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

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. © Font et al.
This work was supported by MINECO/ISCIII (SAF2014-55700-P, PCIN-2013–019 C03-03 and PIE14/ 00034), the Catalan Government (2014 SGR 1054), ICREA (ICREA Academia-2010), Fundació la Marató de TV3 (Grant 20152031) and IWT (SBO-140028) to FC. MINECO (PCIN-2013–018 C03-02 and SAF2014-58396-R) to JG. MINECO (PCIN-2013–017 C03-01 and CTQ2014-57020-R), the Catalan Government (2014SGR109 and 2014CTP0002) to AL. ERANET Neuron project ‘LIGHTPAIN’ (to AL, JG, PC and FN). MINECO (CTQ2013-48767-C3-1-R and CTQ2015-71896-REDT), the Catalan Government (2014SGR304) to SN RB-O thanks the European Social Funds and the SUR del DEC de la Generalitat de Catalunya for a predoctoral fellowship (2016 FI_B1 00021).