Chronic pain is a debilitating disease with substantial impact on quality of life and, affecting 20% of adults, there is a large and urgent unmet medical need to treat sufferers of chronic pain. Many patients do not get satisfying response from available analgesics because of insufficient pain relief or intolerable side-effects.
Despite extensive efforts, current drug discovery aimed at chronic pain has seen a number of failures in recent years, mainly due to the lack of predictive in vitro models. In order to better envisage target engagement and the effects of candidate compounds it is important to use relevant cell and tissue models as early as possible. With our partners we are using primary dorsal root ganglion (DRG) neurons in culture as cellular models for chronic pain. These neurons retain their sensory functionality and remain responsive to thermal, mechanical and functional stimuli, and when supplemented with nerve growth factor (NGF) they can be used to mimic peripheral pain sensitization.
NGF is critical for growth and survival of DRGs during development, but in adult animals NGF’s primary function appears to be as a mediator of the inflammatory and immune responses following tissue injury. NGF induces hypersensitivity to pain via interaction with its receptors leading to, for example, increased expression of pain-signaling receptors. Since there are several putative ways NGF can sensitize the pain signal, we believe that this is best addressed using a phenotypic assay approach. Relevant novel targets may be identified along a pain pathway including inhibition of NGF-binding receptors or interference with the assembly of ion channel subunits in sensory neurons. Moreover, the trafficking mechanisms of relevant pain targets such as voltage-gated sodium channels may also provide novel targets for the treatment of chronic pain.
Our Discovery Services employ our Cellaxess® Elektra platform to electrically excite 384-well microplate seeded primary cell DRG neurons using an electrode array integrated with an imaging-based microplate analyzer that simultaneously monitors the transient fluorescence response of the sensory neurons. We therefore identify compounds that inhibit peripheral sensitization in DRG neurons with an assay capable of characterizing a medium throughput compound screening library.