DECIPAIN · An integrated approach towards drug discovery and target validation for pain

An integrated approach towards drug discovery and target validation for pain

The social and economic burden associated with persistent pain is comparatively greater than for most other health conditions and is expected to grow even more in future due to population ageing. Drug discovery for novel pain therapeutics relies almost exclusively on in vivo and ex vivo animal preparations. These experimental models offer the advantage of maintaining the nociceptive circuits structurally and functionally intact, allowing to investigate transmission and modulation of somatic and visceral pain from nerve terminals to the central nervous system. On the other hand they require a very high number of animals to obtain statistically significant amount of data. To fill this gap and reduce the number of animals used for the development of new analgesics, DECIPAIN aimed to develop a novel in vitro assay allowing screening of identified ion channel blockers for their functional efficacies at primary sensory neurons, one of the main sites of action of analgesics in vivo. Development of such cell-culture based high-throughput assay was based on the combination of microfluidics and microelectrode fabrication into a single device. This allowed the functional examination of nociceptive pathways and the non-invasive recording of action potential initiation and conduction in vitro along specific neuronal compartments. This new approach has the potential to provide a platform that enables parallel recording of high quality data from thousands of neurons from each single animal preparation. Compared to current techniques, which provide only a few recordings / data points for each animal, this represents at least 100 times more data, an improvement that will lead to a similar reduction in the number of animals required. Once completed and fully validated, such “Pain-on-a-chip” approach will also enable the use of human nociceptive neurons derived from induced pluripotent stem (iPS) cells, as soon as they become available in sufficient quality and number. This will provide an accelerated approach for elucidating peripheral and central pain pathways and identifying novel targets for preclinical pain research while completely avoiding the use of animals. The work initiated under DECIPAIN has fostered a number of new collaborations and international grants, many of which focusing on the development of alternative methods to animal research. This theme of great value to a number of public and private stakeholders. Therefore, despite the major re-adjustment required to DECIPAIN work program, originally conceived as an in vivo animal-based technology development project, a number of important achievements were rapidly obtained suggesting that a clear alternative to animal research was available and needed to be further developed. Ultimately, the need to contribute to such novel and fast-moving research area played an essential role in supporting the promotion of the Researcher at the Host Institute as Head of a newly established Neuro Microphysiological Systems Group, a position awarded on a permanent base.

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