Pain Pathophysiology and Pharmacology

Physiology and Biophysics: We have world-class expertise in this area, including, unparalleled experience, and unique databases of wildtype and variant sodium channels for each of the pain-related channels. We have developed and validated electrophysiological protocols for evaluation, at both the channel and cellular levels, of each of the sodium channel isoforms. Our Center houses seven electrophysiological rigs (voltage-clamp, current-clamp, dynamic clamp) for manual recording, three automated recording platforms, and a multi-electrode array set up, all staffed by highly trained physiologists. A computational facility within this core provides expertise in the construction of computational models (e.g., dynamic clamp), a unique resource for studying sodium currents in native neurons, and in differentiated neurons from patient-specific iPSCs, and mammalian stable cell lines.

Pharmacology and Pharmacogenomics: We have implemented a pharmacogenomics approach, combining structural modeling and in vitro pharmacology to transform treatment of neuropathic pain from ‘trial-and-error’ to success ‘first-time-around’. Using this approach, we have predicted the clinical efficacy of existing and novel sodium channel blockers in individuals carrying several sodium channel variants. These studies have provided proof-of-principle that pharmacogenomically-guided pain pharmacotherapy is achievable. We are poised to assess the potential of a large repertoire of existing drugs in a similar manner. The recent addition of an 8-channel Patchliner robot adds to our throughput.

High-Throughput Investigations of Pain Pathophysiology: Our Center has developed high-throughput platforms to rapidly analyze sodium channel variants and determine their effect on excitability of pain-signaling neurons, and identify new agents that are most likely to be effective in the context of a given patient’s unique genetic profile. Traditional patch-clamp recordings of neurons are time consuming, and do not permit repeated exposure of neurons to different treatments. Our high-throughput platforms (Patch Express, Patchliner, Ion Flux) are paralleled by methods that utilize calcium indicator dyes to optically measure intracellular calcium transients for rapid, repeat, and simultaneous examinations of excitability of large numbers of DRG neurons including neurons expressing pain-associated sodium channel variants and multi-electro arrays that permit in-depth assessments of sensory neurons under conditions that mimic disease experienced in patients, and in response to pharmacotherapy.