Chronic resveratrol treatment exerts antihyperalgesic effect and corrects co-morbid depressive like behaviors in mice with mononeuropathy: involvement of serotonergic system.

Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. This work aimed to investigate the effects of resveratrol, a phenolic monomer enriched in red wine and grapes, on pain-related and depressive-like behaviors in mice with mononeuropathy, and explored the mechanism(s). Mice received chronic constriction injury (CCI) of sciatic nerves, and sequentially developed pain-related and depressive-like behaviors, as evidenced by sensory hypersensitivity (thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test) and behavioral despair (prolonged immobility time in forced swim test). Chronic treatment of neuropathic mice with resveratrol (30 mg/kg, p.o., twice per day for three weeks) normalized their thermal hyperalgesia (but not mechanical allodynia) and depressive-like behaviors, and these actions were abolished by chemical depletion of central serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. The anti-hyperalgesia and anti-depression exerted by resveratrol may be pharmacologically segregated, since intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of methysergide, a non-selective 5-HT receptor antagonist, separately abrogated the two actions. Furthermore, the antihyperalgesic action of resveratrol was preferentially counteracted by co-administration of the 5-HT7 receptor antagonist SB-258719, while the anti-depression was abrogated by 5-HT1A receptor antagonist WAY-100635. These results confirm that chronic resveratrol administration exerts curative-like effects on thermal hyperalgesia and co-morbid depressive-like behaviors in mice with mononeuropathy. Spinal and supraspinal serotonergic systems (coupled with 5-HT7 and 5-HT1A receptors, respectively) are differentially responsible for the antihyperalgesic and antidepressant-like properties of resveratrol.