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）：寻找一种有效的治疗HIV感染者疼痛的方法是一项巨大的公共卫生需求。我们已经证明阿片受体和趋化因子受体可以通过异源脱敏相互影响对方的功能。特别是，我们已经证明PAG中CXCR4的激活会降低吗啡的镇痛效果（Adler et al., 2006）。基于gp120 （T向性）和CXCR4拮抗剂（如AMD 3100、T40）在作用机制上具有相同的受体[gp120效应（T向性）是通过其与CXCR4受体的结合和激活介导的，而AMD 3100是该受体的拮抗剂]，并且CXCR4的激活会减弱吗啡诱导的镇痛作用（Adler等，2006），我们拟研究CXCR4拮抗剂阻断gp120对CXCR4的作用是否会影响阿片类药物的镇痛效果。我们的假设是，除了能够减少HIV进入细胞外，CXCR4拮抗剂通过阻断gp120对CXCR4受体的利用，可以预防或减少gp120诱导的疼痛。这是通过CXCR4与mu-阿片受体的相互作用发生的，从而阻止了mu-阿片受体的异源脱敏导致的阻断作用，从而提高了阿片药物的镇痛效果。在本提案中，我们将研究CXCR4拮抗剂和吗啡联合作用对gp120诱导的疼痛的体内影响（AIM#1）。药物组合经常用于治疗，以达到增强的效果，而不使用过量的药物。鉴于最近小的趋化因子拮抗剂被批准用于治疗HIV及其阻止HIV进入细胞的能力，确定趋化因子拮抗剂和阿片类药物的组合是否会在治疗HIV相关疼痛方面取得更好的疗效是至关重要的，及时的和完全新颖的。在大脑中存在HIV-gp120的情况下，有效解决趋化因子拮抗剂和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领域。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合理的基础。！ ！