ABSTRACT Chronic neuropathic pain, which is one of the most common forms of chronic pain, is a highly prevalent condition that dramatically decreases productivity and quality of life; it is often associated with insomnia, anxiety and depression, and does not respond well to existing treatments with >50% of patients who are refractory to current medications. Additionally, many pain relief medications are highly addictive, and may involve numerous issues with withdrawal and risks of overdosing. In 2017, more than 47,000 Americans died from an opioid overdose, according to the Centers for Disease Control and Prevention, causing a National Emergency. Thus, there is an urgent need to develop non-opioid analgesics to treat chronic neuropathic pain. To date, attempts at developing novel analgesics have been and continue to be hindered by high clinical attrition and cross-species translational difficulties, resulting in lack of efficacy in pivotal Phase II clinical studies. A very promising avenue for advancing pain research is provided by the recently-established possibility of performing of studies directly on human sensory neurons. Functional, electrophysiology-based studies of human nociceptive neurons are now possible, allowing the direct phenotypic screening and drug candidate profiling in human tissue- based assays at the preclinical stage. This approach has the potential to overcome many of the limitations associated with cross-species differences encountered when using animal models of pain for the identification and selection of clinical drug candidates. AnaBios has developed a novel translational drug screening platform for the generation of human-relevant data in preclinical pain drug discovery. Over the past 9 years, we have developed methods that enable the recovery and interrogation of hDRG; these technologies allow for studies aimed at advancing knowledge of basic pain biology as well as supporting drug discovery efforts. For preclinical-stage drug development programs it is critical to assess: 1) the potential of a new drug candidate in human-relevant models; 2) the activity in specific pain states; 3) the potency. Our proposal aims at introducing new in vitro models to enable the assessment of potential analgesic activity, directly on human samples, at early preclinical stages. Specifically, the development and qualification of in vitro models of pathological states associated with pain is a central goal of the proposal. The availability of qualified pathological models will provide a highly valuable tools for advancing the development of new non-addictive drugs for the treatment of pain. The utilization of primary human cells in translational research and drug discovery can provide data that are essential for addressing two critical translational challenges: the selection of the dose for first-in-human studies and, the selection of the appropriate patient population for proof of concept pivotal Phase 2 clinical studies. This proposal w...