Evidence for 5-HT 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-HT 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 ), 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-HT 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 [ S]GTPγS binding) of the 5-HT 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-HT receptors and indicate it could be used to treat neuropathic pain.