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证明趋化因子，特别是HIV共受体和大脑中阿片系统之间的功能性相互作用。事实上，最近我们已经表明，尽管吗啡目前代表了治疗急性和慢性严重疼痛的最佳选择，但升高的基质细胞衍生生长因子-1 α（SDF-1 α/CXCL 12）（HIV共受体CXCR 4的配体（一种与神经炎性疾病包括HIV脑炎一起发生的病症））的脑水平降低了吗啡的镇痛作用（Adler et al.，2006年）。我们目前的初步数据表明，这种作用并不是所有阿片类药物的一般特征。将SDF-1 α/CXCL 12给药至脑中不能改变丁丙诺啡的抗伤害感受作用，而其降低了美沙酮诱导的抗伤害感受。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（用于疼痛和阿片类药物依赖管理的最常见的临床使用的阿片类药物）相比，丁丙诺啡是一种部分μ-阿片类激动剂，是啮齿动物和人类中的强效镇痛剂，具有非常持久的疗效，高安全性，低水平的身体依赖性，并且未显示与抗逆转录病毒治疗产生不良药物相互作用。虽然尚未探索，但这种阿片类药物的独特药理学特征及其与HIV共受体（CXCR 4）缺乏相互作用，可能使其与美沙酮相比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。HIV-1包膜糖蛋白（gp 120）已在HIV-1感染者的大脑中检测到。已知它通过结合和激活CXCR 4引起大脑中的炎症。这项提议的中心目标是测试大脑中gp 120的存在是否调节丁丙诺啡和美沙酮的镇痛作用以及耐受性和依赖性的发展。基于将SDF-1 α/CXCL 12施用到脑中会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/CXCL 12和gp 120都与CXCR 4结合的事实，与美沙酮相比，在脑中存在gp 120的情况下丁丙诺啡更有效地发挥作用是一个站得住脚的假设，通过一种独立于CXCR 4受体的机制。在这个提议中，我们将研究中枢给药gp 120对镇痛（AIM # 1）和镇痛耐受性和依赖性的发展对慢性丁丙诺啡和美沙酮（AIM # 2）的体内后果。gp 120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。这些研究是第一个检查一个重要的问题，直到现在仍然没有探索：镇痛功能，耐受性和依赖性的发展，以最常见的临床使用的阿片类药物疼痛和阿片类药物成瘾管理（丁丙诺啡和美沙酮）在大脑中存在的gp 120。艾滋病毒和丁丙诺啡/美沙酮相互作用的知识有很大的影响疼痛和/或阿片类药物依赖管理与艾滋病毒患者。有效解决gp 120和这两种阿片类药物之间的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。 公共卫生相关性：这些研究是第一次检查一个重要的问题，到目前为止仍然没有探索：镇痛功能，耐受性和依赖性的发展，最常见的临床使用的阿片类药物疼痛和阿片类药物成瘾管理（丁丙诺啡和美沙酮）的存在下，HIV-1包膜糖蛋白（gp 120）在大脑中。拟议的研究如果成功，将首次揭示临床上最常用的阿片类药物用于疼痛和阿片类药物依赖管理（丁丙诺啡或美沙酮），当它在HIV-1包膜糖蛋白（gp 120）产生的神经炎症下急性和慢性使用时更有效和安全。HIV和丁丙诺啡/美沙酮相互作用的知识对HIV患者使用阿片类药物进行疼痛和/或阿片类药物依赖管理具有重要意义。有效解决gp 120和这两种阿片类药物之间的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.