Tilman Gross, Daniel Stehle, Chantal Nagel, Fangyuan Zhou, Emre Duman, Victor Hernandez-Olmos, Rekia Sinderwald, Hannah Gerninghaus, Jonas Petersen, Susanne Feil, Wiebke Kallenborn-Gerhardt, Ruirui Lu, Katharina Metzner, Robert Feil, Ewgenij Proschak, Achim Schmidtko
{"title":"Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice.","authors":"Tilman Gross, Daniel Stehle, Chantal Nagel, Fangyuan Zhou, Emre Duman, Victor Hernandez-Olmos, Rekia Sinderwald, Hannah Gerninghaus, Jonas Petersen, Susanne Feil, Wiebke Kallenborn-Gerhardt, Ruirui Lu, Katharina Metzner, Robert Feil, Ewgenij Proschak, Achim Schmidtko","doi":"10.1097/ALN.0000000000005287","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform PDE10A might be a target for analgesic therapy.</p><p><strong>Methods: </strong>In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors.</p><p><strong>Results: </strong>PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD; 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (Two-way ANOVA, group, F(1, 18) = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund's adjuvant (F(1, 14) = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920.</p><p><strong>Conclusion: </strong>Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.</p>","PeriodicalId":7970,"journal":{"name":"Anesthesiology","volume":null,"pages":null},"PeriodicalIF":9.1000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anesthesiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/ALN.0000000000005287","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ANESTHESIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform PDE10A might be a target for analgesic therapy.
Methods: In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors.
Results: PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD; 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (Two-way ANOVA, group, F(1, 18) = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund's adjuvant (F(1, 14) = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920.
Conclusion: Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.
期刊介绍:
With its establishment in 1940, Anesthesiology has emerged as a prominent leader in the field of anesthesiology, encompassing perioperative, critical care, and pain medicine. As the esteemed journal of the American Society of Anesthesiologists, Anesthesiology operates independently with full editorial freedom. Its distinguished Editorial Board, comprising renowned professionals from across the globe, drives the advancement of the specialty by presenting innovative research through immediate open access to select articles and granting free access to all published articles after a six-month period. Furthermore, Anesthesiology actively promotes groundbreaking studies through an influential press release program. The journal's unwavering commitment lies in the dissemination of exemplary work that enhances clinical practice and revolutionizes the practice of medicine within our discipline.