A Comparative Study on the Antinociceptive Effects of Phosphodiesterase Inhibitors on Sciatic Nerve Ligation Induced Neuropathic Pain in Mice

Introduction: The role of phosphodiesterase (PDE) inhibitors in reducing neuropathic pains is uncertain. In this study, the antinociceptive effects of theophylline, milrinone, and tadalafil were investigated on sciatic nerve ligation-induced neuropathic pain (NP).Methods: Male mice (25-30 g) were purchased and housed in controlled environmental conditions before and during the experiments. The mice received identical diet and water ad libitum. Two weeks after sciatic nerve ligation, either theophylline (75 mg/kg), milrinone (4.5 mg/kg), or tadalafil (20 mg/kg) was intraperitoneally (IP) injected for either 1, 3, or 7 consecutive days. Antinociceptive effects were evaluated using the hot plate test. Negative controls received time course IP injections of saline (5 mL/kg). A single dose of imipramine (40 mg/kg,) was intraperitoneally administrated to the mice in the positive control group. Results: As was found for this study, a single-dose IP injection of either theophylline (75 mg/kg), milrinone (4.5 mg/kg), or tadalafil (20 mg/kg) on day 14th following sciatic nerve ligation induced significant antinociceptive effects at 30 minutes (P < 0.01), 60 minutes (P < 0.01), and 90 minutes (P < 0.05) compared to the control (saline– treated) animals. Accordingly, both 3- (on days 12–14) and 7-day (on days 8– 14) IP injections of tadalafil (20 mg/kg) induced significant antinociceptive effects at 30 minutes (P < 0.05), 60 minutes (P < 0.01), and 90 minutes (P < 0.01) after sciatic nerve ligation compared to the control (saline–treated) animals. However, the 3- and 7-day IP injections of theophylline and milrinone did not reveal any significant differences compared to the control group. Conclusion: Taken together, the results of this study suggested that selective PDE inhibitors that act predominantly on cGMP pathway, may contribute to the management of sciatic nerve ligation–induced pain.