There has been considerable interest in the mechanisms that underpin neuropathic pain, and observations in experimental animals and patients have demonstrated that both peripheral nociceptors and central pain-signalling circuits become hyper-excitable in these states. One of the major surprises to have emerged over the last decade is that in experimental models of neuropathic pain non-neuronal cells play a very active role in the development of sensory abnormalities. In particular, multiple studies have demonstrated a critical role for a number of glial cells, most prominently spinal microglia, but also Schwann cells of the peripheral nervous system and in some cases spinal astrocytes. The importance of these mechanisms in clinical neuropathic pain states is difficult to assess for technical reasons, but evidence is now emerging from PET studies that central glia are activated in chronic pain patients.
What is less clear is exactly how glial cells induce the hyper-excitable state in pain-signalling neurones. Several candidate mechanisms have been proposed on the basis of preclinical studies. These include the release of classical inflammatory cytokines (IL1b, TNFa, IL6) from glial cells; the release of BDNF by activated microglia; the activation of glial cells by neuregulin acting on Erb receptors, or by ATP acting on P2X receptors, or the chemokines CCL2 or CCL21 acting on their cognate receptors. Most recently CSF1 released from damaged sensory nociceptors has been implicated in driving abnormal glial responses via the adaptor protein DAP12 (Guan et al., 2016). The majority of these mechanisms have been identified in animal models of neuropathic pain associated with traumatic nerve injury. While such injuries do cause neuropathic pain in humans, they account for only a very small number of cases. This proposal therefore aims at exploring neuron-glial interactions in forms of neuropathic pain more commonly found in the clinic, such as chemotherapy-induced pain.
A need for better clinical outcomes has also heightened interest in the use of physiologically relevant human cells in the drug discovery process. Human induced pluripotent stem cells (hiPSC) may offer a relevant, robust, scalable, and cost effective model of human disease physiology. Combined with cell-based high-content screening (HCS) assays they could become an extremely attractive alternative to traditional in vitro testing in pharmaceutical drug development. Small molecules could be screened in a high-throughput fashion in a clinically relevant system to identify novel therapeutic compounds with maximum efficiency. Currently this system still remains to be widely adopted, primarily because deriving sensory neurons and glial cells from hiPSC is challenging, as is combining them with high throughput screening technologies HCS. Our team of experts is in a unique position to overcome these final hurdles and put this transformative technology to use for the screening of novel analgesics.