Abstract
Chronic pain is defined as any kind of pain that lasts more than 3 months. About 20% of the global population is affected by chronic pain, with little to none effective treatment available, or with various side effects. Moreover, it has strong comorbidities with emotional disorders such as anxiodepression or vulnerability to addiction. Better understanding of the mechanisms involved in pain sensitization and recovery is then needed to find out more efficient treatments. One particular system that is known to have a strong involvement in the recovery of pain as well as in its emotional component, is the Endogenous Opioid System. But the precise implication of each actor of this system in pain recovery, and their respective deregulation during each type of chronic pain remain debated.Besides, in previous studies we have identified a key protein involved in chronic pain, the FLT3 receptor. The inhibition of this receptor in the peripheral nervous system allows a faster recovery in rodent models of neuropathic and postsurgical, but not of inflammatory pain, suggesting an interaction of FLT3 with the actors specifically responsible for the recovery from neuropathic and postsurgical pain.In this study, using pharmacological approaches, we have explored the endogenous opioid system actors responsible for the recovery in mice expressing FLT3 or not, in various pain models. We found that the inhibition of the mu opioid receptor (MOR) in the spinal cord specifically reinstates a mechanical pain hypersensitivity in the chronic inflammatory pain model during the recovery, but not in the neuropathic or postsurgical pain model. In contrast, the inhibition of the delta opioid receptor (DOR) in the spinal cord induces pain hypersensitivity only in the neuropathic and postsurgical pain models. Importantly, the faster recovery observed in Flt3 knock-out animals in comparison with wild type animals after nerve injury or surgery is completely blocked by the administration of a DOR antagonist. Conversely, the known beneficial effects of a DOR agonist on mechanical hypersensitivity that were lost during chronic pain, were restored with the blocking of FLT3. Interestingly, we weren’t able to observe any regulation of the opioid system by FLT3 at the RNA level. Therefore, we developed different specific tools and transgenic line to both be able to visualize the expression of FLT3 and DOR in the nervous system, and to inhibit DOR expression in specific neuronal subpopulations.To resume, our results show that while MOR seems to be implicated in inflammatory pain recovery, DOR is responsible for the recovery of neuropathic and postsurgical mechanical pain. An interaction between the DOR and FLT3 receptors seems to downregulate the activity of DOR responsible for sustained pain hypersensitivity after nerve injury or surgery. Thanks to the development of new specific tools, we will be able to better characterize this interaction in the future. In all cases, the blocking of FTL3 could be a promising strategy to treat neuropathic and postsurgical pain by restoring endogenous activity of DOR.