速激肽-1阳性细胞中的缪阿片受体介导了阿片类药物芬太尼的呼吸和抗痛觉效应。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-11-06 DOI:10.1111/bph.17369
Andreea Furdui, Carolina da Silveira Scarpellini, Gaspard Montandon
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引用次数: 0

摘要

背景和目的:阿片类药物是一种强效镇痛药,由于作用于控制呼吸的脑干区域的μ-阿片受体(MORs),因此有可能对呼吸系统产生副作用。P 物质由 Tac1 基因编码,在调节呼吸、痛觉和运动的神经元中表达。Tac1 阳性细胞还在脑干区域表达 MORs,介导阿片类药物诱导的呼吸抑制。我们确定了 Tac1 阳性细胞在介导阿片类药物呼吸效应中的作用:实验方法:采用原位杂交法测定阿片类药物呼吸抑制调节区 Tac1 阳性细胞中 Oprm1 mRNA(编码 MORs 的基因)的表达。制备了在 Tac1 阳性细胞中缺乏功能性 MORs 的条件基因剔除小鼠,并使用全身褶压计评估了小鼠对阿片类镇痛药芬太尼的呼吸和运动反应。使用尾部浸泡试验评估对芬太尼的抗痛觉反应:主要结果:Oprm1 mRNA在前伯丁格复合体、孤束核和Kölliker-Fuse/外侧腕旁区域的Tac1阳性细胞亚群中高度表达(>80%)。与对照组小鼠相比,有条件地敲除 Tac1 阳性细胞中的 MORs 可消除芬太尼对呼吸频率、相对潮气量和相对分钟通气量的影响。重要的是,在 Tac1 阳性细胞中缺乏功能性 MORs 的小鼠中,芬太尼的抗痛觉反应被消除,而芬太尼诱导的运动效应却得以保留:我们的研究结果表明,Tac1 阳性细胞介导了阿片类药物芬太尼的呼吸抑制和抗痛觉效应,为开发可降低呼吸副作用风险的疼痛疗法提供了重要启示。
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Mu-opioid receptors in tachykinin-1-positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl.

Background and purpose: Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ-opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1-positive cells also express MORs in brainstem regions mediating opioid-induced respiratory depression. We determined the role of Tac1-positive cells in mediating the respiratory effects of opioid drugs.

Experimental approach: In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1-positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1-positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole-body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl.

Key results: Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1-positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker-Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1-positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1-positive cells, whereas locomotor effects induced by fentanyl were preserved.

Conclusions and implications: Our findings suggest that Tac1-positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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Mu-opioid receptors in tachykinin-1-positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl. Issue Information Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids. Have plastic culture models prevented the discovery of effective cancer therapeutics? Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.
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