Chemokines—proteins best known for directing immune cells to sites of injury—may also directly trigger pain by activating sensory neurons. The researchers will screen biopsy samples from chronic pain patients to identify which chemokines are present, then test those candidates in both human tissue and animal experiments to confirm whether they act as pain mediators. Chronic pain affects millions of people, yet existing treatments are often ineffective because the molecules that actually cause pain in patients remain largely unknown. This project systematically maps which chemokine receptors sit on sensory neurons, how those neurons respond to different chemokines, and whether blocking specific chemokine–receptor pairs can reduce pain in animal models. If the hypothesis holds, the work could identify entirely new targets for painkillers. Because chemokine receptors are druggable—several drugs already exist for other conditions—success could accelerate development of therapies that work where current options fail. The translational design, starting from patient biopsies, means any mediators discovered are likely to be clinically relevant from the outset, not just laboratory curiosities.
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Summary Chronic pain remains an area of great unmet medical need with considerable socio-economic burdens because of the limited number and efficacy of existing therapies. A key problem is that the mediators which are clinically relevant are mostly unknown. This proposal will examine the sensory neurobiology of chemokines and test the hypothesis that some of these function as novel pain mediators. Chemokines are a large family of secreted proteins with an established role in recruiting immune cells to a site of pathology. They act on a family of about 20 chemokine receptors. In the last decade several lines of evidence suggest that these factors may also directly activate neurons and in particular small diameter nociceptive neurons, though the roles of most chemokines in pain remain undefined. An important feature of the work is that it will include a large translational element. Biopsy specimens from chronic pain patients will be screened for chemokine expression and the candida te mediators identified will be validated in human and animal experiments. I have already established the feasibility of this approach and identified one novel pain mediator. The specific aims of the proposed studies are to: 1) systematically explore the expression of chemokines receptors in sensory systems in health and disease; 2) define the functional responses of sensory neurons to different chemokines; 3) test the hypothesis that some chemokines act as peripheral pain me diators in clinical pain states; 4) identify the role played by different classes of immune cell in animal models of persistent pain.
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