Scopoletin Attenuates Reserpine-Induced Pain-Depression Dyad in Mice via Modulation of Inflammation, Oxidative Stress, and Monoaminergic Pathways.

Pain and depression frequently are comorbid and have common mechanisms such as monoamine depletion, inflammation, and oxidative stress. Hence, this study aimed to investigate the effects of bioactive coumarin on reserpine induced pain-depression dyad in mice. Mechanical allodynia, depressive-like behavior, and cognitive deficits were induced by reserpine (0.5 mg/kg, subcutaneously, once daily on days 1-3) in male BALB/c mice. Scopoletin (50 mg/kg, p.o.) or gabapentin (10 mg/kg, p.o.) was given twice daily (at 9:00 am and 5:00 pm) for 5 days. For days 1-3, the initial daily dose of scopoletin or gabapentin was given 30 min before reserpine injection, with the second dose at the evening. Control animals, which received vehicle, were given 0.1% CMC. Behavioural tests (Electronic von Frey (eVF) test, Pressure Application Measurement (PAM) test) (Forced Swim Test (FST) and Morris Water Maze (MWM) test) were performed on day 4 and 6, and tissue collection was conducted on day 6 for biochemical analyses (cytokines (TNF-α and IL-1β), neurotransmitters (Serotonin, Norepinephrine, and Glutamate), MAO-A activity, GSH, TBARS). Paw withdrawal thresholds (eVF day 4: F(3,20) = 28.75, p < 0.001; PAM: F(3,20) = 35.17, p < 0.001) were markedly diminished and immobility time in FST (F(3,20) = 29.11, p < 0.001) was notably prolonged by reserpine. Moreover, it impaired the spatial memory (MWM: F(3,20) = 30.56, p < 0.001), and increased the serum TNF-α and IL-1β (F(3,20) = 24.32 and 18.50, respectively; p < 0.01), the brain MAO-A activity (F(3,20) = 16.83, p < 0.01), glutamate and TBARS (F(3,20) = 25.11, p < 0.001; F(3,20) = 19.76, p < 0.01), and decreased the brain serotonin, norepinephrine and GSH (p < 0.01-0.001). Supplementation with scopoletin markedly retarded deficits in behavior (eVF and PAL, p < 0.001; FST, p < 0.001; MWM, p < 0.001) and biochemistry (reduction of UG [TNF-α, IL-1β], MAO-A activity and glutamate level along with restoration of monoamine and antioxidant status, p < 0.05-0.001). Scopoletin is a promising candidate drug for comorbid pain and depression due to its significant counteracting effects on reserpine-induced behavioral and biochemical alterations.