INTERFERON-ALPHA, OPIOID RECEPTORS AND DRUG ADDICTION

干扰素-α、阿片受体和药物成瘾

• 批准号: 3424333
• 负责人: ROBERT A MENZIES
• 金额: $ 7.21万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3424333
• 关键词: chemical association; chemical kinetics; cytokine; endogenous opioid; interferon alpha; iodine; laboratory rat; ligands; neuroimmunomodulation; neuropharmacology; opioid receptor; radionuclides; radiotracer; receptor binding

It has been reported that IFNalpha is able to modulate a number of central nervous system (CNS) functions and related behaviors, in particular those related to morphine withdrawal in rats. IFNalpha has also been reported to cause antinociception when administered intracerebrally, cause excitation of neurons in culture and directly effects the activity of temperature and glucose sensitive neurons. Some of the effects of IFNalpha are reversible by naloxone, an opioid antagonist. Interferon alpha (IFNalpha), when used therapeutically as an antiviral or anticancer agent causes a variety of neurologic and psychiatric side effects. In human clinical trials IFNalpha has been reported to elicit behavioral patterns and psychiatric complications similar to those observed in AIDS related dementia (HIV-1 associated cognitive/motor complex). Symptoms include depression, paranoia, suicidal tendencies, etc. In the case of IFNalpha therapeutic use, the symptoms disappear when treatment is discontinued. The possible cause of AIDS dementia by inappropriate modulation of CNS immune system products or receptors is further suggested by the following: (1) an unusual acid labile form of IFN is observed in high levels in AIDS patients, (2) there may be regions of structural homology between IFNalpha and HIV protein, pl7, and (3) although the ability of leukocytes to produce IFNalpha decreases with severity of HIV-1 symptoms, IFNalpha in serum is elevated in early and mid stages of HIV-1 progression. Both IFNalpha and gamma activate the tryptophan degradation pathway which produces the neurotoxin, quinolinic acid. The principle cells involved in producing quinolinic acid, the glia, are sensitive to opioids and have opioid receptors. Thus, it is possible that the action of IFNalpha in these dementias may be mediated through receptors sensitive to certain opioids. Data from rat brain membrane binding studies by our laboratory and others are consistent with the hypothesis that some of the CNS effects of IFNalpha directly involve opioid receptors. This project is aimed at systematically (1) characterizing the binding of IFNalpha to rat brain membranes, and (2) the effect of opioid ligands on IFNalpha binding to rat brain membranes. Membrane binding studies using nonlabelled opioid ligands to inhibit radiolabelled IFNalpha binding or, conversely, using IFNalpha to inhibit receptor class specific opioid radioligand binding, will identify the receptor class of IFNalpha interactions. These studies will be done in vitro using membrane fractions from rat brain, incubations with labelled ligands, e.g., 3H-opioid ligands or 125I-labelled IFNalpha, and scintillation counting. From these studies it will be possible to determine the degree of specificity of IFNalpha-opioid receptor interactions to allow design of studies to further explore the biological relevance of these interactions.

据报道，ifnalpha能够调节许多中央 神经系统（CNS）功能和相关行为，尤其是这些行为 与大鼠的吗啡戒断有关。 ifnalpha也已报道 当脑内施用时会引起抗伤害感受，引起激发 培养中神经元的神经元，直接影响温度和温度的活性 葡萄糖敏感神经元。 ifnalpha的某些影响是可逆的 由阿片类药物拮抗剂纳洛酮作用。 干扰素α（Ifnalpha），当使用时 在治疗上作为抗病毒或抗癌剂会引起多种 神经和精神病副作用。在人类临床试验中 据报道引起行为模式和精神病学 并发症类似于与艾滋病相关痴呆中观察到的并发症（HIV-1 相关的认知/运动复合物）。症状包括抑郁， 在IFNALPHA治疗的情况下，偏执狂，自杀趋势等 使用时，症状在停止治疗时消失。 可能 CNS免疫系统的不适当调节艾滋病痴呆症原因 产品或受体进一步提出：（1） 在AIDS中观察到IFN的异常酸不稳定形式 患者，（2）Ifnalpha之间可能存在结构同源的区域 和HIV蛋白，PL7和（3），尽管白细胞的能力 产生IFNALPHA随着HIV-1症状的严重程度而降低 在HIV-1进展的早期和中期，血清升高。两个都 Ifnalpha和Gamma激活色氨酸降解途径 产生神经毒素，喹啉酸。涉及的主要单元 产生喹啉酸，神经胶质对阿片类药物敏感，具有 阿片受体。因此，Ifnalpha在 这些痴呆可以通过对某些人敏感的受体介导 阿片类药物。 我们实验室和其他人的大鼠脑膜结合研究的数据 与以下假设一致。 IFNALPHA直接涉及阿片类受体。这个项目针对 系统地（1）表征ifnalpha与大鼠脑的结合 膜和（2）阿片类配体对IFNALPHA与大鼠结合的影响 脑膜。使用未标记的阿片类配体的膜结合研究 抑制放射性标记的IFNALPHA结合，或者相反，使用ifnalpha 为了抑制受体类特异性阿片类药物的结合，将 确定IFNALPHA相互作用的受体类别。这些研究会 使用大鼠大脑的膜分数在体外完成，与 标记的配体，例如3H-阿片类配体或125i标记的Ifnalpha，并且 闪烁计数。从这些研究可以 确定ifnalpha-Apoid受体的特异性程度 相互作用以允许研究进一步探索生物学 这些相互作用的相关性。