• J Pain · Dec 2024

    TRPA1 agonist-responsive afferents contribute to central sensitization by suppressing spinal GABAergic interneurons through Somatostatin 2A receptors.

    • Ramesh Pariyar, Jigong Wang, Regan Hammond, Ho Koo, Nicholas Dalley, and Jun-Ho La.
    • Department of Neurobiology, The University of Texas Medical Branch, Galveston, Texas.
    • J Pain. 2024 Dec 1; 25 (12): 104686104686.

    AbstractAltered nociception, a key feature of nociplastic pain, often involves central sensitization. We previously found that central sensitization underlying a nociplastic pain state in female mice depends on the ongoing activity of TRPA1 agonist-responsive afferents. Here, we investigated how the activity of these afferents induces and maintains central sensitization at the spinal level. We hypothesized that, in the superficial dorsal horn where somatostatin (SST) is expressed in excitatory interneurons and the SST2A receptor (SST2A-R) in GABAergic inhibitory interneurons (GABAn), TRPA1 agonist-responsive afferents stimulate SST-expressing excitatory interneurons (SSTn), leading to GABAn suppression through SST2A-R and resulting in altered nociception. We tested this hypothesis using ex vivo Ca2+ imaging of dorsal root-attached spinal cord slices expressing GCaMP6f in either SSTn or GABAn and in vivo assessment of mechanical hypersensitivity. The dorsal root was chemically (with allyl isothiocyanate [AITC]) and electrically stimulated to activate TRPA1-expressing nociceptors and all afferents, respectively. The stimulation of dorsal root with AITC excited SSTn. During activation of AITC-responsive afferents, a subset of SSTn showed potentiated responses to both low- and high-threshold afferent inputs, whereas a subset of GABAn showed suppressed responses to those afferents in an SST2A-R-dependent manner. Intrathecally administered SST2A-R antagonist inhibited the development of mechanical hypersensitivity by intraplantar AITC injection and alleviated persistent mechanical hypersensitivity in the murine model of nociplastic pain. These results suggest that the activity of TRPA1 agonist-responsive afferents induces and maintains central sensitization by activating dorsal horn SSTn and suppressing GABAn via SST2A-R, resulting in altered nociception that manifests as mechanical hypersensitivity. PERSPECTIVE: This article presents experimental evidence that TRPA1 agonist-responsive afferents induce and maintain central sensitization at the spinal level by activating SST-expressing excitatory interneurons and suppressing GABAergic inhibitory interneurons via SST2A-R. Spinal SST2A-R may represent a promising target for treating mechanical pain hypersensitivity due to central sensitization by TRPA1 agonist-responsive afferents.Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

      Pubmed     Copy Citation     Plaintext  

      Add institutional full text...

    Notes

     
    Knowledge, pearl, summary or comment to share?
    300 characters remaining
    help        
    You can also include formatting, links, images and footnotes in your notes
    • Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.
    • Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.
    • Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.
    • Links can be included with: [my link to pubmed](http://pubmed.com)
    • Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")
    • For footnotes use [^1](This is a footnote.) inline.
    • Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..

    hide…

What will the 'Medical Journal of You' look like?

Start your free 21 day trial now.

We guarantee your privacy. Your email address will not be shared.