Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

De, Carmen; Russo, Roberto; Avagliano, Carmen; Cristiano, Claudia; Calignano, Antonio; Aramini, Andrea; Bianchini, Gianluca; Allegretti, Marcello; Brandolini, Laura

doi:10.1111/bph.14177

Cited by 39 publications

(57 citation statements)

References 66 publications

(79 reference statements)

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“…However, cold stimulation was not examined by our team, which is likely the key modality to evaluate for this mechanism (Patel et al 2014). In contrast, other teams have reported that TRPM8 receptor antagonists were efficacious against mechanical allodynia in rodent models (De Caro et al 2018;Salat and Filipek 2015), but it is unclear how this effect was induced since these studies did not determine the pathways/sites that were modulated by the antagonists.…”

Section: Discussionmentioning

confidence: 92%

Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain

McGaraughty

Chu

2018

Journal of Neurophysiology

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This overview compares the activity of wide dynamic range (WDR) and nociceptive specific (NS) neurons located in the deep dorsal horn across different rat models of pathological pain and following modulation by diverse pharmacology. The data were collected by our group under the same experimental conditions over numerous studies to facilitate comparison. Spontaneous firing of WDR neurons was significantly elevated (>3.7 Hz) in models of neuropathic, inflammation, and osteoarthritic pain compared with naive animals (1.9 Hz) but was very low (<0.5 Hz) and remained unchanged in NS neurons. WDR responses to low-intensity mechanical stimulation were elevated in neuropathic and inflammation models. WDR responses to high-intensity stimuli were enhanced in inflammatory (heat) and osteoarthritis (mechanical) models. NS responses to high-intensity stimulation did not change relative to control in any model examined. Several therapeutic agents reduced both evoked and spontaneous firing of WDR neurons (e.g., TRPV1, TRPV3, Na1.7, Na1.8, P2X7, P2X3, H), other targets affected neither evoked nor spontaneous firing of WDR neurons (e.g., H, TRPM8, KCNQ2/3), and some only modulated evoked (e.g, ASIC1a, Ca3.2) whereas others decreased evoked but affected spontaneous activity only in specific models (e.g., TRPA1, CB2). Spontaneous firing of WDR neurons was not altered by any peripherally restricted compound or by direct administration of compounds to peripheral sites, although the same compounds decreased evoked activity. Compounds acting centrally were effective against this endpoint. The diversity of incoming/modulating inputs to the deep dorsal horn positions this group of neurons as an important intersection within the pain system to validate novel therapeutics. NEW & NOTEWORTHY Data from multiple individual experiments were combined to show firing properties of wide dynamic range and nociceptive specific spinal dorsal horn neurons across varied pathological pain models. This high-powered analysis describes the sensitization following different forms of injury. Effects of diverse pharmacology on these neurons is also summarized from published and unpublished data all recorded under the same conditions to facilitate comparison. This comprehensive overview describes the function and utility of these neurons.

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Section: Discussionmentioning

confidence: 92%

Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain

McGaraughty

Chu

2018

Journal of Neurophysiology

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“… 99 It has been reported that TRPM8 activation produces analgesia, 73 but TRPM8 inhibition has also been found crucial to reduce acute and chronic pain. 16 , 17 Effect of the variants on the functional properties of the TRPM8 channel are not known, and thus their contribution to the pain phenotype in the 2 carriers awaits further studies. Expanding understanding of TRP channels involved in ocular itch and pain 48 and of how injury and inflammation can induce changes in ocular pain pathways 5 likely add to our understanding of CN in the future.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of 21 patients with corneal neuralgia after refractive surgery

Yuan

Schulman

Effraim

et al. 2020

PR9

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“…TRPM8 has a role in core body temperature regulation and detection of TRM8 antagonist underline its competence in paintreatment [17,42]. A pharmacological blockage of TRPM8 signaling determines a reduction in cold hypersensitivity induced by nerve injury [6,15,43].…”

Section: Discussionmentioning

confidence: 99%

TRPV4 and TRPM8 as putative targets for chronic low back pain alleviation

Fozzato

Baranzini

Bossi

et al. 2020

Pflugers Arch - Eur J Physiol

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The purpose of this study is to investigate the presence of nervous fibers and expression of TRP channels in samples harvested during decompressive/fusion spine surgeries from patients affected by chronic low back pain (CLBP). The aim was to understand if members of this family of receptors played a role in detection and processing of painful stimuli, to eventually define them as potential targets for CLBP alleviation. Expression of transient receptor potential (TRP) channels (A1, V1, V2, V4, and M8) was evaluated in samples from different periarticular sites of 6 patients affected by CLBP, at both protein and transcript levels. The capsular connective pathological tissue appeared infiltrated by sensitive unmyelinated nervous fibers. An increase in TRP channel mRNAs and proteins was observed in the pathological capsule compared with tissues collected from the non-symptomatic area in five of the six analyzed patients, independently by the location and number of affected sites. In particular, TRPV4 and TRPM8 were consistently upregulated in pathological tissues. Interestingly, the only patient showing a different pattern of expression also had a different clinical history. TRPV4 and TRPM8 channels may play a role in CLBP and warrant further investigations as possible therapeutic targets.

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Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

Abstract: Our findings, in agreement with previous literature, encourage further studies for a better comprehension of the therapeutic potential of TRPM8 blockers as novel agents for pain management.

Cited by 39 publications

References 66 publications

Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain

Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain

Genomic analysis of 21 patients with corneal neuralgia after refractive surgery

TRPV4 and TRPM8 as putative targets for chronic low back pain alleviation

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