Gp120 in the brain and opioid medications: Functional interactions

描述（由申请人提供）：我们已经开发了足够的证据来证明趋化因子，特别是HIV共受体和大脑中的阿片系统之间的功能相互作用。事实上，最近我们已经表明，尽管吗啡目前是治疗急性和慢性剧烈疼痛的最佳选择，但大脑中基质细胞衍生生长因子-1 α (SDF-1 α /CXCL12)， HIV共受体CXCR4的配体水平升高（一种发生在神经炎性疾病，包括HIV脑炎的情况），会减弱吗啡的镇痛作用（Adler等，2006）。我们目前的初步数据表明，这种效应并不是所有阿片类药物的普遍特征。将SDF-1 α /CXCL12注入大脑不能改变丁丙诺啡的抗痛觉作用，但可以降低美沙酮诱导的抗痛觉作用。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。与临床上用于治疗疼痛和阿片类药物依赖的最常用阿片类药物美沙酮相比，丁丙诺啡是一种部分阿片类药物激动剂，在啮齿类动物和人类中都是一种强效镇痛药，具有非常持久的疗效，高安全性，低水平的身体依赖性，并且没有显示出与抗逆转录病毒治疗产生不良药物相互作用。虽然尚未被探索，但与美沙酮相比，这种阿片类药物的独特药理学特征及其与HIV共受体（CXCR4）缺乏相互作用可能使其更适合和有效地治疗HIV感染条件下的疼痛（急性和慢性）和/或阿片类药物依赖。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。本研究的中心目标是测试脑内gp120的存在是否调节对丁丙诺啡和美沙酮的镇痛以及耐受和依赖的发展。基于SDF-1 α /CXCL12进入大脑减少美沙酮诱导的镇痛，而它不能干扰丁丙诺啡，并且SDF-1 α /CXCL12和gp120都与CXCR4结合这一事实，一个成立的假设是，与美沙酮相比，在大脑中gp120存在时，丁丙诺啡的功能更有效，通过一个独立于CXCR4受体的机制。在本提案中，我们将研究gp120在体内对镇痛的影响（AIM # 1），以及慢性丁丙诺啡和美沙酮对镇痛耐受和依赖的发展（AIM # 2）。gp120是否通过趋化因子受体机制与阿片类药物相互作用将被研究。这些研究首次探讨了迄今为止尚未探索的一个重要问题：在脑内gp120存在的情况下，对临床上最常用的阿片类药物（丁丙诺啡和美沙酮）的镇痛功能、耐受性和依赖性的发展。了解艾滋病毒和丁丙诺啡/美沙酮相互作用对艾滋病毒患者的疼痛和/或阿片类药物依赖管理具有重要意义。有效解决gp120与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，特别是与艾滋病毒相关的疼痛和阿片类药物依赖领域。

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.