Title: Exploration of human C-nociceptor pathophysiology
Funder: The Academy of Medical Sciences

Abstract: Aim: To develop C-nociceptor microneurography into a mechanism-based tool to stratify patients with chronic pain. Objectives: 1. Sensitise nociceptor transduction to cause on-going activity analogous to that seen in chronic pain states. Test whether this sensitisation can be detected by applying my novel heat–electrical co-stimulation protocol. 2. Reverse translate the co-stimulation technique to the mouse skin-nerve preparation to enable application of established pharmacological agents to explore mechanisms of transduction and sensitisation in pain models. This approach will demonstrate whether the two parallel protocols (human and mouse) are viable on-target biomarkers for development of novel pharmacology. Background There is mounting evidence of spontaneous C-nociceptor activity in the pathology of a diverse range of conditions generating chronic pain. Stratification of neuropathic pain patients into groups with spontaneous activity or not (using quantitative sensory testing as a proxy) has been shown to have implications for treatment success (Demant et al 2014). The hypothesis therefore appears sound, but a definitive diagnostic test to identify and, importantly, to determine the cause of spontaneous activity is lacking. Microneurography can directly identify this abnormal C-nociceptor activity (Orstavik et al 2010, Kleggetveit et al 2012, Evdokimov et al 2019). I have developed a co-stimulation protocol that I hypothesise will enable not only detection of C-nociceptor on-going activity but also dissection of the mechanisms of that sensitisation. This proposal will test this hypothesis in a pain model in healthy volunteers and a rodent model, enabling forward and reverse translation, mechanistic insight and, eventually, stratification for pain management.

Lay abstract: Pain normally serves to protect and allow healing. Pain which lasts beyond the time taken for healing does not provide these benefits. It then becomes a disease in its own right. Unfortunately, chronic pain is very difficult to treat. The normal “pain message” starts in nerves that supply the skin and other tissues. These nerves that detect painful insults are called nociceptors. We can record nerve activity in nociceptors using a technique called microneurography. Such recordings have revealed that in many different forms of chronic pain, there is abnormal on-going activity in these nociceptors (they are normally silent in health). Being able to detect this abnormal activity in patients could, in itself, be important for determining the best management options. I propose to expand the scope of microneurography to examine if it can be used to determine why that nociceptor has abnormal activity. I propose to do this by using a technique that I have developed and perform regularly in healthy volunteers. In the first instance, I propose to transfer this technique to a model of chronic pain in healthy volunteers – this is via the application of cinnamon extracts to the skin. In parallel I will use exactly the same approach in a mouse model - establishing a method allowing detailed assessment of mechanisms and testing of newly developed drugs. A better understanding of why this abnormal activity arises could help both to choose the best treatments for patients and to develop new drugs to rectify it.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL