Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of anticancer agents that seriously compromises the patient’s quality of life, limits dosage, and leads to changes in treatment to non-neurotoxic agents with the risk of limiting the effective clinical outcome. Among these compounds, oxaliplatin (used in the treatment of several solid tumors such as colorectal cancer) induces a quasi-systematic acute neurotoxicity which persists in more than 30% of survivors. The pathophysiology of sensory and motor symptoms induced by anticancer chemotherapeutic drugs is still poorly understood and no effective preventive or curative treatment is available. Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels family is composed of four members (HCN1-4) widely distributed throughout pain pathways and playing an important role in the development and maintenance of neuropathic pain. Non-selective HCN blockers ae known to alleviate pain symptoms in CIPN rodent models but their potential cardiac side effects limit the clinical translation of their use in CIPN patients. Interestingly, both the function and membrane expression of HCN are tightly regulated by its auxiliary subunit, tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), which is not expressed in the heart, hence limiting the risk of cardiac side effects. Therefore, the recent development of molecules disrupting the TRIP8b-HCN interaction should provide new understanding regarding the involvement of these proteins in neuropathic pain signaling and propose the modulation of HCN function as a new innovating and better tolerated therapeutic analgesic strategy. The aims of this project are (i) to gain insight into the role played by TRIP8b-HCN interaction in the pathophysiology of CIPN, (ii) to demonstrate their pharmacological interest for the treatment of neuropathic pain using compounds with peripheral and/or central distribution specificity. To achieve these aims, experiments will be performed using in vivo rodent models of CIPN that will be challenged using TRIP8b-HCN interactions disrupting reference molecules as well as new and specific peptidomimetic compounds, coupled to up to date electrophysiological techniques and behavior studies. In this project we will (i) perform an extensive cellular and molecular characterization of TRIP8b-HCN interactions in peripheral, spinal and supraspinal neurons in CIPN; (ii) assess the functional and neurophysiological consequences of disrupting TRIP8b-HCN interactions in naïve and CIPN animals; (iii) evaluate the well-tolerated effect of this strategy. Altogether, the completion of this proposal will foster our understanding of the role of HCN channels and their protein partner TRIP8b in the pain pathways and critically help the development of innovative therapeutic strategies in pain treatment that remains an unmet medical need today. Specifically, the project will provide:-a detailed characterization of HCN channels and of their partner protein TRIP8b involvement in the sensori-discriminative and emotional neuronal circuits sustaining neuropathic pain-a validation of the disruption of HCN-Trip8b interaction as an innovative and well tolerated strategy to treat or prevent CIPN The outcome of our project and its therapeutic potential would have a great impact on improving the quality of life of patients suffering from chemotherapy-induced neuropathic pain and possibly their survival. This will consequently have important industrial and economic outcomes. Moreover, since HCN channels have also been involved in other neuropathic pain and in inflammatory pain, this project will pave the way toward new classes of analgesic drugs, active on chronic pain. .