Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain

Pereira, Vanessa; Arias, Juri Aparicio; Llebaría, Amadeu; Goudet, Cyril

doi:10.1016/j.phrs.2022.106602

Cited by 8 publications

(8 citation statements)

References 46 publications

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“…These photoisomerization properties are similar to other photoswitchable allosteric modulators for mGlu receptors, including alloswitch-1 30 and aBINA. 31 Additionally, both alloswitch-1 and optogluram were found to have excellent photoswitching properties in experiments in vivo , 26 , 27 , 30 , 35 indicating that a moderate photoisomerization in vitro may induce considerable changes in highly regulated physiological systems.…”

Section: Discussionmentioning

confidence: 95%

“…Thus, we validated the role of mGlu 4 receptor in amygdala as a key signaling effector bypassing central sensitization processes to dynamically modulate chronic pain symptoms. 27 , 35 However, the mGlu receptor subtype selectivity of optogluram was not optimal, since it was also activating mGlu 6 , and in a lower degree mGlu 8 receptor. Given the restricted expression of mGlu 6 receptor, predominantly in retina, 60 this lack of selectivity does not hinder the study of mGlu 4 biological function in different brain areas.…”

Section: Discussionmentioning

confidence: 99%

“… 27 This allowed a dynamic on/off control of pain transmission associated with mGlu 4 receptors localized in the amygdala. 27 , 35 …”

Section: Introductionmentioning

confidence: 99%

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Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

Panarello,

González-Díez,

Berizzi

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

Panarello,

González-Díez,

Berizzi

et al. 2024

iScience

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“…Photopharmacology represents a powerful means of optically controlling biological function through the use of light-sensitive compounds 1,2 . In addition to its use in a wide variety of basic science applications [3][4][5][6][7][8][9][10][11][12] , photopharmacology has now entered clinical trials via KIO-301, a photoswitchable ion channel blocker with great potential for vision restoration 13 . This compound utilizes an azobenzene-based photoswitch, which represents one of the primary chemical moieties used in photopharmacological probes 14 .…”

Section: Main Textmentioning

confidence: 99%

Deuteration provides a general strategy to enhance azobenzene-based photopharmacology

Roßmann,

Gonzalez-Hernandez,

Bhuyan

et al. 2023

Preprint

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Herein, we present deuterated azobenzene photoswitches as a general means of enhancing photopharmacological molecules. Deuteration can improve azobenzene performance in terms of light sensitivity, photoswitch efficiency, and photoswitch kinetics with minimal alteration to the underlying structure of the photopharmacological ligand. We report synthesized deuterated azobenzene-based ligands for the optimized optical control of ion channel and G protein-coupled receptor function in live cells, setting the stage for the straightforward, widespread adoption of this approach.

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“…Photopharmacological approaches have recently been explored for pain modulation by members of our team (12)(13)(14) and by others (15,16). The drug treatment of neuropathic pain, i.e., chronic pain originating from damage or disease of the somatosensory system, remains a major therapeutic challenge and unmet medical need because of severe side effects and a high percentage of patients resistant to medication (17,18).…”

Section: Introductionmentioning

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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Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain

Cited by 8 publications

References 46 publications

Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

Deuteration provides a general strategy to enhance azobenzene-based photopharmacology

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

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