Targeting dorsal root ganglia to combat chronic pain resulting from spinal cord injury

Are you passionate about neuroscience and pain research? Do you want to develop cutting-edge treatments that could transform the lives of people with spinal cord injuries? This PhD project offers an exciting opportunity to investigate the sources and mechanisms of chronic pain after spinal cord injury (SCI).

<p>Neuropathic pain (NP) is one of the most prevalent complications of spinal cord injury (SCI), affecting up to 80% of SCI sufferers. NP is a significant factor reducing life quality and wellbeing of SCI sufferers, furthermore, it contributes to other SCI comorbidities, such as anxiety and depression. SCI-NP is produced by pathological changes in both, peripheral and central nociceptive pathways, with current research mostly focused on the spinal/supraspinal pathologies. Peripheral mechanisms of SCI-NP are relatively understudied, moreover, relative contribution of both types of mechanisms to overall severity of SCI-NP is unclear. Yet, clarity in these matters is urgently needed to develop better, more targeted, therapies benefiting SCI sufferers. </p> <p><br /> Our recent findings reveal ‘peripheral gate’ in somatosensory system, whereby peripherally induced nociceptive signals can be effectively filtered at the dorsal root ganglia (DRG) (1-3). This robust and complex phenomenon can lead to a complete block of nociceptive signals, providing effective analgesia. One mechanism of peripheral ‘gating’ is GABA-ergic inhibition within the DRG. We have shown that DRG’s intrinsic GABAergic system is weakened in peripheral neuropathic injury. Intriguingly, ‘diminishing GABAergic inhibition of central pain pathways also contributes to central sensitization following SCI. Hence, there may be converging mechanisms for both, peripheral and central components of SCI-NP. Yet, peripheral and central origins of pain require different targeting strategies.  </p> <p>Moreover, because DRG are not well protected by hematoencephalic barrier, they represent a unique target for treatment of SCI-NP by medications that do not penetrate the CNS and, hence, devoid of common side effects of mainstream analgesics, such as opioids. <br /> We propose to use a combination of in vivo and in vitro approaches, including a group’s own know-how, to answer the following scientific questions: </p> <p><br /> 1) What is relative contribution of peripheral and central mechanisms to the SCI-induced neuropathic pain? We will perform SCI injury in mice and study the resulting nociception using a unique approach, developed by us: a decerebrate, arterially-perfused preparation, DAPP of the mouse. This unique preparation allows to record nerve activity in an in-vivo-like conditions without the need for ongoing anaesthesia. Simultaneous recordings can be made from multiple points along the nociceptive pathways, including peripheral nerve, DRG, dorsal root, spinal dorsal horn, brainstem. We will directly measure SCI-induced hyperexcitability within peripheral and central nociceptive pathways with and without peripheral input (which can be directly blocked pharmacologically). These experiments will result in direct evaluation of peripheral contribution to the SCI-induced nociception </p> <p><br /> 2) How peripheral input from different types of sensory fibers contributes to SCI-induced pain? It has been long suggested that input from ‘non-pain’ mechanosensitive fibers can alleviate pain generated by nociceptive fibers ; the substrate for this integration can be both peripheral or central. We will use transgenic mouse lines with Channelrhodopsin-2 expressed in either low-threshold mechanoreceptors (under TrKC promotor) or in nociceptors (TRPV1 promotor) and DAPP approach to investigate how optogenetic stimulation of either fiber types affects SCI-induced hyperexcitability. These mice are already in place.</p> <p><br /> 3) Can peripheral or GABAergic systems be leveraged to combat SCI-induced nociception? We will use approaches outlined above, in combination with systemic or local application of GABA-mimetics and modulators (such as benzodiazepines) to investigate efficacy of peripheral vs. central GABA-ergic systems in SCI pain control. </p> <p><br /> As a PhD student, you will gain valuable skills in preclinical SCI and pain models, advanced microscopy, molecular biology, and cutting-edge neurophysiology technologies. You will work within a collaborative and supportive research environment, contributing to real-world solutions for SCI pain management.</p> <p>This project is ideal for students from neuroscience, biomedical sciences, physiology, sport sciences or related fields who are eager to make a difference in chronic pain research. No prior experience in SCI research is required, just enthusiasm, curiosity, and a drive to improve patient outcomes.</p> <p>This scholarship is part of the Doctoral Training Programme at the Leeds Centre for Spinal Cord Injuries Research. This is a unique opportunity to develop research in an inter- and multidisciplinary environment involving experts from several different areas of basic and clinical sciences. Centre members include neuroscientists, cell and molecular biologists, physiologists, clinicians, engineers, computer scientists, exercise physiologists, rehabilitation scientists, etc.</p> <p>The scholarship is for 4 years, including all fees and a competitive stipend.</p> <p> <br /> <strong>References:</strong></p> <p><br /> 1. Du X, Hao H, Yang Y, Huang S, Wang C, Gigout S, et al. Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission. J Clin Invest. 2017;127(5):1741-56.<br /> 2. Hao H, Ramli R, Wang C, Liu C, Shah S, Mullen P, et al. Dorsal root ganglia control nociceptive input to the central nervous system. PLoS Biology. 2023;21(1):e3001958.<br /> 3. Li X, Prudente AS, Prato V, Guo X, Hao H, Jones F, et al. Peripheral gating of mechanosensation by glial diazepam binding inhibitor. J Clin Invest. 2024:18:e176227.<br />  </p>

<p>Formal applications for research degree study should be made online through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University's website</a>. Please state clearly in the research information section that the research degree you wish to be considered for is Targeting dorsal root ganglia to combat chronic pain resulting from spinal cord injury as well as <a href="https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/70/prof-nikita-gamper">Prof Nikita Gamper | School of Biomedical Sciences | University of Leeds</a> as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p>PhD scholarship covering academic fees and tax-free maintenance grant at the standard UKRI rate (£20,780 per year for 4-years) is available in the School of Biomedical Sciences. The scholarship provides an exciting opportunity to pursue postgraduate research in fields related to chronic pain resulting from spinal cord injuries commencing in the academic year 2025/26. The award is open to full-time candidates who meet the eligibility criteria.</p>

<p>For further information please contact the Graduate School Office<br /> e: fbsgrad@leeds.ac.uk</p> <p> </p>