Development of an in vitro model of 'pain'

Pathological changes in axonal function are integral features of many neurological disorders, yet our knowledge of the molecular basis of axonal dysfunction remains limited. This is due difficulties in using animal model to study detailed neurophysiology of nociceptors. Nerve injury results in long lasting pain hypersensitivity in animal models of pain. We show that microfluidic chambers can provide unique insight into the axonal compartment independent of the soma and can be used to assay the physiological properties of the axonal and somal compartments. We illustrate the ease and versatility to assay electrogenesis and conduction of action potentials (APs) in naïve, damaged or sensitized (using chemotherapeutic agents for instance) nociceptive axons using calcium imaging at the soma  or patch-clamp electrophysiology for detailed biophysical characterisation. Impact of non-neuronal cells can be readily studied on the co-culture system through additional microfluidic compartments. We further demonstrate adaptability of the system for co-culturing and studying synaptic function between sensory neurons and dorsal horn neurons of the spinal cord.  Hence we describe a novel in vitro platform for the study peripheral pain signalling and as surrogate model for nerve injury and sensitization in animals. We further show the iPSC-derived neurons can be used in this platform and inform major insights into the physiological responses of human neurons to injury.

This toolbox can have significant advantages over in vivo models in deciphering intricate molecular relationships underpinning pain hypersensitivity. As such it has immense potential to impact replacement of animal models in pain research.