title: Optical control of painin vivowith a photoactive mGlu5receptor negative allosteric modulator.
abstract: Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug's release, which effectively controls mGlu5receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesiain vivousing a photocaged mGlu5receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders.
authors.affiliation: MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.|Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Font
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, Barcelona, Spain.|Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: López-Cano
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Serena
authors.identifier: http://orcid.org/0000-0003-4374-9233
authors.initials: S
authors.lastname: Notartomaso
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Pamela
authors.identifier: http://orcid.org/0000-0002-4245-0849
authors.initials: P
authors.lastname: Scarselli
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Paola
authors.identifier: http://orcid.org/0000-0003-1327-1961
authors.initials: P
authors.lastname: Di Pietro
authors.affiliation: Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: Roger
authors.identifier: http://orcid.org/0000-0002-7819-7750
authors.initials: R
authors.lastname: Bresolí-Obach
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Giuseppe
authors.identifier: http://orcid.org/0000-0001-7571-3417
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Malhaire
authors.affiliation: IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
authors.forename: Xavier
authors.identifier: http://orcid.org/0000-0002-9764-9927
authors.initials: X
authors.lastname: Rovira
authors.affiliation: MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
authors.forename: Juanlo
authors.initials: J
authors.lastname: Catena
authors.affiliation: Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Network Biomedical Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jesús
authors.identifier: http://orcid.org/0000-0001-7082-4695
authors.initials: J
authors.lastname: Giraldo
authors.affiliation: IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
authors.forename: Jean-Philippe
authors.identifier: http://orcid.org/0000-0002-1423-345X
authors.initials: JP
authors.lastname: Pin
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, Barcelona, Spain.|Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Víctor
authors.identifier: http://orcid.org/0000-0001-7834-2965
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.affiliation: IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
authors.forename: Cyril
authors.identifier: http://orcid.org/0000-0002-8255-3535
authors.initials: C
authors.lastname: Goudet
authors.affiliation: Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: Santi
authors.initials: S
authors.lastname: Nonell
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.|Department of Physiology and Pharmacology, University Sapienza, Rome, Italy.
authors.forename: Ferdinando
authors.identifier: http://orcid.org/0000-0003-0917-443X
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
authors.forename: Amadeu
authors.identifier: http://orcid.org/0000-0002-8200-4827
authors.initials: A
authors.lastname: Llebaria
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, Barcelona, Spain.|Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Francisco
authors.identifier: http://orcid.org/0000-0003-0832-3739
authors.initials: F
authors.lastname: Ciruela
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D008027:Light; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010146:Pain; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects*
chemical_list: D000700:Analgesics; D017319:Photosensitizing Agents; D064529:Receptor, Metabotropic Glutamate 5
keywords: allosteric modulation; analgesia; mGlu5 receptor; mouse; neuroscience; optopharmacology; pain neuraxis