The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the "crosstalk" between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms - an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) - each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F3,36 = 3.345, p = 0.030) and IL-10 (F3,53.2 = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.

中文翻译：

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外源性生长素释放肽给药和生长素释放肽受体阻断与酒精联合对重度饮酒个体外周炎症标志物的影响：两项人体实验室研究的结果。

ghrelin 系统因其在不同神经精神疾病（包括酒精使用障碍 (AUD)）中的作用而备受关注。因此，针对生长素释放肽系统的研究正在作为一种潜在的新型治疗方法进行研究。虽然酒精会激发免疫系统和炎症反应，但生长素释放肽具有强大的免疫调节和抗炎特性。本研究旨在通过在两项人体实验室酒精给药研究的背景下检查外源性生长素释放肽给药和生长素释放肽受体阻断对外周炎症标志物的影响，阐明生长​​素释放肽与炎症之间的“串扰”。研究对象包括不寻求治疗、酗酒且有酒精依赖的人，其中大多数是非裔美国男性。在第一个随机中，在交叉、双盲、安慰剂对照的人体实验室研究中，参与者接受了两种实验范式——静脉内酒精自我给药 (IV-ASA) 和静脉内酒精钳夹 (IV-AC)——每一种都包含两个平衡疗程（ghrelin，安慰剂）。给予负荷剂量的静脉内生长素释放肽 (3 mcg/kg) 或安慰剂，然后连续输注生长素释放肽 (16.9 ng/kg/min) 或安慰剂。在第二项剂量递增、单盲、安慰剂对照的人体实验室 1b 期研究中，参与者服用口服生长素释放肽受体阻滞剂 (PF-5190457) 并接受口服酒精挑战。重复采集血液样本，并测量以下炎症标志物的血浆浓度：C-反应蛋白 (CRP)、白细胞介素 (IL)-6、IL-10、IL-18、和肿瘤坏死因子 α (TNF-α)。在 IV-ASA 实验期间，观察到 IL-6 (F3,36 = 3.345, p = 0.030) 和 IL-10 (F3,53.2 = 4.638, p = 0.006) 的显着药物×时间相互作用效应，表明生长素释放肽，与安慰剂相比，显着降低促炎细胞因子 IL-6 的血液浓度，同时增加抗炎细胞因子 IL-10 的血液浓度。在 IV-AC 实验期间未观察到显着的药物×时间相互作用效应，可能是因为其持续时间更短和/或样本更小。与安慰剂相比，PF-5190457 治疗对所研究的炎症标志物没有显着影响。综上所述，在大量饮酒的个体中，外源性生长素释放肽的超生理药理学挑战在静脉注射酒精的情况下产生了抗炎作用。相反，ghrelin 受体阻断不会导致本研究中包括的炎症标志物发生任何变化。需要进行机理研究以更好地了解生长素释放肽、酒精和炎症过程之间的相互作用。