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: 8266369
• 负责人: Khalid Benamar
• 金额: $ 15.3万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266369
• 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. ! !

描述（由申请人提供）：在寻找用于HIV感染个体的疼痛管理的有效疗法方面存在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来影响彼此的功能。特别地，我们已经证明PAG中CXCR 4的活化降低了吗啡的镇痛功效（Adler等人，2006年）。基于gp 120（T-嗜性）和CXCR 4拮抗剂（例如AMD 3100、T40）对于它们的作用机制共享相同受体的事实[gp 120效应（T-嗜性）由其与CXCR 4受体的结合和活化介导，并且AMD 3100是该受体的拮抗剂]，并且CXCR 4的活化减少吗啡诱导的镇痛（Adler等人，2006]，我们建议研究CXCR 4拮抗剂对gp 120对CXCR 4作用的阻断是否会影响阿片类药物的镇痛功效。我们的假设是，除了其减少HIV进入细胞的能力之外，CXCR 4拮抗剂通过阻断CXCR 4受体的gp 120利用，可以预防或减少gp 120诱导的疼痛。这是通过CXCR 4和μ阿片受体之间的相互作用发生的，因此防止了μ阿片受体的异源脱敏引起的阻断作用，从而增加了阿片类药物的镇痛功效。在本提案中，我们将研究CXCR 4拮抗剂和吗啡对gp 120诱导的疼痛的联合作用的体内结果（AIM#1）。药物的组合经常在治疗上使用以实现增强的效果，而不使用过量的任一药物。考虑到最近批准用于治疗HIV的小趋化因子拮抗剂及其防止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将在管理HIV相关疼痛中实现上级功效是至关重要的、及时的和完全新颖的。在脑中存在HIV-gp 120的情况下，有效解决趋化因子拮抗剂和阿片类药物之间的功能性相互作用的机会与公共卫生相关，特别是与HIV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。! !