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

Font, Joan; López-Cano, Marc; Notartomaso, Serena; Scarselli, Pamela; Prieto, P.; Bresolí‐Obach, Roger; Battaglia, Giuseppe; Malhaire, Fanny; Rovira, Xavier; Catena, Juanlo; Giraldo, Jesús; Pin, Jean‐Philippe; Fernández-Dueñas, Víctor; Goudet, Cyril; Nonell, Santi; Nicoletti, Ferdinando; Llebaría, Amadeu; Ciruela, Francisco

doi:10.7554/elife.34752

Cited by 4 publications

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“…2b ). JF-NP-26 is an inactive pro-drug of the mGlu5 receptor NAM raseglurant and can be activated by blue-violet light (405 nm) ( 34 ). The trans- isomer of alloswitch-1 is a systemically active mGlu5 receptor NAM, which can be isomerized into inactive cis- alloswitch-1 by blue-violet light (405 nm) and converted back into the active trans- isomer by green light (520 nm) ( 30 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

Notartomaso,

Antenucci,

Mazzitelli

et al. 2024

Preprint

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Knowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of BLA input, and decreased feedforward inhibition of amygdala output neurons by BLA. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.

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Section: Resultsmentioning

confidence: 99%

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

Notartomaso,

Antenucci,

Mazzitelli

et al. 2024

Preprint

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“…To examine the efficacy of light-induced activation of JF-NP-26 in the ET-1 BTcP model, different groups of mice were bilaterally implanted with optic fibers in the ventral basal thalamus or in the prelimbic cortex, two brain regions in which mGlu5 receptors are involved in pain transmission and nociceptive sensibilization [ 17 , 18 ]. Light was delivered at a wavelength of 405 nm, which has been identified as the optimal VS wavelength causing photolysis of JF-NP-26, into the active mGlu5 receptor NAM, raseglurant [ 6 ]. Light delivery into the thalamus 5 min following ET-1, caused fast analgesia in mice that had been treated systemically with JF-NP-26 (10 mg/kg, i.p., injected at the same time as morphine) ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…JF-NP-26, (10 mg/kg, i.p., dissolved in saline containing 6% DMSO and 6% Tween-80) was synthesized by A.L. An in-depth characterization of JF-NP-26 is reported in [ 6 ].…”

Section: Methodsmentioning

confidence: 99%

“…Application of optopharmacology to the control of pain is an emerging field in neuroscience, and light-sensitive ligands of metabotropic glutamate (mGlu) receptors have been tested in several preclinical models of chronic pain [ 6 , 7 ]. mGlu receptors, which are glutamate receptors coupled to G proteins, form a family of eight subtypes, subdivided into three groups based on their amino acid sequence, transduction mechanisms, and pharmacological profile of activation/inhibition.…”

Section: Introductionmentioning

confidence: 99%

“…Using this compound, we could demonstrate that optical control of mGlu5 receptors may provide a new strategy for the experimental treatment of chronic pain. For example, in mice developing neuropathic pain in response to sciatic nerve ligation and systemically injected with JF-NP-26, bilateral delivery of light in the visible spectrum (VS, 405 nm) in the ventrobasal thalamus caused prompt and substantial analgesia, which was even greater than that produced by systemic administration of raseglurant [ 6 ]. The use of a compound activated by VS light is particularly valuable from a translational standpoint because, as opposed to UV light, VS light dose not damage brain tissue.…”

Section: Introductionmentioning

confidence: 99%

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Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain

Notartomaso

Antenucci

Liberatore

et al. 2022

IJMS

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Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic drugs. mGlu5 metabotropic glutamate receptor antagonists display potent analgesic activity, and light-induced activation of one of these compounds (JF-NP-26) in the thalamus was found to induce analgesia in models of inflammatory and neuropathic pain. We used an established mouse model of BTcP based on the injection of cancer cells into the femur, followed, 16 days later, by systemic administration of morphine. BTcP was induced by injection of endothelin-1 (ET-1) into the tumor, 20 min after morphine administration. Mice were implanted with optic fibers delivering light in the visible spectrum (405 nm) in the thalamus or prelimbic cortex to locally activate systemically injected JF-NP-26. Light delivery in the thalamus caused rapid and substantial analgesia, and this effect was specific because light delivery in the prelimbic cortex did not relieve BTcP. This finding lays the groundwork for the use of optopharmacology in the treatment of BTcP.

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The 2020 Roadmap for Bioelectronic Medicine

Lowe

Thakor

2021

Handbook of Neuroengineering

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

Cited by 4 publications

References 0 publications

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain

The 2020 Roadmap for Bioelectronic Medicine

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