Chronic JOINT PAIN: Toward new molecular targets. – JOINT-PAIN

Chronic joint pain is a major health problem representing an economic burden for the society. A recent Inserm survey reports that 93% of the French citizens have already suffered from joint pain, with half suffering at the time of the survey. However, joint pain remains poorly relieved by current analgesics, and this is mainly due to a lack of understanding of the associated pathophysiology. Our preliminary data strongly support a role for Acid-Sensing Ion Channels (ASICs) in this particular type of pain, and we now aim to decipher the molecular mechanisms by which these channels contribute to chronic joint pain all along the pain neuraxis.
Our project strength is to combine the analysis of human samples, i.e., lipids identified in patients suffering from different painful joint disorders that activate ASICs, with neurophysiological studies in rodents to better understand the pathophysiology of joint pain. It is based on the complementary expertise of four teams including rheumatologists, lipidomists and specialists of ion channels and pain, to define novel therapeutical strategies to tackle chronic joint pain, for which there is a clear lack of efficient treatments.
The research project is organized in four tasks to address the following scientific objectives:
TASK-1: What are the lipid profiles of human synovial fluids from patients with different joint pathologies and how are these lipids related to pain and human ASICs activation?
=> Lipid composition of synovial fluids from pain patients with different types of joint pathologies; in vitro patch-clamp experiments on human ASIC channels.
TASK-2: Are the ASIC-activating lipids identified in human able to generate chronic joint pain following intra-articular injections in rodents?
=> Generation of a new clinically-relevant model of joint pain based on intra-articular injections of the lipids previously identified in patients. Comparison with the well-established model of monoarthritis induced by a single intra-articular injection of CFA.
TASK-3: What is the role of spinal ASICs in central sensitization mechanisms of chronic joint pain?
=> In vivo electrohysiological recordings of spinal pain processes. Combination of specific inhibitors of ASICs, conventional ASIC knockouts and floxed-ASIC mice, and viruses expressing ASICs, Cre-recombinase or shRNAs. Study of lipid-induced joint pain model developed in task2 and of the monoarthritis model induced by CFA.
TASK-4: What is the role of supra-spinal ASICs in pain and anxiety associated with chronic joint pain?
=> Analysis of the the consequences of supraspinal ASICs modulation (amygdala, periaqueductal grey matter (PAG), rostro-ventral medulla (RVM)) on spinal sensitization mechanisms studied in task3 and on pain/anxiety behaviors in the two models of chronic joint pain.
The four teams involved in our consortium have already successfully collaborated. Team#1 is specialized in ion channels and pain and one of the world’s leaders on ASICs, Team#2 has a strong track record in behavioral experiments and in vivo pharmacology in animal pain models, Team#3 is doing state-of-the-art lipid analysis, and Team#4 includes rheumatologists to supervise collection of human samples (Clinical Trial NCT 01867840).
Our project will bring important informations about the relationship between human joint pain, ASICs and lipids, which can now be considered as new endogenous activator of these channels. Importantly, this project will demonstrate how ASICs participate to central sensitization processes responsible for joint pain chronicization, including the emotional component often associated with joint diseases but frequently underestimated in experimental approaches.