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

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.PROJECT NARRATIVE The Aim of this proposal is to provide proof-of-principle that a novel technology predicated on pre-clinical studies will ameliorate anxiety and craving associated with the opioid use and abuse. The rationale for this proposal is predicated on the belief that non-invasive, non-pharmacological activation of peripheral mechanoreceptors by focused mechanical stimulation modulates brain substrates dysregulated by opioid use disorder. Our novel technology has much promise to target the brain mechanisms underlying the recreational use and abuse potential of opioids and its development will pave the way for more effective, personalized treatment strategies that could reverse dependence on these drugs and save lives and resources throughout the world.