mGluRs Head to Toe in Pain

Kolber, Benedict J.

doi:10.1016/bs.pmbts.2014.12.003

Cited by 21 publications

(19 citation statements)

References 130 publications

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“…First, we proved the validity of our approach in mice subjected to unilateral CCI of the sciatic nerve, in which we explored the contribution of central mGlu 5 receptors by photomodulating these receptors in the ventrobasal thalamus, a pivotal relay and processing point for somatosensory information ascending from the spinal cord to the cerebral cortex (Kolber, 2015; Palazzo et al, 2014). Accordingly, we implanted optical fibers in the brain to allow precise light delivery into the ventrobasal thalamus (Figure 4A).…”

Section: Resultsmentioning

confidence: 95%

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

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López-Cano

Notartomaso

et al. 2017

eLife

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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.DOI: http://dx.doi.org/10.7554/eLife.23545.001

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Section: Resultsmentioning

confidence: 95%

“…Metabotropic glutamate (mGlu) receptors are widely distributed along the pain neuraxis and modulate pain transmission (Kolber, 2015) at different anatomical levels. Hence, subtype-selective mGlu receptor ligands are considered as promising candidate drugs for the treatment of chronic pain.…”

Section: Introductionmentioning

confidence: 99%

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

Font

López-Cano

Notartomaso

et al. 2017

eLife

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“…Direct agonists for group II mGluRs have been efficacious for relief of pain in animal studies [26], but have only been tested in human clinical trials for non-pain related indications [17; 39]. It remains unclear whether direct, ligand-activated group II mGluRs likewise reduces pain.…”

Section: Discussionmentioning

confidence: 99%

Group II mGluRs suppress hyperexcitability in mouse and human nociceptors

Davidson

Golden

Copits

et al. 2016

Pain

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We introduce a strategy for preclinical research wherein promising targets for analgesia are tested in rodent and subsequently validated in human sensory neurons. Here, we evaluate group II metabotropic glutamate receptors, the activation of which is efficacious in rodent models of pain. Immunohistochemical analysis showed positive immunoreactivity for mGlu2 in rodent dorsal root ganglia (DRG), peripheral fibers in skin, and central labeling in spinal dorsal horn. We also found mGlu2-positive immunoreactivity in human neonatal and adult DRG. RNA-seq analysis of mouse and human DRG revealed a comparative expression profile between species for group II mGluRs and for opioid receptors. In rodent sensory neurons under basal conditions, activation of group II mGluRs with a selective group II agonist produced no changes to membrane excitability. However, membrane hyperexcitability in sensory neurons exposed to the inflammatory mediator prostaglandin E2 (PGE2) was prevented by (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC). In human sensory neurons from donors without history of chronic pain, we show that PGE2 produced hyperexcitability that was similarly blocked by group II mGluR activation. These results reveal a mechanism for peripheral analgesia likely shared by mouse and human and demonstrate a translational research strategy to improve preclinical validation of novel analgesics using cultured human sensory neurons.

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“…Similar to Otoshi et al (2009), our results demonstrated no difference to the cytostructure to laminae I-III despite alteration in gene expression in the absence of descending input. Of significant interest is the alteration of the metabotropic glutamate receptors, in which maladaptive mGluR expression has been linked to neuropathic pain, allodynia and hyperalgesia (Mills et al, 2001;Kolber, 2015;Chiechio, 2016). Our results demonstrate that mGluR expression increased between 15 and 25% following a STx in laminae I-III.…”

Section: Gene Expression In Laminae I-iii Postspinal Transectionmentioning

confidence: 62%

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

Chopek

MacDonell

Shepard

et al. 2018

Eur J of Neuroscience

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Gene expression is altered following a spinal transection (STx) in both motor and sensory systems. Exercise has been shown to influence gene expression in both systems post-STx. Gene expression alterations have also been shown in the dorsal root ganglia and nociceptive laminae of the spinal cord following either an incomplete spinal cord injury (SCI) or a contusive SCI. However, the effect of STx and exercise on gene expression in spinal cord laminae I-III has not fully been examined. Therefore, the purpose of this study was to determine whether gene expression in laminae I-III is altered following STx and determine whether superimposed passive exercise of the hindlimbs would influence gene expression post-STx in laminae I-III. Laser capture microdissection was used to selectively harvest laminae I-III of lumbar spinal cord sections, and quantitative RT-PCR was used to examine relative expression of 23 selected genes in samples collected from control, STx and STx plus exercise rats. We demonstrate that post-STx, gene expression for metabotropic glutamate receptors 1, 5 and 8 were up-regulated, whereas ionotropic glutamatergic receptor (Glur2) and glycinergic subunit GLRA1 expression was down-regulated. Daily exercise attenuated the down-regulation of Glur2 gene expression in laminae I-III. Our results demonstrate that in a STx model, gene expression is altered in laminae I-III and that although passive exercise influences gene expression in both the motor and sensory systems, it had a minimal effect on gene expression in laminae I-III post-STx.

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mGluRs Head to Toe in Pain

Cited by 21 publications

References 130 publications

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

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

Group II mGluRs suppress hyperexcitability in mouse and human nociceptors

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

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