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

项目摘要/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 阿片类药物使用障碍。即使是那些服用处方垫的人，依从率也很低，复发率也很低。 高，同时增加了转移和滥用药物的风险。有一种明确而紧迫的需要 探索替代疗法，以扩大阿片类药物使用障碍的选择和改善结果。 一个很有希望开发的途径是神经免疫系统的一部分，称为 趋化因子系统和阿片系统。趋化因子是一种炎性分子，主要因其 在协调对炎症组织的适当免疫反应中的作用，但也参与了与 阿片系统。毫不奇怪，趋化因子系统和阿片系统作为炎症和疼痛相互作用。 反应通常是同时发生的，比如身体创伤。有证据表明，激活 趋化因子受体可使u-阿片受体脱敏，减少阿片类药物诱导的抗伤害作用。这些 这些发现是至关重要的，因为阿片受体的敏化与阿片类药物等行为效应有关 耐受性和阿片类药物在长期使用阿片类药物后引起痛觉过敏或疼痛增加。抑制肿瘤细胞生长的药物 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 HIV的临床应用和造血干细胞动员在癌症治疗中的应用。早期证据 这表明，尽管CRA本身不能产生任何缓解疼痛的品质，但它有能力增强 阿片类药物的止痛作用，使较低剂量的阿片类药物更有效。虽然对疼痛的影响 知觉本身是令人兴奋的，但CRA对阿片类药物消费动机的影响尚未被研究。的 特别令人感兴趣的是AMD3100，一种与CXCR4结合的CRA，阻断其天然配体CXCL12，两者都是 存在于大脑中的典型奖赏回路，包括伏隔核(NAC)和腹侧 被盖区(VTA)。我们实验室的最新数据显示，VTA中CXCR4蛋白的表达增加 在长期使用吗啡后。下面提供的实验研究了AMD3100的能力 减少男性和女性的海洛因自我管理(目标1)和海洛因寻觅/复吸行为(目标3) 在检测CXCR4在VTA内的多巴胺能神经元中的表达时(无论是增强的还是 减少表达)以改变吸食海洛因(目标2)。

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).