Novel application of pharmaceutical AMD3100 to reduce risk in opioid use disorder: investigations of a causal relationship between CXCR4 expression and addiction vulnerability

药物 AMD3100 降低阿片类药物使用障碍风险的新应用：CXCR4 表达与成瘾脆弱性之间因果关系的研究

• 批准号: 10678062
• 负责人: Elizabeth Smedley
• 金额: $ 6.95万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2026-08-21
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678062
• 关键词: AMD3100; Abstinence; Address; Affect; American; Analgesics; Animal Model; Behavior; Behavioral; Binding; Brain; CXCR4 Receptors; CXCR4 gene; Cells; Chronic; Clinical; Cocaine; Combination Medication; DSM-V; Data; Diagnosis; Disease; Disseminated Malignant Neoplasm; Dose; Dropout; Drug Modelings; Drug Prescriptions; Extinction; FDA approved; Female; HIV; Hematopoietic Stem Cell Mobilization; Heroin; Hyperalgesia; Immune response; Incubated; Individual; Inflammation; Inflammatory; Intervention; Intraperitoneal Injections; Investigation; Ligands; Maintenance; Modeling; Morphine; Motivation; Neuroimmune system; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Receptor; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Prefrontal Cortex; Prevention; Prevention strategy; Property; Quality of life; Rattus; Recovery; Relapse; Rewards; Risk; Risk Reduction; Role; Saline; Self Administration; Sex Differences; Signal Transduction; Signaling Molecule; Stromal Cell-Derived Factor 1; Substance Use Disorder; Sucrose; System; Testing; Therapeutic; Tissues; Translating; Trauma; Treatment outcome; Update; Ventral Tegmental Area; Viral; Withdrawal Symptom; Work; abuse liability; addiction; adherence rate; antagonist; antinociception; blood-brain barrier crossing; brain reward regions; brain tissue; cancer therapy; chemokine; chemokine receptor; combat; craving; desensitization; dopaminergic neuron; drug craving; drug misuse; efficacy testing; experimental study; heroin use; illicit opioid; improved; improved outcome; interest; male; medication-assisted treatment; mu opioid receptors; novel; novel therapeutics; opiate tolerance; opioid epidemic; opioid use; opioid use disorder; pain perception; pain relief; prolonged abstinence; protein expression; public health relevance; receptor; receptor expression; response; reward circuitry; tool

Project Summary/Abstract In 2020, 2.7 million Americans met the criterion for opioid use disorder but only 11.2% of those affected were treated with medication-assisted treatment (MAT), despite it being the gold-standard in treatment for opioid use disorder. Even for those who are prescribed MAT, adherence rates are poor and relapse rates are high along with increased risk of diversion and misuse of medication. There is a clear and pressing need to explore alternative therapeutics to expand options and improve outcomes for opioid use disorder. A promising avenue to exploit is the relationship between part of the neuroimmune system called the chemokine system, and the opioid system. Chemokines are inflammatory molecules primarily known for their role in orchestrating an appropriate immune response to inflamed tissue but also engage in crosstalk with the opioid system. Not surprisingly, the chemokine system and opioid system interact as inflammation and pain responses are often co-occurring, such as with physical trauma. Evidence suggests that activation of chemokine receptors can desensitize mu-opioid receptors and reduce opioid-induced antinociception. These findings are critical since the sensitization of opioid receptors is related to behavioral effects such as opioid tolerance and opioid induced hyperalgesia or increased pain after extended opioid use. Drugs that inhibit the binding of chemokines to their receptors, chemokine receptor antagonists (CRAs), are presently available for clinical use in HIV and the mobilization of hematopoietic stem cells in cancer treatment. Early evidence suggests that CRAs, while alone do not produce any pain-relieving qualities, have the ability to enhance the analgesic effects of opioids and make lower doses of opioids more effective. While the effects on pain perception alone are exciting, the impact of CRAs on motivation to consume opioids has not been studied. Of particular interest is AMD3100, a CRA that binds to CXCR4, blocking its natural ligand CXCL12 which both are present along canonical reward circuitry in the brain including the nucleus accumbens (NAc) and ventral tegmental area (VTA). Recent data from our lab shows CXCR4 protein expression in the VTA is increased following chronic morphine exposure. The experiments presented below investigate the ability for AMD3100 to reduce heroin self-administration in males and females (Aim 1) and heroin seeking/relapse behaviors (Aim 3) while examining the role of CXCR4 expression in dopaminergic neurons within VTA (either enhanced or reduced expression) to modify heroin taking (Aim 2).

项目总结/摘要 2020年，270万美国人符合阿片类药物使用障碍的标准，但只有11.2%的人受到影响 接受药物辅助治疗（MAT），尽管它是治疗的金标准， 阿片类药物使用障碍即使对于那些谁是规定MAT，坚持率是穷人和复发率是 高沿着转移和滥用药物的风险增加。显然迫切需要 探索替代疗法，以扩大选择并改善阿片类药物使用障碍的结局。 一个有希望利用的途径是神经免疫系统中称为“免疫球蛋白”的部分之间的关系。 趋化因子系统和阿片系统。趋化因子是炎症分子，主要以其 在协调对发炎组织的适当免疫反应中的作用，但也参与与炎症组织的串扰。 阿片系统毫不奇怪，趋化因子系统和阿片系统相互作用，导致炎症和疼痛 这些反应通常是同时发生的，例如与身体创伤同时发生。有证据表明， 趋化因子受体可使μ-阿片受体脱敏并减少阿片诱导的抗伤害感受。这些 这些发现是至关重要的，因为阿片受体的致敏作用与行为效应有关， 耐受性和阿片样物质诱导的痛觉过敏或延长阿片样物质使用后疼痛增加。药物抑制 趋化因子与其受体的结合，趋化因子受体拮抗剂（CRA），目前可用于 在HIV中的临床应用以及在癌症治疗中动员造血干细胞。早期证据 表明，CRA，虽然单独不产生任何缓解疼痛的品质，有能力提高 阿片类药物的镇痛作用，并使较低剂量的阿片类药物更有效。虽然对疼痛的影响 尽管仅凭感知是令人兴奋的，但CRA对消费阿片类药物动机的影响尚未研究。的 特别感兴趣的是AMD 3100，一种结合CXCR 4的CRA，阻断其天然配体CXCL 12，两者都是 存在沿着典型的奖励回路在大脑中，包括核丘脑（NAc）和腹侧 被盖区（VTA）。我们实验室的最新数据显示，VTA中CXCR 4蛋白表达增加， 是因为长期接触吗啡以下实验研究了AMD 3100 减少男性和女性的海洛因自我服用（目标1）和海洛因寻求/复吸行为（目标3） 在研究腹侧被盖区多巴胺能神经元中CXCR 4表达的作用时（无论是增强的还是 减少表达）以改变海洛因服用（目的2）。