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.