Amelioration of opioid withdrawal-induced anxiety and craving with heterodyned whole body vibration

项目总结 阿片类药物使用障碍(OUD)在美国和世界各地是一个日益严重的问题，伴随着疼痛和压力 是初次寻求毒品和复发的主要因素。中脑边缘多巴胺系统起源于 中脑腹侧被盖区(VTA)投射到纹状体的伏核(NAC)是一种 阿片类药物和其他成瘾药物的回报特性的重要联系，并与 奥德。目前只有两种设备被FDA批准用于治疗OUD，这促使NIDA向父母发放了 宣布，RFA-DA-19-020与Hear倡议有关，以开发遏制阿片类药物的技术 流行病。这项提议与Hear Initiative和NIDA保持一致，以进一步开发一种新颖的、非 药理、外差全身振动(HWBV)装置治疗与焦虑/渴望相关的 奥德。在以前的研究中，我们已经报道了通过机械刺激激活机械感受器 45-80赫兹频率的颈椎抑制VTA-GABA神经元的活动，增强 DA神经元的活动，并随后通过内源性阿片类药物和Delta增加NAC中DA的释放 在NAC的ORS(DORS)。我们的初步数据表明，啮齿动物的全身振动(WBV)， 在同样的频率下，对于颈椎机械感受器的激活是最佳的，改善神经元， 酒精依赖的神经化学和行为影响，在范围和机制上类似于 阿片类药物依赖。此外，我们使用一种新的外差(HWBV)技术展示了初步证据 由两个独立的致动器组成，它们以不同的频率振动，从而产生低频率 传播到全身的行波。我们提供了初步证据表明这次旅行， 干扰波可改善戒毒受试者的焦虑。这项提议的目标是开发一种 无毒品受试者的标准数据库，精炼参数，遥测和主动振动控制 HWBV技术，并评估我们的临床前研究结果与OUD治疗的翻译相关性。其核心是 假设HWBV将改善与慢性戒断相关的焦虑/渴望 阿片类药物的使用。我们在第一阶段提出了两个具体目标，这两个目标涉及翻译研究，这些研究由我们的预 在啮齿动物和人类身上进行的临床研究。目标1涉及振动目标的持续发展 HWBV装置与无毒非吸毒者最佳治疗参数规范化数据库的建立 和受试者。目的2评估HWBV在男性和女性OUD患者中的效用。 该地区的治疗设施，以缓解焦虑/渴望作为治疗OUD的一种方法。PhotoPharmics，Inc. 与杨百翰大学的研究人员合作，提议进行系统研究，以提供持续的 HWBV在治疗与OUD相关的焦虑/渴望方面有效的原则证明。我们计划提交一份 第二阶段提案，目标是制造更多系统并完成FDA批准的临床 由100多人组成的试验是为了进一步完善系统以实现商业化。

PROJECT SUMMARY Opioid use disorder (OUD) is a rising problem in the United States and around the world, with pain and stress being major factors for initial drug seeking and relapse. The mesolimbic dopamine (DA) system originating in the midbrain ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) in the striatum is an important nexus for the rewarding properties of opioids and other addictive drugs and is strongly implicated in OUD. Only two devices are currently FDA approved to treat OUD, which has prompted NIDA to issue a parent announcement, RFA-DA-19-020 connected with the HEAL Initiative to develop technologies to curb the opioid epidemic. This proposal aligns with the HEAL Initiative and NIDA to further the development of a novel, non- pharmacological, heterodyned whole body vibration (HWBV) device to treat anxiety/craving associated with OUD. In prior studies, we have reported that activation of mechanoreceptors with mechanical stimulation of cervical spine vertebrae at a frequency of 45-80 Hz inhibits the activity of VTA GABA neurons, enhances the activity of DA neurons, and subsequently increases DA release in the NAc via endogenous opioids and delta ORs (DORs) in the NAc. We show preliminary data demonstrating that whole body vibration (WBV) in rodents, at the same frequencies that are optimal for cervical spine mechanoreceptor activation, ameliorates neuronal, neurochemical, and behavioral effects of alcohol dependence, which is similar in scope and mechanism to opioid dependence. Additionally, we show preliminary evidence using a novel heterodyned (HWBV) technology consisting of two independent actuators vibrating at different frequencies that generate a low frequency traveling wave that propagates throughout the body. We show preliminary evidence that this traveling, interferential wave ameliorates anxiety in drug-free subjects. The objectives of this proposal are to develop a normative database in drug-free subjects, refine parameters, telemetrics, and active vibration control of the HWBV technology and evaluate the translational relevancy of our pre-clinical findings to treat OUD. The core hypothesis is that HWBV will ameliorate the anxiety/craving associated with withdrawal from chronic opioid use. We propose two Specific Aims in Phase I that involve translational studies informed by our pre- clinical studies in rodents and humans. Aim 1 involves the continued development of a vibration targeting HWBV device and the creation of a normative data base of optimized treatment parameters in drug-free non- AUD subjects. Aim 2 involves the evaluation of the utility of HWBV in male and female persons with OUD at treatment facilities in the area to ameliorate anxiety/craving as a treatment for OUD. PhotoPharmics, Inc in collaboration with investigators at Brigham Young University, proposes systematic studies to provide continued proof-of-principle that HWBV is effective in treating anxiety/craving associated with OUD. We plan to submit a Phase II proposal with the objective to manufacture more systems and complete an FDA-approved, clinical trial consisting of 100+ persons with OUD to further refine the systems towards commercialization.