GPCRs, pain and inflammation (Dr Frédéric Simonin)

Summary

Research interests

Dr Frédéric Simonin

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors in eukaryotes with more than 800 members in humans. They are stimulated by a wide variety of extracellular signals and are involved in many physiological and pathophysiological processes including neurotransmission, cell division and differentiation, chemotaxis, inflammation and pain. As such, they represent privileged targets for the development of new drugs.

Our team is interested in 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. Consistent with our previous work, we are developing three main lines of research:

First, we are studying the role of RF-amide peptide receptors and related receptors in opioid-induced hyperalgesia (OIH for Opioid induced hyperalgesia) and chronic pain. We have developed pharmacological (antagonists) and genetic (KO mice) tools for the five RF-amide receptors and are using them to understand the respective role of each of these receptors in the modulation of nociception and morphine analgesia.

Second, we are studying the roles of different chemokines in the neuroinflammatory processes associated with opioid-induced hyperalgesia and chronic pain. In recent years, inflammatory processes in the central nervous system have emerged as key phenomena in hyperalgesia induced by chronic pain or opioid treatments. In both cases, it has been proposed that microglia recruitment and activation play an important role in the development of hyperalgesia. However, how neuronal activity leads to glial activation and how glia contribute to pain sensitization remains the subject of many studies. The most recent studies indicate an important role of chemokines in these phenomena. We are currently developing and characterizing compounds capable of neutralizing the action of these chemokines in vitro and in vivo.

Third, we explore the links between signaling, subcellular localization and membrane trafficking of GPCRs with a particular interest in the intracellular partners of GPCRs such as GASP-1 and other members of this family discovered in the laboratory. In particular, we study the dynamics of molecular interactions using fusion proteins coupled to fluorophores allowing biophysical analyses based on resonance energy transfer in living cells.

Funding

Team members

Publications

Delaitre C, Boisbrun M, Acherar S, Dias A, Kleinclauss A, Achard M, Colin M, Nguyen TM, Humbert N, Chmeis K, Martinez KL, Gilles N, Robin P, Lecat S*, Dupuis F* (2024). Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists. J Med Chem Nov 11 Online ahead of print. doi: 10.1021/acs.jmedchem.4c01693.

De Neve J, Elhabazi K, Gonzalez S, Herby C, Schneider S, Utard V, Fellmann-Clauss R, Petit-Demouliere N, Lecat S, Kremer M, Ces A, Daubeuf F, Martin C, Ballet S, Bihel F, Simonin F (2024). Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects. J Med Chem 67(9):7603-7619. doi: 10.1021/acs.jmedchem.4c00442.

Rasheed AAB, Birling MC, Lauria G, Gaveriaux-Ruff C, Herault Y (2024). The COL6A5-p.Glu2272* mutation induces chronic itch in mice. Mamm Genome 35(2):122-134. doi: 10.1007/s00335-024-10032-9.

Zeder-Lutz G, Bornert O, Fellmann-Clauss R, Knittel-Obrecht A, Tranchant T, Bouteben S, Kaeffer J, Quillet R, Villa P, Wagner R, Lecat S, Simonin F (2023). Characterization of anti-GASP motif antibodies that inhibit the interaction between GPRASP1 and G protein-coupled receptors. Anal Biochem 665:115062. doi: 10.1016/j.ab.2023.115062.

Gerum M, Simonin F (2022). Behavioral characterization, potential clinical relevance and mechanisms of latent pain sensitization. Pharmacol Ther 233:108032. doi: 10.1016/j.pharmthera.2021.108032.

Delaitre C, Boisbrun M, Lecat S, Dupuis F (2021). Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes. IntJ Mol Sci 22:6738. doi: 10.3390/ijms22136738.

De Neve J, Barlow TMA, Tourwé D, Bihel F, Simonin F, Ballet S (2021). Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors. RSC Med Chem 12:828-870. doi: 10.1039/d1md00041a.

Quillet R, Schneider S, Utard V, Drieu la Rochelle A, Elhabazi K, Henningsen JB, Gizzi P, Schmitt M, Kugler V, Simonneaux V, Ilien B, Simonin F, Bihel F (2021). Identification of an N-acylated-DArg-Leu-NH2 Dipeptide as a Highly Selective Neuropeptide FF1 Receptor Antagonist That Potently Prevents Opioid-Induced Hyperalgesia. J Med Chem 64:7555-7564. doi: 10.1021/acs.jmedchem.1c00256.

Kaeffer J, Zeder-Lutz G, Simonin F, Lecat S (2020). GPRASP/ARMCX protein family: potential involvement in health and diseases revealed by their novel interacting partners. Curr Top Med Chem 21:227-254. doi: 10.2174/1568026620666201202102448.

Bouressam ML, Lecat S, Raoul A, Gaucher C, Perrin-Sarrado C, Lartaud I, Dupuis F (2019). S-nitrosoglutathione inhibits cerebrovascular angiotensin II-dependent and -independent AT1 receptor responses: A possible role of S-nitrosation. Br J Pharmacol 176:2049-2062. doi: 10.1111/bph.14644.

Bouressam ML, Lartaud I, Dupuis F, Lecat S (2018). No answer to the lack of specificity: mouse monoclonal antibody targeting the angiotensin II type 1 receptor AT1 fails to recognize its target. Naunyn Schmiedebergs Arch Pharmacol 391:883-889. doi: 10.1007/s00210-018-1522-4.

Hammoud H, Elhabazi K, Quillet R, Bertin I, Utard V, Laboureyras E, Bourguignon JJ, Bihel F, Simonnet G, Simonin F, Schmitt M (2018). Aminoguanidine hydrazone derivatives as non-peptide NPFF1 receptor antagonists reverse opioid induced hyperalgesia. ACS Chem Neurosci 9:2599-2609. doi: 10.1021/acschemneuro.8b00099.

Drieu la Rochelle A, Guillemyn K, Dumitrascuta M, Martin C, Utard V, Quillet R, Schneider S, Daubeuf F, Willemse T, Mampuys P, Maes BUW, Frossard N, Bihel F, Spetea M, Simonin F, Ballet S (2018). A bifunctional biased mu opioid agonist - neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects. Pain 159:1705-1718. doi: 10.1097/j.pain.0000000000001262.

Quillet R, Simonin F (2018). The neuropeptide FF: a signal for M1 to M2 type switching in macrophages from the adipose tissue. Med Sci 34:27-29. doi: 10.1051/medsci/20183401008.

Elhabazi K, Humbert JP, Bertin I, Quillet R, Utard V, Schmitt M, Bourguignon JJ, Laboureyras E, Simonnet G, Ancel C, Simonneaux V, Beltramo M, Bucher B, Sorg T, Meziane H, Schneider E, Petit-Demoulière B, Ilien B, Bihel F*, Simonin F* (2017). RF313:an orally bioavailable NPFF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents. Neuropharmacology 118:188-198. doi: 10.1016/j.neuropharm.2017.03.012.

Roeckel LA, Utard V, Reiss D, Mouheiche J, Maurin H, Robé A, Audouard E, Wood JN, Goumon Y, Simonin F, Gaveriaux-Ruff C (2017). Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide. Sci Rep 7:10406. doi: 10.1038/s41598-017-11120-4.

Waqas SFS, Hoang AC, Lin YT, Ampem G, Azegrouz H, Balogh L, Thuróczy J, Chen JC, Gerling IC, Nam S, Lim JS, Martínez-Ibañez J, Real J T, Paschke S, Quillet R, Ayachi S, Simonin F, Schneider M, Brinkman JA, Lamming DW, Seroogy CM, Röszer T (2017). Neuropeptide-FF increases macrophage self-renewal and abrogates inflammation in adipose tissue. J Clin Invest 127(7):2842-2854. doi: 10.1172/JCI90152.

Doebelin C, Bertin I, Schneider S, Schmitt M, Bourguignon JJ, Ancel C, Simonneaux V, Simonin F, Bihel F (2016). Development of Dipeptidic hGPR54 Agonists. ChemMedChem 11(19):2147-2154. doi: 10.1002/cmdc.201600331.

Guillemyn K, Starnowska J, Lagard C, Dyniewicz J, Rojewska E, Mika J, Chung NN, Utard V, Kosson P, Lipkowski AW, Chevillard L, Arranz-Gibert P, Teixidó M, Megarbane B, Tourwé D, Simonin F, Przewlocka B, Schiller PW, Ballet S (2016). Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain. J Med Chem 59:3777-3792. doi: 10.1021/acs.jmedchem.5b01976.

Roeckel LA*, Le Coz GM*, Gavériaux-Ruff C#, Simonin F# (2016). Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338:160-182.

Quillet R, Ayachi S, Bihel F, Elhabazi K, Ilien B*, Simonin F* (2016). RF-amide neuropeptides and their receptors in Mammals : Pharmacological properties, drug development and main physiological functions. Pharmacol Ther 160:84-132.

Buffel I, Meurs A, Portelli J, Raedt R, De Herdt V, Poppe L, De Meulenaere V, Wadman W, Bihel F, Schmitt M, Vonck K, Bourguignon JJ, Simonin F, Smolders I, Boon P (2016). The effect of neuropeptide FF in the amygdala kindling model. Acta Neurol Scand 134(3):181-8.

Bihel F, Humbert JP, Schneider S, Bertin I, Wagner P, Schmitt M, Laboureyras E, Petit-Demoulière B, Schneider E, Mollereau C, Simonnet G, Simonin F*, Bourguignon JJ* (2015). Development of a peptidomimetic antagonist of the neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia. ACS Chem Neurosci 6:438-445.

Buffel I, Meurs A, Portelli J, Raedt R, De Herdt V, Poppe L, De Meulenaere V, Wadman W, Bihel F, Schmitt M, Vonck K, Bourguignon JJ, Simonin F, Smolders I, Boon P (2015). The effect of Neuropeptide FF in the amygdala kindling model. Acta Neurol Scand 134:181-188.

Buffel I, Meurs A, Portelli J, Raedt R, De Herdt V, Sioncke L, Wadman W, Bihel F, Schmitt M, Vonck K, Bourguignon JJ, Simonin F, Smolders I, Boon P (2015). Neuropeptide FF and prolactin releasing peptide decrease cortical excitability through activation of NPFF receptors. Epilepsia 56:489-498.

Lecat S, Belemnaba L, Galzi JL, Bucher B (2015). Neuropeptide Y receptor mediates activation of ERK1/2 via transactivation of the IGF receptor. Cell Signal 27:1297-1304.

Lecat S, Matthes HW, Pepperkok R, Simpson JC, Galzi JL (2015). A Fluorescent Live Imaging Screening Assay Based on Translocation Criteria Identifies Novel Cytoplasmic Proteins Implicated in G Protein-coupled Receptor Signaling Pathways. Mol Cell Proteomics 14:1385-1399.

Portelli J*, Meurs A*, Bihel F, Hammoud H, Schmitt, M De Kock J, Humbert JP , Bertin I, Utard V, Buffel I, Coppens J, Tourwe D, Maes V, Vanhaecke T, Massie A, Balasubramaniam A, Boon P, Michotte Y, Bourguignon JJ*, Simonin F*, Smolders I* (2015). Neuropeptide FF receptors as novel targets for limbic seizure attenuation. Neuropharmacol 95:415-423.

Rouméas L, Humbert JP, Schneider S, Doebelin C, Bertin I, Schmitt M, Bourguignon JJ, Simonin F*, Bihel F* (2015). Effects of systematic N-terminus deletions and benzoylations of endogenous RF-amide peptides on NPFF1R, NPFF2R, GPR10, GPR54 and GPR103 Peptides. Peptides 71:156-61.

Schneider S, Ftouni H, Niu S, Schmitt M, Simonin F, Bihel F (2015). Rapid and scalable synthesis of innovative unnatural α, β or γ-amino acids functionalized with tertiary amines on their side-chains. Org Biomol Chem 13:7020-7026.

Ayachi S, Simonin F (2014). Involvement of Mammalian RF-Amide Peptides and Their Receptors in the Modulation of Nociception in Rodents. Front Endocrinol 5:158-170.

Elhabazi K, Ayachi S, Ilien B, Simonin F (2014). Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities. J Vis Exp e51264.

Logez C, Berger S, Legros C, Cohen W, Delagrange P, Boutin JA, Ferry G, Simonin F*, Wagner R* (2014). Recombinant human MT1 receptor purified in mixed detergents shows a similar pharmacology than in membranes from mammalian cells. PLoS One 9:e100616.

Michel G, Matthes HW, Hachet-Haas M, El Baghdadi K, de Mey J, Pepperkok R, Simpson JC, Galzi JL*, Lecat S* (2014). Plasma membrane translocation of REDD1 governed by GPCRs contributes to mTORC1 activation. J Cell Sci 127:773-87.

Bornert O, Møller TC, Bœuf J, Candusso MP, Wagner R, Martinez KL, Simonin F (2013). Identification of a novel protein-protein interaction motif mediating interaction of gpcr-associated sorting proteins with g protein-coupled receptors. PloS One 8:e56336.

Doebelin C, Wagner P, Bertin I, Simonin F, Schmitt M, Bihel F, Bourguignon JJ (2013). Trisubstitution of pyridine through sequential and regioselective palladium cross-coupling reactions affording analogs of known GPR54 antagonists. RSC Adv 3:10296-10300.

Elhabazi K, Humbert JP, Bertin I, Schmitt M, Bihel F, Bourguignon  JJ, Bucher B, Becker JAJ, Sorg T, Meziane H, Petit-Demoulière B, Ilien B, Simonin F (2013). Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors. Neuropharmacol 75:164-171.

Elhabazi K, Trigo J M, Mollereau C, Moulédous L, Zajac JM, Bihel F, Schmitt M, Bourguignon JJ, Meziane H, Petit-demoulière B, Bockel F, Maldonado R, Simonin F (2012). Involvement of neuropeptide FF receptors in neuroadaptative responses to acute and chronic opiates treatments. Br J Pharmacol 165:424-435.

Gealageas R, Schneider S, Humbert JP, Bertin I, Schmitt M, Laboureyras E, Dugave C, Mollereau C, Simonnet G, Bourguignon JJ, Bihel F*, Simonin F* (2012). Development of sub-nanomolar dipeptidic ligands of neuropeptide FF receptors. Bioorg Med Chem Lett 22:7471-7474.

Elhabazi K, Trigo JM, Mollereau C, Moulédous L, Zajac JM, Bihel F, Schmitt M, Bourguignon JJ, Meziane H, Petit-demoulière B, Bockel F, Maldonado R, Simonin F (2011). Involvement of neuropeptide FF receptors in neuroadaptative responses to acute and chronic opiates treatments. Br J Pharmacol 165:424-35

Lecat S*, Ouédraogo M*, Cherrier T, Noulet F, Rondé P, Glasser N, Galzi JL, Mely Y, Takeda K, Bucher B (2011). Contribution of a tyrosine-based motif to cellular trafficking of wild-type and truncated NPY Y(1) receptors. Cell Signal 23:228-38.

Mathis C, Bott JB, Candusso MP, Cassel JC*, Simonin F* (2011). Impaired striatum-dependent behavior in GASP-1 knockout mice. Genes, Brain and Behavior 10:299-308.

Abu-Helo A, Simonin F (2010). Identification and biological significance of G protein-coupled receptor associated sorting proteins (GASP). Pharmacol Ther 126:244-250.

Bœuf J, Trigo JM, Moreau PH, Lecourtier L, Vogel E, Cassel JC, Mathis C, Klosen P, Maldonado R, Simonin F (2009). Attenuated behavioural responses to acute and chronic cocaine in GASP-1 deficient mice. Eur J Neurosci 30:860-868.

Ma L, MacTavish D, Simonin F, Bourguignon JJ, Watanabe T, Jhamandas JH (2009). Prolactin-releasing peptide effects in the rat brain are mediated through the Neuropeptide FF receptor. Eur J Neurosci 30:1585-1593.

Jhamandas JH, Simonin F, Bourguignon JJ, Harris KH (2007). Neuropeptide FF and neuropeptide VF inhibit GABAergic neurotransmission in parvocellular neurons of the rat hypothalamic paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 292:R1872-80

Bourguignon JJ, Simonnet G, Simonin F (2006). RF9, a powerful and selective antagonist of the neuropeptide FF receptors, prevents the development of the tolerance to opioids. Med Sci 22:579-80.

Hachet-Haas M, Converset N, Marchal O, Matthes H, Gioria S, Galzi JL, Lecat S (2006). FRET and colocalization analyzer : a method to validate measurements of sensitized emission FRET acquired by confocal microscopy and available as an ImageJ plug-in. Microsc Res Tech 69:941-56.

Simonin F (2006). Neuropeptide FF receptors as therapeutic targets. Drugs of the Future 31:603-609.

Simonin F, Schmitt M, Laulin JP, Laboureyras E, Jhamandas JH, MacTavish D, Matifas A, Mollereau C, Laurent P, Parmentier M, Kieffer BL, Bourguignon JJ, Simonnet G (2006). RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia. Proc Natl Acad Sci USA 103:466-71.