2. Academic Validation
  3. Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

  • Elife. 2017 Apr 11;6:e23545. doi: 10.7554/eLife.23545.
Joan Font  # 1 2 3,  Marc López-Cano  # 4 5,  Serena Notartomaso 6,  Pamela Scarselli 6,  Paola Di Pietro 6,  Roger Bresolí-Obach 7,  Giuseppe Battaglia 6,  Fanny Malhaire 8,  Xavier Rovira 8,  Juanlo Catena 1,  Jesús Giraldo 2 3 9,  Jean-Philippe Pin 8,  Víctor Fernández-Dueñas 4 5,  Cyril Goudet 8,  Santi Nonell 7,  Ferdinando Nicoletti 6 10,  Amadeu Llebaria 1,  Francisco Ciruela 4 5
Affiliations

Affiliations

  • 1 MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
  • 2 Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 3 Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 4 Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, Barcelona, Spain.
  • 5 Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
  • 6 I.R.C.C.S. Neuromed, Pozzilli, Italy.
  • 7 Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, Spain.
  • 8 IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
  • 9 Network Biomedical Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
  • 10 Department of Physiology and Pharmacology, University Sapienza, Rome, Italy.
  • # Contributed equally.
PMID: 28395733 DOI: 10.7554/eLife.23545
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 mGlu5 receptor 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 analgesia in vivo using a photocaged mGlu5 receptor 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.

Keywords

allosteric modulation; analgesia; mGlu5 receptor; mouse; neuroscience; optopharmacology; pain neuraxis.

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