Unravelling dorsal root ganglion as an intrinsic filtering device

Lead Research Organisation: University of Leeds
Department Name: School of Biomedical Sciences

Abstract

Pathological pain continues to constitute an enormous yet unresolved health problem. Despite centuries of research and investment, the precise mechanistic understanding of numerous pathological pain conditions remains incomplete and opioids (such as morphine) are still a 'gold standard' in analgesia. Accordingly, many types of pain (such as chronic arthritis pain, migraine, neuropathic and cancer pains) are particularly difficult to treat since most of the conventional pain-killers either do not relieve such pain or have serious side-effects.

In order to perceive and evaluate our environment, humans are equipped with peripheral nerves (peripheral somatosensory system). These nerves run through our body and collect information about rigidity, warmth and chemical composition of the surrounding milieu and also about our own body's integrity. Specific 'damage-sensing' nerves (nociceptors) are responsible for generating pain sensation. In order to understand and treat pain we need a better understanding of the mechanisms of how nociceptive nerve fibers conduct signals from the periphery to the central nervous system (CNS) where the perception of pain is formed. We have discovered that there is a structure within each nerve that can limit how much of 'pain' signal is delivered to CNS. These microscopic 'filters' may hold a key to our ability to block these signals off so that they do not reach the brain. This project is focused on deciphering how these 'signal filters' work, with an ultimate goal to leveraging these to provide new ways to relieve pain in a range of debilitating conditions. Our preliminary work established that such filtering is robust in nerves that deal with pain specifically but less so in other sensory nerves. However, hardly anything is known about the overall principles of how these filters work, why they work differently in nerves of different type or how this filtering changes in chronic pain conditions. Our project attempts to answer these intriguing questions through three specific aims:

i) Obtain detailed information on the design of these filters in sensory nerves of different types.
ii) Create biologically realistic computer models for the filtering process in different nerves.
iii) Test how such filtering is altered in preclinical models of chronic pain due to nerve injury.

To achieve the above aims we have developed a comprehensive and multidisciplinary approach which combines cutting-edge biology approaches, such as what is called light-sheet microscopy allowing to look deep into animal tissue, in vivo studies and extensive computer modelling. We are confident that this research will bring new understanding of human sensory systems and, particularly, of chronic pain mechanisms. Importantly, our findings may shape new approaches for analgesic drug development and effective pain management, thus having significant benefit for individuals who suffer from chronic pain conditions

Technical Summary

This project builds on our recent discovery that spinal somatosensory ganglia actively filter peripherally-born action potentials traveling along sensory nerves to the CNS. We aim to answer three main questions: i) how peripheral nociceptive input is filtered by the spinal ganglia; ii) why this filtering is more efficient in nociceptive nerve fibers as compared to those transmitting non-pain-related sensory inputs; iii) how this filtering changes with the development of chronic neuropathic pain. Our ultimate goal is to unravel basic principles of ganglionic filtering in order to develop new or improve existing therapeutic interventions. We will use iDISCO tissue clearing and light sheet microscopy in combination with genetic labelling of DRG neurons with defined and distinct sensory modalities to obtain accurate morphometry of the DRG-localised segments of the fibers. This will be further supplemented by generating a database of biophysical parameters of different fiber types obtained by electrophysiology. These measurements will generate parameters for realistic computational modelling of the t-junctional filtering in different types of afferent fibers. We will then use mouse neuropathic pain models in combination with in vivo electrophysiological recordings to directly measure changes in filtering efficiency in neuropathic animals. We will integrate these data with the computational modelling to obtain comprehensive understanding of the effect of neuropathy on peripheral pain processing. Fulfilling our research aims will identify basic principles of transmission of sensory signals through the spinal ganglia and how this transmission changes in chronic pain; ultimately this research will inform current and future therapeutic interventions for treatment/control of chronic pain.

Publications

10 25 50