抑制磷酸二酯酶10A可减轻小鼠的疼痛样行为。

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

作者信息

Gross Tilman, Stehle Daniel, Nagel Chantal, Zhou Fangyuan, Duman Emre, Hernandez-Olmos Victor, Sinderwald Rekia, Gerninghaus Hannah, Petersen Jonas, Feil Susanne, Kallenborn-Gerhardt Wiebke, Lu Ruirui, Metzner Katharina, Feil Robert, Proschak Ewgenij, Schmidtko Achim

机构信息

Institute of Pharmacology and Clinical Pharmacy, Goethe University Frankfurt, Frankfurt am Main, Germany.

Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.

出版信息

Anesthesiology. 2025 Feb 1;142(2):332-348. doi: 10.1097/ALN.0000000000005287. Epub 2024 Nov 5.

DOI:10.1097/ALN.0000000000005287

PMID:39503623

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 phosphodiesterase 10A (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.

CONCLUSIONS

Collectively, the data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.

摘要

背景

新出现的证据表明，环核苷酸磷酸二酯酶在疼痛处理中发挥着独特作用，靶向磷酸二酯酶可能是一种缓解疼痛的新策略。本研究假设磷酸二酯酶同工型磷酸二酯酶10A（PDE10A）可能是镇痛治疗的靶点。

方法

采用原位杂交、免疫染色、环核苷酸酶免疫测定、实时环磷酸鸟苷成像和实时定量逆转录聚合酶链反应，研究PDE10A在背根神经节和脊髓中的表达及活性。在给予特异性PDE10A抑制剂后，对雌雄小鼠在多种疼痛模型中进行评估。

结果

PDE10A在小鼠背根神经节和脊髓的伤害性神经元中特异性表达。在酶免疫测定和单细胞水平的实时成像中，用PDE10A抑制剂TAK-063（150 nM）孵育培养的感觉神经元可提高环磷酸鸟苷水平。令人惊讶的是，在足底注射辣椒素（平均值±标准差，8.87±8.78秒[TAK-063]对51.24±36.36秒[溶媒]，P = 0.020）或异硫氰酸烯丙酯（2.46±3.43秒[TAK-063]对10.36±4.87秒[溶媒]；P = 0.018）后的急性伤害性疼痛模型中，TAK-063（0.3 mg/kg腹腔注射）改善了雌性和雄性小鼠的疼痛样行为。此外，TAK-063（0.3 mg/kg腹腔注射）减轻了足底注射酵母聚糖（双向方差分析，组，F[1,18] = 48.51，TAK-063对溶媒；P≤0.0001）或完全弗氏佐剂（F[1,14] = 46.10，TAK-063对溶媒；P≤0.0\001）诱导的炎症性疼痛模型中已建立的疼痛样行为，且未产生抗伤害感受耐受性。使用PDE10A抑制剂PF-2545920可重现抗伤害感受作用。