The Low-Dose of Pde5 Inhibitor, Sildenafil, Attenuates Morphine-Induced Memory Impairment in Male Mice Publisher



A Maleki ADELEH ; Ma Manavi Mohammad AMIN ; A Shirzadian ARMIN ; Ar Dehpour Ahmad REZA
Source: Learning and Motivation Published:2025

Abstract

Objectives: The study aimed to evaluate the effect of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, on morphine (MOR)-induced memory impairment. Methods: Male mice received morphine (MOR; 3 or 10 mg/kg, i.p.) 30 min before the acquisition phase to induce memory deficits. Sildenafil (1, 2, or 5 mg/kg, i.p.) was administered 15 min after MOR. Memory performance was evaluated using the Y-maze (spatial recognition) and passive avoidance (aversive learning) tasks. To explore underlying mechanisms, naltrexone (NTX; 3 mg/kg, i.p.) and L-NAME (10 mg/kg, i.p.) were administered as an opioid receptor antagonist and nitric oxide synthase inhibitor, respectively. In addition to behavioral tests, hippocampal nitric oxide (NO) levels were measured using the Griess assay, TNF-α and IL-1β were quantified with ELISA, and protein expression of ERK and phosphorylated ERK (p-ERK) was examined by western blotting. Key findings: A low dose of sildenafil (1 mg/kg) effectively improved spatial recognition memory and learning impaired by MOR (3 mg/kg and 10 mg/kg, respectively). While sildenafil (5 mg/kg) showed no significant benefit, NTX significantly enhanced its effects. Sildenafil also reversed the increased NO and TNF-α levels induced by MOR (3 mg/kg) in the hippocampus. Additionally, MOR (3 mg/kg)-induced memory impairment, linked with decreased p-ERK protein expression in the hippocampus, was significantly mitigated by sildenafil (1 mg/kg). Conclusions: Learning and memory for spatial recognition are enhanced by low doses of sildenafil. Short-term memory performance is improved by NTX and L-NAME, which counteract the effects of morphine. © 2025 Elsevier B.V., All rights reserved.