Phosphodiesterase 2A Localized in the Spinal Cord Contributes to Inflammatory Pain Processing

Kallenborn-Gerhardt, Wiebke; Lu, Ruirui; Bothe, A. M.; Thomas, Dominique; Schlaudraff, Jessica; Lorenz, Jana E.; Lippold, Nancy; Real, CI; Ferreiròs, Nerea; Geißlinger, Gerd; Turco, Domenico Del; Schmidtko, Achim

doi:10.1097/aln.0000000000000270

Cited by 14 publications

(10 citation statements)

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“…Knockout studies of PDE11A have implicated this gene in regulating social behaviors and anxiety 43 . In the dorsal horn, cyclic nucleotide signaling contributes to pain-related neuronal plasticity, and other members of the phosphodiesterase family have been directly implicated in the pathogenesis of inflammatory and neuropathic pain 44 . Accordingly, we selected Pde11a for further examination.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

Chamessian

Young

Qadri

et al. 2018

Sci Rep

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The spinal dorsal horn (SDH) is comprised of distinct neuronal populations that process different somatosensory modalities. Somatostatin (SST)-expressing interneurons in the SDH have been implicated specifically in mediating mechanical pain. Identifying the transcriptomic profile of SST neurons could elucidate the unique genetic features of this population and enable selective analgesic targeting. To that end, we combined the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) method and Fluorescence Activated Nuclei Sorting (FANS) to capture tagged SST nuclei in the SDH of adult male mice. Using RNA-sequencing (RNA-seq), we uncovered more than 13,000 genes. Differential gene expression analysis revealed more than 900 genes with at least 2-fold enrichment. In addition to many known dorsal horn genes, we identified and validated several novel transcripts from pharmacologically tractable functional classes: Carbonic Anhydrase 12 (Car12), Phosphodiesterase 11 A (Pde11a), and Protease-Activated Receptor 3 (F2rl2). In situ hybridization of these novel genes showed differential expression patterns in the SDH, demonstrating the presence of transcriptionally distinct subpopulations within the SST population. Overall, our findings provide new insights into the gene repertoire of SST dorsal horn neurons and reveal several novel targets for pharmacological modulation of this pain-mediating population and treatment of pathological pain.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

Chamessian

Young

Qadri

et al. 2018

Sci Rep

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“…Knockout studies of PDE11A have implicated this gene in regulating social behaviors and anxiety (Hegde et al, 2016a;2016b). In the dorsal horn, cyclic nucleotide signaling contributes to pain-related neuronal plasticity, and other members of the phosphodiesterase family have been directly implicated in the pathogenesis of inflammatory and neuropathic pain (Kallenborn-Gerhardt et al, 2014). Previous studies have detected Pde11a transcript and PDE11A protein in the bulk analyses of the spinal cord, but its cellular expression pattern is unknown (Kelly, 2015).…”

Section: Enzymesmentioning

confidence: 99%

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

Chamessian

Young

Qadri

et al. 2017

Preprint

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The spinal dorsal horn (SDH) is comprised of distinct neuronal populations that process different . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/215657 doi: bioRxiv preprint first posted online Nov. 8, 2017; and Gpr26). Taken together, our study unveils a comprehensive transcriptional signature for SST neurons, highlights promising candidate genes for future analgesic development, and establishes a flexible method for transcriptional profiling of any spinal cord cell type.

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“…There is general consensus that PDE2A is abundant in the central nervous system of mammals, especially in the laminae I and II of spinal dorsal horn in rats [20, 34]. In addition, PDE2A might contribute to acute inflammatory pain processing [19]. Recent experiments have detected that an inhibitor of PDE2A had anti-inflammatory and analgesic effects [35].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have demonstrated that inhibitors of PDEs inhibit the release of proinflammatory cytokines by cAMP/cGMP signaling pathways in depression, pulmonary hypertension, erectile dysfunction, and sepsis [17, 18]. Wiebke and Ruirui et al found transient PDE2A mRNA upregulation after hind paw inflammation that was accompanied by enhanced acute mechanical paw withdrawal latencies, which indicated that PDE2A likely contributed to acute radicular inflammation and pain [19]. PDE2A can hydrolyze both cAMP and cGMP and preferentially hydrolyzes cAMP after activation by cGMP [20].…”

Section: Introductionmentioning

confidence: 99%

Low-Concentration Oxygen/Ozone Treatment Attenuated Radiculitis and Mechanical Allodynia via PDE2A-cAMP/cGMP-NF-κB/p65 Signaling in Chronic Radiculitis Rats

Wang

Lin

et al. 2018

Pain Research and Management

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Background Oxygen/ozone therapy is a minimally invasive technique for the treatment of radiculitis from lumbar disc herniation. This study aimed at investigating whether intrathecal administration of low-concentration oxygen/ozone could attenuate chronic radiculitis and mechanical allodynia after noncompressive lumbar disc herniation and at elucidating the underlying mechanisms. Methods First, we transplanted autologous nucleus pulposus into dorsal root ganglions to establish chronic radiculitis in rats. Then, filtered oxygen or oxygen/ozone (10, 20, or 30 μg/mL) was intrathecally injected on day 1 after surgery. The ipsilateral paw withdrawal thresholds (PWTs) to mechanical stimuli were tested daily with von Frey filaments. The expression of the tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), phosphodiesterase 2A (PDE2A), and nuclear factor- (NF-) κB/p65 in spinal dorsal horns was measured by enzyme-linked immunosorbent assay, polymerase chain reaction, and western blot on day 7 after surgery. Results Chronic radiculitis was established in rats. Intrathecal administration of 10 μg/mL, 20 μg/mL, or 30 μg/mL oxygen/ozone significantly attenuated the decreased mechanical PWTs, downregulated the overexpression of spinal TNF-α, IL-1β, and IL-6, and increased the expression of cGMP and cAMP in chronic radiculitis rats. In addition, the effects of treatment with 20 μg/mL oxygen/ozone were greater than the effects of the 10 μg/mL or 30 μg/mL doses. Moreover, intrathecal administration of 20 μg/mL oxygen/ozone reversed the increased levels of spinal PDE2A and NF-κB/p65 mRNA and protein expressions in rats with chronic radiculitis. Conclusion Intrathecal administration of low-concentration oxygen/ozone alleviated mechanical allodynia and attenuated radiculitis, likely by a PDE2A-cGMP/cAMP-NF-κB/p65 signaling pathway in chronic radiculitis rats.

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Phosphodiesterase 2A Localized in the Spinal Cord Contributes to Inflammatory Pain Processing

Abstract: Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.

Cited by 14 publications

References 49 publications

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

Low-Concentration Oxygen/Ozone Treatment Attenuated Radiculitis and Mechanical Allodynia via PDE2A-cAMP/cGMP-NF-κB/p65 Signaling in Chronic Radiculitis Rats

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