A cluster of nerve cells just outside the spinal cord—the dorsal root ganglia—can block pain signals before they reach the brain, and a new experimental setup lets scientists watch that process happen in real time. Chronic pain affects roughly one in three people worldwide, yet existing treatments often fail or carry serious risks, such as opioid addiction. The problem is that researchers lack both a clear understanding of how pain signals are controlled and good laboratory models to study them. This project tackles both gaps. The team has already shown that the dorsal root ganglia act as a peripheral gate, regulating how much pain information travels to the central nervous system. They have also built a reduced, anaesthetised preparation—called DAPP—that allows precise electrical and computational measurement of these signals without relying on behavioural tests in animals. If successful, this work will clarify how the dorsal root ganglia control pain, both in healthy states and in chronic pain. It will also provide a scientific basis for DRG neuromodulation, an existing but poorly understood clinical technique that uses implanted electrodes to stimulate the ganglia. The project could lead to safer, non-opioid pain therapies and more effective stimulation protocols, ultimately improving treatment for millions of people.
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Chronic pain is a debilitating condition that affects up to a third of the world’s population. This not only brings suffering to people affected by the condition but also costs our economies billions in healthcare costs, lost productivity etc. Current treatments are often inadequate and may even cause other socioeconomic downfalls, such as the prescription opioid abuse epidemic. Development of new analgesic therapies is hampered by low success rates and underinvestment. This highlights both, the insufficient understanding of pain mechanisms and limitations of our preclinical models to study pain. We will capitalise on two significant advancements by our team in both of the above areas: (i) We discovered that specific neural structures residing outside the brain and the spinal cord can control how much of a ‘pain’ signal is delivered by a nerve to the central nervous system (CNS). These structures are called ‘dorsal root ganglia’ (DRGs) and these can be targeted for pain relief with drugs and treatments that do not affect the brain in the way opioid drugs do. (ii) We developed a reduced preparation that we call ‘decerebrate arterially perfused preparation’ (DAPP), which allows an unprecedented level of access for measurement of neural processes associated with pain and excludes animal suffering. It combines advanced electrophysiology with computational processing of recorded signals and allows precise, unbiased measurement of key signals mediating pain responses, circumventing analysis of behavioural responses to painful stimuli. Furthermore, the approach allows a unique opportunity to precisely quantify how DRG controls pain. As DRGs are outside the CNS and are accessible to circulation, this creates a window of opportunity to discover therapies with much better safety profiles than currently available drugs. Moreover, our approach helps to develop an understanding of an effective approach to treat chronic pain, whereby an electrical stimulation of the DRG via implanted electrode is performed, it is called ‘DRG neuromodulation’. The approach is powerful but controversial, as it involves electrical stimulation of a nerve that can trigger pain in a person. Yet, our approach reveals a possibility of how such stimulation of a DRG can effectively block the painful signals travelling through the nerve. The overall objective of this proposal is to use our innovative approach to develop a precise understanding of how DRG controls pain, with an overarching aim to develop better pain treatments. This objective will be achieved through four focused aims: Aim-1: To understand how DRG controls pain using DAPP. Aim-2: To understand how DRG neuromodulation produces analgesia and to develop a way for selecting the best parameters for such neuromodulation. Aim-3: To understand how chronic pain changes the DRG’s function and how to adjust DRG neuromodulation to combat chronic pain better. Upon completion of this project, we will establish a new preclinical approach for pain research, will provide critical new insight into the mechanisms of pain control by the structures within the peripheral nervous system and will provide a basic understanding of an efficient but poorly understood clinical procedure to treat chronic pain. Additionally, we will develop guidelines for adjusting this therapy for more efficient pain control. This project may shape new and innovative approaches for analgesia and chronic pain management, bringing far-reaching benefits not only for the fundamental science but, ultimately, for individuals suffering from chronic pain.
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