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.

中文翻译：

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磷酸二酯酶 10A 的抑制可减轻小鼠的疼痛样行为。


背景 新出现的证据表明，环核苷酸磷酸二酯酶在疼痛加工中发挥着不同的功能，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亚型 PDE10A 可能是镇痛治疗的靶点。方法 采用原位杂交、免疫染色、环核苷酸酶免疫分析、实时环磷酸鸟苷成像和实时定量逆转录聚合酶链反应检测 PDE10A 在背根神经节和脊髓中的表达和活性。在施用特异性 PDE10A 抑制剂后，在多种疼痛模型中评估了两性小鼠。结果 PDE10A 在小鼠背根神经节和脊髓的伤害感受性神经元中显著表达。培养的感觉神经元与 PDE10A 抑制剂 TAK-063 （150 nM） 一起孵育，增加了酶免疫测定和单细胞水平实时成像中的环鸟苷单磷酸水平。引人注目的是，在足底内注射辣椒素后急性伤害性疼痛模型中，用 TAK-063（腹膜内 0.3 mg/kg 腹膜内注射）治疗改善了雌性和雄性小鼠的疼痛样行为（平均 ± SD;8.87 ± 8.78 秒 [TAK-063] vs. 51.24 ± 36.36 秒 [载体]，P = 0.020）或异硫氰酸烯丙酯（2.46 ± 3.43 秒 [TAK-063] vs. 10.36 ± 4.87 秒 [载体];P = 0.018）。此外，TAK-063 （0.3 mg/kg 腹膜内注射） 减少了足底内注射酵母聚糖诱导的炎症性疼痛模型中已建立的疼痛样行为 （双向方差分析，组，F（1,18） = 48.51，TAK-063 vs. 载体;P ≤ 0.0001）或完全弗氏佐剂 （F（1， 14） = 46.10，TAK-063 vs. 载体;P ≤ 0。0001），没有抗伤害耐受的发展。使用 PDE10A 抑制剂 PF-2545920 概括了抗伤害作用。结论 总的来说，我们的数据支持 PDE10A 是开发有效镇痛药物的合适靶点的观点。