的复杂作用来调节。急性芬太尼暴露在体外和在多巴胺 D2 中减弱纹状体中型多棘神经元（MSN）的活性，但在表达 D1 的 MSN 中没有作用。相比之下，持续的芬太尼暴露通过非阿片受体依赖性机制抑制与神经胶质共培养的 MSN 的自发活动，该机制部分受α-肾上腺素受体调节。芬太尼暴露可以通过非阿片受体作用机制影响纹状体功能，该机制似乎通过表达α-肾上腺素受体的纹状体神经元和/或星形胶质细胞介导。
