Implication of chemokines in neuroimmune relationships in peripheral neuropathic pain – ChemokPain

Pain is the most common symptom for which patients seek medical attention. According to the International Society of Pain (IASP) the prevalence of chronic pain is 18% of general population. In Europe, the pain just does not weigh on individuals and their families. Indeed, the social burden of chronic pain costs about billions of euros in Europe: probably not less than 300 billion euros to the EU as overall, 1.5 - 3% of gross domestic product. Nowadays, chronic pain is seen in industrialized countries as a broad public health problem particularly due to its high social cost. Although a number of pain medications are available on the pharmaceutical market, it is still today unfortunately observed that some chronic pain syndromes have completely escape these medicines, thus affecting considerably the quality of life for these patients. Indeed, many clinical cases of neuropathic pain are relatively insensitive to classical medicine. In addition, chronic use of morphine or its derivatives, in cases of the most rebellious pain, causes states of tolerance and dependence. It is important to explore new therapeutic approaches to block the mechanisms underlying chronic pain and to relieve its syndromes. Recently, it has been established that ongoing pain associated with peripheral nerve lesions is not only linked to a heightened excitability of sensory neurons but would also be the result of a persistent inflammation affecting nociceptive pathways. Patients suffering from these chronic pain syndromes are subject to hyperalgesia and/or allodynia. Thus, our incomplete understanding of the mechanisms underlying chronic pain sensitivity accounts for the general ineffectiveness of current options for the treatment of chronic pain syndromes. Nowadays, neuroimmune interactions are increasingly recognized as important factor in alteration of the nociceptive processing during neuropathic pain. As part of this neuro-immune relation, recent evidences suggest that the up-regulated expression of inflammatory chemotactic cytokine (chemokine) in association with tissue damage or infection serves not only in the capacity of leukocytes chemotaxis but also in the generation of exacerbated hyperexcitability state of sensory neurons. This interdisciplinary project proposal brings together two research fields: neuroscience and immunopathology. Indeed, the overall objective of this research project is to define, the functional role of chemokines CCL2 and/or CX3CL1 in the interactions between immune cells (in particular monocytes/macrophages) and sensory neurons and their implications in the mechanisms of initiation and maintenance of painful syndromes. We hypothesize that these chemokines after peripheral nerve injury could induce, via theirs chemotactic properties, the recruitment of immune cells locally at the lesion and Dorsal root ganglia levels, and thus could participate in mechanisms leading to Wallerian degeneration and chronicity of pain. Thus, directly through its neuro-modulatory effects and indirectly, through its influence on immune-competent cells that broadly alter the neuronal function, these chemokines may fundamentally impact on nociceptive information processing. In this context, this project presents three aspects: i) - the fundamental one, devoted to the understanding of the relationship between effects exerted by chemokines (ie CCL2 and CX3CL1) on neurons, glial, schwann and immune cells, and importance of these relations in the initiation of pain, then the shift from acute to chronic pain syndromes; ii) –deciphering in an appropriate preclinical models of peripheral neuropathic pain, the cellular and molecular mechanisms leading to chronic inflammation to understand the pathogenesis of this disease III) bring in these appropriate preclinical models of pain the rational use of chemokine receptor antagonists as potential therapeutic agents for the treatment of pathological chronic pain.