Chemokine Antagonist, Opioid Medication and HIV gp120

趋化因子拮抗剂、阿片类药物和 HIV gp120

• 批准号: 8140920
• 负责人: Khalid Benamar
• 金额: $ 15.29万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140920
• 关键词: AIDS/HIV problem; Absence of pain sensation; Address; Agonist; Analgesics; Anti-Retroviral Agents; Binding; Brain; CCR5 gene; CXCR4 Receptors; CXCR4 gene; Cells; Clinic; Development; Disease; Drug Combinations; Effectiveness; Enzymes; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV Infections; HIV therapy; HIV-1; Individual; Mediating; Morphine; Motor; Narcotic Antagonists; Neurologic; Neuropathy; Opioid; Opioid Receptor; Pain; Pain management; Pathogenesis; Patients; Pharmaceutical Preparations; Public Health; Receptor Activation; Sensory; Staging; Symptoms; System; Therapeutic; Viral; Virus; base; cell determination; chemokine; chemokine receptor; desensitization; in vivo; interest; mu opioid receptors; nervous system disorder; novel; prevent; receptor; small molecule

DESCRIPTION (provided by applicant): There is a great public health need in finding an efficacious therapy for pain management for HIV- infected individuals. We have shown that both opioid and chemokine receptors can influence each other's functions by heterologous desensitization. Particularly, we have demonstrated that the activation of CXCR4 in the PAG diminishes the analgesic efficacy of morphine (Adler et al., 2006). Based on the fact that gp120 (T- tropic) and a CXCR4 antagonist (e.g. AMD 3100, T40) share the same receptor for their mechanism of action [the gp120 effect (T-tropic) is mediated by its binding to and activation of CXCR4 receptor, and AMD 3100 is an antagonist for this receptor], and the activation of CXCR4 diminishes morphine-induced analgesia (Adler et al., 2006], we propose to investigate whether the blockade of gp120 action on CXCR4 by CXCR4 antagonists will impact the analgesic efficacy of opioid medication. Our hypothesis is that, in addition to its ability to decrease HIV entry into cells, CXCR4 antagonists, by blocking the gp120 utilization of the CXCR4 receptor, can prevent or diminish gp120-induced pain. This occurs via an interaction between CXCR4 and mu-opioid receptors, thus preventing the blocking action that results from the heterologous desensitization of the mu opioid receptor, thereby increasing the analgesic efficacy of opioid medications. In this proposal we will investigate the in vivo consequences of the combined effect CXCR4 antagonists and morphine on gp120-induced pain (AIM#1). Combinations of drugs are frequently used therapeutically to achieve an enhanced effect without using an excess quantity of either drug. Given the recent approval of small chemokine antagonists for treatment of HIV and their ability to prevent HIV from entering cells, the determination of whether the combinations of chemokine antagonists and opioid medication will achieve superior efficacy in managing HIV-related pain is crucial, timely and completely novel. The opportunities for effectively addressing the functional interaction between chemokine antagonists and opioid medications in the presence of HIV-gp120 in the brain is relevant for public health, particularly the field of HIV- related pain and opioids. Ultimately, these studies may provide a rational basis for a therapeutic strategy that targets simultaneously the HIV infection and related pain. ! ! PUBLIC HEALTH RELEVANCE: Finding an efficacious therapy that targets simultaneously the HIV-related pain and HIV infection is of great interest. Combinations of drugs are frequently used therapeutically to achieve an enhanced effect without using an excess quantity of either drug. The opportunities for effectively addressing the functional interaction between chemokine antagonists and opioid medications in the presence of HIV-gp120 in the brain is relevant for public health, particularly the field of HIV-related pain and opioids, and ultimately, these studies may provide a rational basis for a therapeutic strategy that targets simultaneously the HIV infection and related pain.

描述（由申请人提供）：为艾滋病毒感染的个体寻找有效的疼痛治疗疗法有很大的公共卫生需求。我们已经表明，阿片类药物和趋化因子受体都可以通过异源脱敏影响彼此的功能。特别是，我们已经证明了CXCR4在PAG中的激活会降低吗啡的镇痛功效（Adler等，2006）。基于这一事实，即GP120（T-热带）和CXCR4拮抗剂（例如AMD 3100，T40）共享相同的受体，其作用机理[GP120效应（T-Tropic）与CXCR4受体的结合和激活是CXCR4受体的结合和激活，并且AMD 3100是该受体的拮抗剂，以及AMD 3100的拮抗作用。 analgesia (Adler et al., 2006], we propose to investigate whether the blockade of gp120 action on CXCR4 by CXCR4 antagonists will impact the analgesic efficacy of opioid medication. Our hypothesis is that, in addition to its ability to decrease HIV entry into cells, CXCR4 antagonists, by blocking the gp120 utilization of the CXCR4 receptor, can prevent or diminish GP120引起的疼痛是通过CXCR4和MU-Apioid受体之间的相互作用发生的，从而阻止了由MU阿片类受体的异源脱敏的阻塞作用，从而在此提案中逐渐效应的痛苦，我们将在此提高痛苦。 （AIM＃1）。药物的组合经常在治疗上用于实现增强的效果，而无需使用过量的任何一种药物。鉴于小型趋化因子拮抗剂最近批准了治疗HIV的治疗及其预防HIV进入细胞的能力，因此确定趋化因子拮抗剂和阿片类药物的组合是否会在管理HIV相关的疼痛方面获得较高的功效，这是至关重要的，及时的，及时的，并且是完全新颖的。在大脑中HIV-GP120存在下，有效解决趋化因子拮抗剂与阿片类药物之间功能相互作用的机会与公共卫生有关，尤其是与HIV相关的疼痛和阿片类药物领域有关。最终，这些研究可能为同时针对HIV感染和相关疼痛的治疗策略提供了合理的基础。呢呢 公共卫生相关性：找到一种有效的疗法，该疗法同时针对HIV相关的疼痛和HIV感染引起了极大的兴趣。药物的组合经常在治疗上用于实现增强的效果，而无需使用过量的任何一种药物。在大脑中HIV-GP120存在下，有效解决趋化因子拮抗剂与阿片类药物之间功能相互作用的机会与公共卫生有关，尤其是与HIV相关的疼痛和阿片类药物领域有关，最终，这些研究可能为靶向同时靶向HIV HIV感染和相关疼痛的治疗策略提供了合理的基础。