Optical Control of Brain Receptors Using Photoactive Drugs in Behaving Animals

Abstract

Photopharmacology, a pioneering research field, relies on the use of light to activate drugs with high spatiotemporal resolution. Interestingly, some light-regulated agents targeting G protein-coupled receptors (GPCRs) have been recently developed, providing great pharmacological precision while controlling pain. Indeed, GPCRs, such as metabotropic glutamate type 5 (mGlu5) receptor or mu-opioid receptor (μOR), play a key role in pain transmission. Thus, selective mGlu5 receptor negative allosteric modulators (NAMs) have been shown to have antinociceptive activity in preclinical models of inflammatory pain, but not without some off-target effects. Accordingly, we synthesized a light-deliverable drug (i.e., caged compound) using the chemical structure of raseglurant, a mGlu5 receptor NAM, as a molecular scaffold. We evaluated the light-dependent antinociceptive activity of the caged compound in the formalin-based mouse model of pain while light was delivered both at the peripheral (i.e., hind paw) and central level (i.e., thalamus). Interestingly, the novel photocaged compound, JF-NP-26, showed antinociceptive efficacy upon violet (405 nm) light irradiation, either of the hind paw or on the central nervous system. Therefore, here we describe in detail the protocol to implement a photopharmacological manipulation of pain transmission in the formalin model of nociception in mice.