Low Dose Morphine Enhances Morphine Antinociception Effects in the Animals Pretreated with Selective and Non-Selective Phosphodiestrase Inhibitors

In this study, we investigated the interactive effects of intraperitoneal (i.p.) injections of three different phosphodiesterase inhibitors (PDEIs) on morphine-induced analgesia in mice using tail-flick method. Subcutaneous administration of morphine (1, 3 and 6 mg/kg) caused significant antinociceptive effects in a dose dependent manner. Administration of pentoxifylline (12.5, 25, 50 and 100 mg/kg, i.p.), milrinone (3 and 4.5 mg/kg, i.p.) and theophylline (25, 50 and 100 mg/kg, i.p.) as selective and non-seletive phosphodiesterase inhibitors induced analgesia in mice. We also examined the antinociceptive effects of these three PDEIs in combination with non-effective dose of morphine (1 mg/kg). These combinations increased analgesia effects compared to the either morphine or respective phospho-diestrase inhibitor groups significantly. Our findings strongly suggest that PDEIs can induce analgesia and potentiate morphine antinociception effect via possible interactions on the same molecular or biochemical pathways.