Résumé
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.
In adult mice, the phosphodiesterase isoform PDE10A is expressed in nociceptive neurons in the dorsal root ganglia and the spinal cord. Treatment of mice with a specific PDE10A inhibitor profoundly ameliorates pain-like behavior in models of acute nociceptive and chronic inflammatory pain. These laboratory observations suggest that the use of PDE10A inhibitors may be a novel therapeutic strategy for pain treatment.