Gp120 in the brain and opioid medications: Functional interactions

大脑中的 Gp120 和阿片类药物：功能相互作用

• 批准号: 8034340
• 负责人: Khalid Benamar
• 金额: $ 18.52万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034340
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Agonist; Analgesics; Binding; Brain; Buprenorphine; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Characteristics; Chronic; Data; Dependence; Development; Disease; Drug Interactions; FDA approved; Glycoproteins; Goals; Growth Factor; HIV; HIV Envelope Protein gp120; HIV Infections; HIV encephalitis; HIV-1; Human; Individual; Inflammation; Knowledge; Ligands; Maintenance; Methadone; Morphine; Opiate Addiction; Opioid; Opioid Receptor; Pain; Patients; Pharmaceutical Preparations; Physical Dependence; Public Health; Rodent; Safety; Stromal Cell-Derived Factor 1; Stromal Cells; System; Testing; Time; Withdrawal; antiretroviral therapy; base; chemokine; chemokine receptor; in vivo; neuroinflammation; public health relevance; response

DESCRIPTION (provided by applicant): We have developed enough evidence for a functional interaction between chemokines, particularly the HIV co-receptors, and the opioid system in the brain. Indeed, recently we have shown that although morphine currently represents the best option for treating acute and chronic severe pain, elevated brain levels of Stromal cell-Derived growth Factor-1alpha (SDF-1 alpha/CXCL12), the ligand of the HIV co-receptor CXCR4 (a condition that occurs with neuroinflammatory diseases, including HIV encephalitis), diminish the analgesic effect of morphine (Adler et al., 2006). Our present preliminary data show that this effect is not a general characteristic of all opioid medications. The administration of SDF-1 alpha/CXCL12 into the brain fails to alter the antinociceptive action of buprenorphine, while it reduces methadone-induced antinociception. Buprenorphine was approved by the FDA in 2002 for use in supervised withdrawal and maintenance treatment of opioid dependence. Compared to methadone, the most common clinically used opioid medication for pain and opioid dependence management, buprenorphine is a partial mu-opioid agonist, a powerful analgesic in both rodents and humans, has a very long-lasting efficacy, high safety profile, low level of physical dependence and has not been shown to produce adverse drug interaction with antiretroviral therapy. While as yet unexplored, the unique pharmacological characteristics of this opioid together with its lack of interaction with the HIV co-receptor (CXCR4) may make it more suitable and effective for treating pain (acute and chronic) and/or opioid dependence under HIV infection conditions compared to methadone. The HIV-1 envelope glycoprotein (gp120) has been detected in the brains of HIV-1-infected individuals. It is known to elicit inflammation in the brain through binding and activating CXCR4. The central goal of this proposal is to test whether the presence of gp120 in the brain modulates the analgesia and the development of tolerance and dependence to buprenorphine and methadone. Based on the fact that the administration of the SDF-1 alpha/CXCL12 into the brain diminishes methadone-induced analgesia, while it fails to interfere with buprenorphine, and that SDF-1 alpha/CXCL12 and gp120 both bind to CXCR4, it is a tenable hypothesis that buprenorphine functions more effectively in the presence of gp120 in the brain, as compared to methadone, via a mechanism that is independent of the CXCR4 receptor. In this proposal, we will investigate the in vivo consequences of the central administration the gp120 on analgesia (AIM # 1) and the development of analgesic tolerance and dependence in response to chronic buprenorphine and methadone (AIM # 2). Whether gp120 interacts with opioid medications via chemokine receptor mechanisms will be investigated. These studies are the first to examine an important issue that until now remains unexplored: the analgesic function, development of tolerance and dependence to the most common clinically used opioids for pain and opioid addiction management (buprenorphine and methadone) in the presence of gp120 in the brain. Knowledge of HIV and buprenorphine/methadone interaction has great implications for pain and/or opioid dependence management with opioid medications in HIV patients. The opportunities for effectively addressing the functional interaction between gp120 and these two opioid medications, is relevant for public health, particularly the field of HIV-related pain and opioid dependence. PUBLIC HEALTH RELEVANCE: These studies are the first to examine an important issue that until now remains unexplored: the analgesic function, development of tolerance and dependence to the most common clinically used opioids for pain and opioid addiction management (buprenorphine and methadone) in the presence of HIV-1 envelope glycoprotein (gp120) in the brain. The proposed studies, if successful will reveal for the first time, which of the most common clinically used opioid medications for pain and opioid dependence management (buprenorphine or methadone) is more effective and safe when it is used acutely and chronically under neuroinflammation produced by HIV-1 envelope glycoprotein (gp120). Knowledge of HIV and buprenorphine/methadone interaction has great implications for pain and/or opioid dependence management with the opioid medications in HIV patients. The opportunities for effectively addressing the functional interaction between gp120 and these two opioid medications, is relevant for public health, particularly the field of HIV-related pain and opioid dependence.

描述(由申请人提供)：我们已经找到了足够的证据证明趋化因子，特别是HIV辅助受体与大脑中的阿片系统之间存在功能性相互作用。事实上，最近我们已经证明，尽管吗啡目前是治疗急性和慢性严重疼痛的最佳选择，但脑内基质细胞衍生生长因子-1α(SDF-1α/CXCL12)水平的升高(艾滋病毒共受体CXCR4的配体(这种情况发生于包括艾滋病毒脑炎在内的神经炎症性疾病))减弱了吗啡的止痛效果(Adler等，2006)。我们目前的初步数据表明，这种效果并不是所有阿片类药物的普遍特征。脑内注射SDF-1α/CXCL12不能改变丁丙诺啡的抗伤害作用，但可减少美沙酮诱导的抗伤害作用。丁丙诺啡于2002年被FDA批准用于阿片类药物依赖的监督戒断和维持治疗。与美沙酮相比，丁丙诺啡是一种部分阿片激动剂，对啮齿动物和人类都是一种强大的止痛剂，具有非常持久的疗效，安全性高，身体依赖性低，并未被证明与抗逆转录病毒治疗产生不良药物相互作用。美沙酮是临床上最常用的阿片类药物和阿片依赖治疗药物。虽然尚未被探索，但这种阿片类药物的独特药理学特征，加上它缺乏与艾滋病毒共同受体(CXCR4)的相互作用，可能使其比美沙酮更适合和更有效地治疗艾滋病毒感染条件下的疼痛(急性和慢性)和/或阿片依赖。已在HIV-1感染者的大脑中检测到HIV-1包膜糖蛋白(Gp120)。众所周知，它通过结合和激活CXCR4在大脑中引发炎症。这项提议的中心目标是测试大脑中gp120的存在是否调节了对丁丙诺啡和美沙酮的止痛以及对丁丙诺啡和美沙酮的耐受和依赖。脑内给药SDF-1α/CXCL12可减弱美沙酮的镇痛作用，但不能干扰丁丙诺啡，且SDF-1α/CXCL12和gp120均与CXCR4结合，这是一个站得住脚的假设：与美沙酮相比，丁丙诺啡在脑内存在gp120时通过一种独立于CXCR4受体的机制发挥更有效的作用。在这项提案中，我们将研究中枢应用gp120对镇痛(AIM#1)以及对慢性丁丙诺啡和美沙酮(AIM#2)反应的止痛耐受和依赖的发展的体内影响。将研究gp120是否通过趋化因子受体机制与阿片类药物相互作用。这些研究首次探讨了一个到目前为止仍未探索的重要问题：在大脑中存在gp120的情况下，止痛功能、对临床上最常用的阿片类药物(丁丙诺啡和美沙酮)的耐受性和依赖性的发展。了解艾滋病毒和丁丙诺啡/美沙酮的相互作用对艾滋病毒患者使用阿片类药物治疗疼痛和/或阿片依赖具有重要意义。有效解决gp120和这两种阿片类药物之间功能相互作用的机会与公共卫生有关，特别是在艾滋病毒相关疼痛和阿片依赖领域。 公共卫生相关性：这些研究首次探讨了一个迄今仍未探索的重要问题：在大脑中存在HIV-1包膜糖蛋白(Gp120)的情况下，止痛功能、对临床上最常见的止痛阿片类药物(丁丙诺啡和美沙酮)的耐受性和依赖性的发展。拟议的研究如果成功，将首次揭示临床上最常见的用于疼痛和阿片依赖管理的阿片类药物(丁丙诺啡或美沙酮)，当它在艾滋病毒-1包膜糖蛋白(Gp120)产生的神经炎症下急性和慢性使用时，更有效和安全。了解艾滋病毒和丁丙诺啡/美沙酮的相互作用对艾滋病毒患者使用阿片类药物治疗疼痛和/或阿片依赖具有重要意义。有效解决gp120和这两种阿片类药物之间功能相互作用的机会与公共卫生有关，特别是在艾滋病毒相关疼痛和阿片依赖领域。