Purpurin ameliorated neuropathic allodynia and hyperalgesia by modulating neuronal mitochondrial bioenergetics and redox status in type 1 diabetic mice.

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Purpurin, a natural anthraquinone compound from Rubia tinctorum L., has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of purpurin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess the pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with purpurin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although purpurin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons and restored nerve conduction velocity in sciatic nerves. Notably, the analgesic actions of purpurin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of purpurin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes.

Evidence for 5-HT1A receptor-mediated antiallodynic and antihyperalgesic effects of apigenin in mice suffering from mononeuropathy.

BACKGROUND AND PURPOSE: Neuropathic pain places a devastating health burden, with very few effective therapies. We investigated the potential antiallodynic and antihyperalgesic effects of apigenin, a natural flavonoid with momoamine oxidase (MAO) inhibitory activity, against neuropathic pain and investigated the mechanism(s). EXPERIMENTAL APPROACH: The neuropathic pain model was produced by chronic constriction injury of sciatic nerves in male C57BL/6J mice, with pain-related behaviours being assayed by von Frey test and Hargreaves test. In this model the role of 5-HT and 5-HT1A receptor-related mechanisms were investigated in vivo/in vitro. KEY RESULTS: Apigenin repeated treatment (p.o., once per day for 2 weeks), in a dose-related manner (3, 10 and 30 mg·kg-1 ), ameliorated the allodynia and hyperalgesia in chronic nerve constriction injury in mice. These effects seem dependent on neuronal 5-hydroxytryptamine, because (i) the antihyperalgesia and antiallodynia were attenuated by depletion of 5-HT with p-chlorophenylalanine and potentiated by 5-hydroxytryptophan and (ii), apigenin-treated chronic constriction injury mice caused an increased level of spinal 5-HT, associated with diminished MAO activity. In vivo administration, spinally or systematically, of the 5-HT1A antagonist WAY-100635 inhibited the apigenin-induced antiallodynia and antihyperalgesia. In vitro, apigenin acted as a positive allosteric modulator to increase the efficacy (stimulation of [35 S]GTPγS binding) of the 5-HT1A agonist 8-OH-DPAT. Apigenin attenuated neuronal changes caused by chronic constriction of the sciatic nerve in mice, without causing a hypertensive crisis. CONCLUSION AND IMPLICATIONS: Apigenin antiallodynic and antihyperalgesic actions against neuropathic pain crucially involve spinal 5-HT1A receptors and indicate it could be used to treat neuropathic pain.