Light-Controlled Modulation and Analysis of Neuronal Functions

Matera, Carlo; Bregestovski, Pìotr

doi:10.3390/ijms232112921

Cited by 3 publications

(2 citation statements)

References 67 publications

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“…Bar histograms show means ± SEM of 10 (b), 3-5 (c), 4-5 (d), 4-5 (e), 5-8 (f), 10 (g) mice per group. Two-way ANOVA: (b) sham vs CCI, F(1,36)=16.04; p=0.0003; ipsi vs contra, F(1,36)=7.304; p=0.0104; interaction F(1,36)=5.062, p=0.0307; (c) sham vs CCI, F(1,11)=0.5569; p=0.4712; vehicle vs VU0360172, F(1,11)=5.741, p=0.0355; interaction (F1,11)=0.8168, p=0.3855; (d) sham vs CCI, F(1,15)=1.075; p=0.3163; vehicle vs VU0360172, F(1,15)=6.452, p=0.0226; interaction (F1,15)=0.7034, p=0.4148; (e) sham vs CCI, F(1,13)=3.951; p=0.0683; vehicle vs VU0360172, F(1,13)=11.21, p=0.0052; interaction (F1,13)=0.1553, p=0.6999; (f) sham vs CCI, F(1,22)=0.01997, p=0.8889; vehicle vs VU0360172, F(1,22)=8.888, p=0.0069; interaction (F1,22)=6.099, p=0.0218; (g) sham vs CCI, F(1,36)=0.4861, p=0.4902; vehicle vs VU0360172, F(1,36)=4.557, p=0.0397; interaction (F1,36)=2.313, p=0.1370. *p<0.05, **p<0.01; ***p<0.001, Bonferroni’s multiple comparison post hoc test.…”

Section: Resultsmentioning

confidence: 99%

“…Using light-sensitive drugs, it is possible to optimize the efficacy of new therapeutic agents and minimize their adverse effects resulting from widespread actions after systemic administration. The use of photopharmacology-based approaches to interrogate receptors in brain is attractive due to the possibilities of manipulating the activity of specific localizations during defined times ( 10, 11 ).…”

Section: Introductionmentioning

confidence: 99%

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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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

WAY-262611 ameliorates the inflammatory bowel disease by activating Wnt/β-catenin pathway

Du,

Luo,

Zhu

et al. 2024

In Vitro Cell.Dev.Biol.-Animal

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

Notartomaso,

Antenucci,

Mazzitelli

et al. 2024

eLife

View full text Add to dashboard Cite

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 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 the 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 presumed BLA input, and decreased BLA-driven feedforward inhibition of amygdala output neurons. 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.

show abstract

Light-Controlled Modulation and Analysis of Neuronal Functions

Cited by 3 publications

References 67 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

WAY-262611 ameliorates the inflammatory bowel disease by activating Wnt/β-catenin pathway

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

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