GPCRs, pain and inflammation (Team F. Simonin)
G Protein coupled receptors (GPCRs) are heptahelical receptors that constitute the largest membrane protein family in eukaryotes, including more than 800 members in human. They are sensing a large panel of extracellular stimuli and transduce them into the cells, and play therefore a pivotal role in the regulation of major physiological processes including neurotransmission, cell proliferation and differentiation, chemotaxis, inflammation and pain. These key signaling proteins thus represent ideal therapeutic targets for a number of disorders and diseases and represent the largest class of therapeutic targets in medicine, accounting for one-third of the druggable genome.
Our team is studying the role of different GPCRs in the development of pain and inflammation as well as the mechanisms that regulate GPCR signaling from the cell surface to intracellular compartments. In line with our previous work, we develop mainly three projects:
First, we study the role of RF-amide and related receptors in hyperalgesia (increased sensitivity to pain) induced by chronic opiates and persistent pain. We have generated and characterized pharmacological (antagonists) and genetic (KO mice) tools for each of the five different RF-amide receptors and we are currently using these tools to better understand the respective role of each of these receptors in the modulation of nociception and opiate analgesia.
Second, we study the role of different chemokines in neuroinflammatory processes associated with hyperalgesia induced by opiates and chronic pain. In the last years, inflammatory processes within the CNS have emerged as key contributors to pain hypersensitivity in chronic pain as well as upon chronic opiates administration. In both cases, microglia recruitment and activation, have been proposed to play a critical role in the development of hyperalgesia. However, how neuronal activity leads to glia activation and how activated glia participates to pain sensitization is still the matter of intense research. Several chemokine and their receptors have been involved in these phenomena. We are currently developing and characterizing novel compounds that can neutralize the action of these chemokines both in vitro and in vivo.
Third, we explore the role of GPCR intracellular partners in signaling, desensitization and downregulation of GPCRs with the help of cellular models. We are particularly focusing on GASP-1 and the other members of this family, which have been discovered in our laboratory.