Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice.

IF 9.1 1区医学 Q1 ANESTHESIOLOGY Anesthesiology Pub Date : 2024-11-05 DOI:10.1097/ALN.0000000000005287

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

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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.

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抑制磷酸二酯酶 10A 可减轻小鼠的类疼痛行为

背景：新的证据表明，环核苷酸磷酸二酯酶在疼痛处理过程中发挥着不同的功能，以磷酸二酯酶为靶点可能是一种新的镇痛策略。本研究假设磷酸二酯酶同工酶PDE10A可能是镇痛治疗的靶点：方法：通过原位杂交、免疫染色、环核苷酸酶免疫测定、实时环鸟苷酸单磷酸成像和实时定量反转录聚合酶链反应来研究背根神经节和脊髓中 PDE10A 的表达和活性。给小鼠注射特定的 PDE10A 抑制剂后，在多种疼痛模型中对雌雄小鼠进行了评估：结果：PDE10A 在小鼠背根神经节和脊髓的痛觉神经元中明显表达。用PDE10A抑制剂TAK-063（150 nM）诱导培养的感觉神经元，在酶免疫测定和单细胞实时成像中会增加环鸟苷单磷酸的水平。令人震惊的是，在急性痛觉模型中，雌性和雄性小鼠在跖内注射辣椒素后，TAK-063（0.3 mg/kg，腹腔注射）可改善其疼痛样行为（平均值±标度；8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [载体]，P = 0.020）或异硫氰酸烯丙酯（2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [载体]；P = 0.018）。此外，TAK-063（0.3 毫克/千克，腹腔注射）减少了跖内注射zymosan（双向方差分析，组，F（1，18）= 48.51，TAK-063 vs. 车辆；P ≤ 0.0001）或完全弗氏佐剂（F（1，14）= 46.10，TAK-063 vs. 车辆；P ≤ 0.0001）诱导的炎症性疼痛模型中已建立的疼痛样行为，且不会产生抗痛觉耐受性。使用 PDE10A 抑制剂 PF-2545920 可以重现这种抗痛觉效应：总之，我们的数据支持了 PDE10A 是开发有效镇痛药物的合适靶点这一观点。

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来源期刊

Anesthesiology 医学-麻醉学

CiteScore

10.40

自引率

5.70%

发文量

542

审稿时长

3-6 weeks

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.