MORPAIN

Opioids are the gold standard for the treatment of moderate to severe pain. However, sustained exposure to opioids can produce analgesic tolerance and/or hyperalgesia. These effects are known to drastically mitigate their effectiveness requiring increasing the dose. These properties have attracted considerable attention from both scientists and clinicians, especially in the context of the current epidemic of prescription opioid abuse. Mu opioid receptors (MORs) are the most important opioid receptors in the mediation of morphine analgesia but also in morphine-induced tolerance (MIT) and hyperalgesia (MIH). The molecular mechanisms underlying MIT are currently thought to be MOR-dependent interaction with multiple cellular effector systems regulating both MOR desensitization at receptor level and MOR activation of intracellular pathways that leads to MIH. Of note, MIH shares some common pathways with those underlying the peripheral and central sensitizations to noxious and non-noxious stimuli observed in neuropathic pain (NP) models. Interestingly, we recently evidenced that neuronal fms-like tyrosine kinase 3 receptor (FLT3) in DRG is a critical trigger of NP arising after peripheral nerve injury in the mouse. FLT3 is expressed in the immune cell lineage and in various regions of the nervous system and, notably in human and mouse DRGs. At the molecular level, FLT3 in sensory neurons is involved in NP-induced hyperexcitability by mechanisms common with MIT and MIH. These observations led us to consider a potential implication of FLT3 in the development of these latter phenomena. Our preliminary data clearly demonstrate that FLT3 is specifically involved in analgesic tolerance and hyperalgesia produced by chronic morphine exposure via a molecular and functional interaction between FLT3 and MOR. Our project therefore will aim at understanding the role of FLT3 in the regulation of morphine analgesia to improve opioid use for pain management. For this purpose, we developed a consortium in which each partner contributes unique and complementary knowledge in persistent pain and advanced technologies on somatosensory system analysis. First, we will demonstrate the implication of peripheral sensory neuron FLT3 signaling in morphine-induced hyperexcitability. To do this, we will take advantage of specific tools developed by the consortium i.g. transgenic mice, shRNA Associated Adenovirus (AAVs) to target peripheral FLT3, combined with electrophysiological recordings and behavioral assays. Second, we will study the consequences of the interaction between FLT3 and MOR on MOR functioning by examining whether the crosstalk between MOR and FLT3 occurs directly at the receptor level through physical interactions and/or at the level of signaling pathways (Gi protein coupling, internalization, ERK activation). To this purpose, we will use in vitro cellular models to specifically address the molecular interactions between MOR and FLT3. Finally, we will decipher the FLT3 signaling pathway(s) modulating morphine analgesia. A better understanding of signaling pathways and downstream effectors from MOR would facilitate finding new targets for improving morphine analgesia while decreasing side effects. The achievement of these objectives will have an impact on the fundamental knowledge of functional interactions between pro- and anti-nociceptive circuits in the sensory system. In addition, a strong impact on pain management and a better reinsertion of patients in our society can be anticipated by developing a novel strategy for improving opioid-based pain treatments.