Chronic pain is the single biggest global disease burden. Chronic pain conditions originate after periods of intense neuronal activity but the cellular and molecular mechanisms underlying nociception, particularly the transition from acute to chronic pain, are not well understood. Nociceptive circuits are complex and involve interplay between several different neuron types. This complexity is difficult to model with current in vitro models and studies of nociception typically rely on in vivo systems. However, there have been issues with animal models accurately predicting clinical efficacy of analgesics.
Why we funded it
This PhD Studentship aims to reduce the requirements of animal models in the study of nociception by developing a compartmentalised microfluidic cell culture system.
An in vivo study of a behavioural test of nociceptive function comparing a single dose of a candidate drug to a control group requires approximately 20 rats. A hypothetical study of 15 different experimental conditions, for example screening 15 different drugs, would therefore typically require approximately 300 rats. The microfluidic systems developed in this proposal have the potential to reduce the number of rats required by 90%, reducing the rats needed for the aforementioned hypothetical study from 300 to 30.
Nociceptive circuits extend from the central nervous system (CNS) to the periphery, connecting a multitude of target tissues to the CNS. Sub-cellular compartments of the nervous cells are separate and exist in differing environments, for example the cell body is in the dorsal root ganglion whereas the terminals are in either the CNS or in peripheral tissues. This compartmentalisation and the polarisation of the nociceptive circuits are not currently reflected in in vitro models. This proposal uses a compartmentalised microfluidic system to allow the culturing of primary neurons isolated from rat embryos whilst retaining the morphological development seen in vivo. Embryos isolated from one rat are able to generate enough neurons to culture in ~30 microfluidic chambers. Once developed, this system will be used to determine the role of microRNA (miRNA) regulation in the transition from acute to chronic nociception. The microfluidic system has the capacity to allow investigation of novel molecular mechanisms in addition to the potential for screening of compounds in pain research.