An Ex-Vivo Human Model of Inflammatory Pain for Enabling Translational Research and Drug Discovery

The incomplete understanding of chronic neuropathic and inflammatory pain mechanisms poses a major challenge for the development of new, non-addictive pain medications. Cross-species differences in pharmacological responses and analgesic effects lead to poor translation of preclinical animal models to clinical studies in humans. We have developed methodologies for the isolation of human sensory neurons, from organ donors, which allow for ex-vivo studies of sensory neurons physiology and pharmacology. The cells remain phenotypically stable for up to 14 days in culture and can be used to assess pharmacological responses by employing imaging- or electrophysiology-based methods. Here we present a novel preclinical discovery strategy, which utilizes human sensory neurons to establish cellular models of pathological states. In this model, we recapitulate inflammatory conditions by incubating human sensory neurons with pro-inflammatory agents (PGE2 and bradykinin) for 72 hrs. This treatment induced changes in neuronal excitability and in the nociceptive profile of human sensory neurons. Indeed, sensory neurons showed increased excitability, heightened responsiveness to TRPV1 agonists and increased expression of TTX-resistant voltage gated sodium channels. These changes are consistent with phenotypes of inflammatory pain observed in the clinic. Furthermore, we demonstrated that this cell-based model can be used to differentiate the effects of analgesic drugs that have demonstrated varying degree of success in clinical trials with patient populations affected by different pain indications. This approach demonstrates high potential for ranking drug candidates based on potential analgesic efficacy and for predicting the most appropriate pain indication for clinical trial development. The research presented was sponsored by AnaBios Corporation.