PROJECT SUMMARY/ABSTRACT Opioid use disorder (OUD) is a rising problem, not only in the United States, but across the globe, with pain and stress being a major factor for initial drug seeking and relapse. Over the past decade, OUD has reached epidemic proportions, in part due to inappropriate use of prescription opioid pain killers. 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. The current FDA-approved treatments for OUD include pharmacological and various types of counseling and behavioral therapies. As many consider pharmacological treatments to be woefully inadequate, the public is in desperate need of more efficacious treatments for OUD. Only two devices are currently FDA approved to treat OUD, which has prompted NIDA to issue a parent announcement, RFA-DA-24-038, to develop device technologies to curb the opioid epidemic. This proposal aligns with this initiative to further the development of a novel, non-pharmacological whole body vibration (WBV) device to treat anxiety/craving and opioid use associated OUD. We have reported that selective activation of specific spinal mechanoreceptors (MRs) for 1-2 min 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 for hours. We have recently reported that WBV in rodents, at the same frequencies that are optimal for cervical spine mechanoreceptor activation, ameliorates neuronal, neurochemical, and behavioral effects of alcohol dependence, including anxiety, and we will show preliminary evidence that WBV ameliorates the same measures in opioid dependence in rodents. Additionally, we present preliminary evidence that our novel technology, termed heterodyned WBV (HWBV), at the same frequencies informed by rodent students reduces generalized anxiety and, in a prior NIH-sponsored Phase I study, anxiety associated with OUD. The objective of this proposal is to evaluate the translational relevancy of these pre-clinical and clinical findings to treat OUD with a de novo device along the FDA clearance pathway. We propose three Specific Aims in Phase I (Yr 1) that involve: 1) improvement of technical aspects of the device, evaluation of physiological indices of anxiety, implementation of telemetry to control and record from the device; 2) evaluation blood catecholamines and leukocyte DA D2 receptors (D2Rs) in drug- free student volunteers following acute and chronic anxiety and creation of a normative database; and 3) engagement with the FDA for creation of a commercial prototype for de novo device clearance. We propose two Specific Aims in Phase II (Yrs 2-4) that involve: 1) evaluation of the effects of HWBV vs sham treatment ...