Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

Aim: Tadalafil is a potent, selective and reversible inhibitor of phosphodiesterase type 5 (PDE5) enzyme breakdowning cyclic guanosine monophosphate (cGMP). In this study, we aimed to investigate the effects of tadalafil on nociception, morphine analgesia and tolerance. Methods: In this study, 54 Wistar Albino (230-250 g) male rats were used. First of all, four different doses (2, 4, 8, 16 mg/kg) were used to determine the optimum effective dose of tadalafil on nociception. Optimum activity was found at 8 mg/kg and animals were divided into six groups: Saline (S), 8mg/kg tadalafil, 5mg/kg morphine (M), M+ tadalafil, morphine tolerance (MT) and MT+ tadalafil. Saline was given to the control group, tadalafil intraperitoneally and morphine subcutaneously administered at the indicated doses. To develop tolerance to morphine, 10mg/kg morphine was injected daily in the morning and evening for five days and tolerance was evaluated with single dose of morphine on sixth days. The resulting analgesic effect was measured with hot plate and tail flick analgesia tests and recorded at 30th, 60th, 90th and 120th minutes. Results: Tadalafil showed anti-nociceptive effect when given alone at different doses (p<0.05). However, tadalafil significantly decreased the analgesic effect of morphine (p<0.05). In addition, tadalafil significantly increased the tolerance to morphine (p<0.05). Conclusions: The phosphodiesterase type 5 inhibitor tadalafil have anti-nociceptive properties and it decreases analgesic effect of morphine, in addition improves tolerance development. These effects probably may occur via NO/cGMP pathway. &nbsp

Positive effects of angiotensin-converting enzyme (ACE) inhibitor, captopril, on pentylenetetrazole-induced epileptic seizures in mice

Purpose: To evaluate the effects of an angiotensin-converting enzyme (ACE) inhibitor, captopril, on pentylenetetrazole (PTZ)-induced seizures and post-seizure hippocampal injury. Materials: Thirty-five male Balb-c mice weighing 30 - 33 g were divided into control, saline PTZ, s(erum physiologic 1 ml/kg as solvent), positive control (valproic acid 200 mg/kg), captopril (25 mg/kg/day for 7 days), and captopril (50 mg/kg/day for 7 days) groups. PTZ (60 mg/kg) was administered thirty minutes after medication administration to induce epileptic seizures. The animals were observed for 30 min to record Racine stages, the time of the first myoclonic jerk (FMJ), and the occurrence of the first generalized tonic-clonic seizure (GTCS). Cornu Ammonis (CA)1, CA2, CA3, and the dentate gyrus (DG) of the hippocampus underwent histopathological examinations. The levels of total oxidant status (TOS), oxidative stress markers (total antioxidant status, TAS), and oxidative stress index (OSI) were measured in the brain tissue. Results: Compared to PTZ group, 25 mg/kg captopril decreased seizure scores and delayed FMJ and GTCS (p < 0.05). Histopathological assessment demonstrated that both 25 and 50 mg/kg captopril alleviated neuronal injury in CA1, CA2, CA3, and DG compared to PTZ (p < 0.05). Also, TOS and OSI levels in the brain tissue were reduced by both 25 and 50 mg/kg doses of captopril (p < 0.05). Conclusion: Captopril favorably improves epileptic seizure parameters and acts against post-seizure neuronal injury in the hippocampus. Captopril may be a drug of choice in epileptic individuals with hypertension. Keywords: Captopril, Angiotensin-converting enzyme, Epilepsy, Pentylenetetrazole, Neuronal damag