Morphine-Induced Antinociception Is Potentiated and Dopamine Elevations Are Inhibited by the Biased Kappa Opioid Receptor Agonist Triazole 1.1.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Neuroscience Pub Date : 2025-04-02 Epub Date: 2025-03-25 DOI:10.1021/acschemneuro.5c00075
Emanuel F Lopes, Alyssa M West, Jason L Locke, Katherine Holleran, Leighelle A Adrian, Monica H Dawes, Alyson M Curry, Harlie A McKelvey, Thomas Martin, Sara R Jones
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引用次数: 0

Abstract

Traditional analgesic opioid compounds, which act through μ opioid receptors (MORs), engender a high risk for misuse and dependence. κ opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.

偏置阿片受体激动剂三唑可增强吗啡诱导的抗痛觉,抑制多巴胺升高1.1。
传统的镇痛类阿片化合物通过μ阿片受体(MORs)起作用,存在滥用和依赖的高风险。κ阿片受体(KOR)激活是疼痛治疗的潜在靶点,可产生抗痛觉作用,无欣快副作用,但会导致烦躁不安和厌恶。三唑1.1是一种偏向于g蛋白偶联信号的KOR激动剂,可能促进无烦躁不安的抗痛觉作用。我们对三唑1.1是否具有抗避孕作用及与吗啡联用的效果进行了试验。我们采用乳酸性腹痛模型,诱导急性疼痛行为,降低伏隔核(NAc)的基础多巴胺水平,增加KOR功能。我们使用了几种干预措施,包括三唑1.1 (30 mg/kg)和吗啡(12或24 mg/kg),单独或联合使用。单独三唑1.1可降低疼痛行为反应和KOR功能的改变,但不能阻止基础多巴胺水平的降低。吗啡不仅可以剂量依赖性地阻止行为性疼痛反应,还可以升高NAc多巴胺,但不能阻止疼痛引起的KOR功能增加。然而,低剂量吗啡联合三唑1.1可阻止行为性疼痛反应、NAc多巴胺水平的改变和KOR功能的改变。因此,我们提出三唑1.1作为一种剂量节约的疼痛治疗药物,可与低剂量吗啡联合使用,从而减少阿片类药物滥用的可能性。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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