Rutin engages opioid/benzodiazepine receptors towards anti-neuropathic potential in a rat model of chronic constriction injury: relevance to its antioxidant and anti-inflammatory effects

Abstract

Neuropathic pain is a chronic type of pain caused by damage or dysfunction in the nervous system. It can be quite bothersome and often doesn't well respond to common painkillers. Among natural compounds, rutin (Rut) stands out for its remarkable antioxidant, and anti-inflammatory properties. In this research, our objective is to investigate the impact of Rut on an animal model of chronic constriction injury (CCI). A total of 54 adult Wistar rats were divided randomly into nine separate groups. Groups included sham, CCI, gabapentin (GBP, 100 mg/kg), Rut (10, 25 mg/kg), flumazenil (FLU, 0.5 mg/kg), naloxone (NAL, 0.1 mg/kg), Rut (10 mg/kg) + FLU (0.5 mg/kg), and Rut (10 mg/kg) + NAL (0.1 mg/kg). The aforementioned drug injection (intraperitoneal, i.p.) and sensorimotor behavioral tests were performed on days 1, 3, 5, 7, 9, 11, and 14. Biochemical (e.g., nitrite, catalase, glutathione), zymography (matrix-metalloproteinase 2 and 9), and histopathological tests were performed on day 14 after surgery. The findings demonstrated that Rut administration effectively alleviated symptoms of allodynia/hyperalgesia, and improved locomotor activity following CCI. Additionally, Rut administration resulted in increased catalase and glutathione activity, while reducing serum nitrite levels, as well as matrix metalloproteinase 2 and 9 activity. Additionally, histological results indicated that Rut improved sciatic nerve regeneration. Since the aforementioned effects of Rut were reversed by using opioid and benzodiazepine receptor antagonists (i.e., NAL and FLU, respectively), the receptors' involvement was revealed in the anti-neuropathic effects of Rut. In conclusion, Rut emerged as a potentially effective candidate for treating neuropathic pain and improving motor function by increasing antioxidant mediators, suppressing inflammation, and activating opioid/benzodiazepine receptors.

Keywords: Benzodiazepine pathway; Chronic constriction injury; Inflammation; Neuropathic pain; Opioid pathway; Oxidative stress; Rutin.