Br J Pharmacol. 2021 May 24. doi: 10.1111/bph.15574. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: Neuropathic pain places a devastating health burden, with effective therapies or drugs being scarce. We aimed to investigate the potential antiallodynic and antihyperalgesic effects of apigenin, a natural flavonoid with monoamine oxidase (MAO) inhibitory activity, against neuropathic pain and probe mechanism(s).
EXPERIMENTAL APPROACH: The neuropathic pain model was produced by chronic constriction injury (CCI) of sciatic nerves in male C57BL/6J mice, with pain-related behaviours being assayed by von-Frey test and Hargreaves test. The 5-hydroxytryptamine (5-HT) and 5-HT1A receptor related mechanisms were investigated in vivo and in vitro.
KEY RESULTS: Repeated apigenin treatment (p.o., once per day for two weeks) ameliorated allodynia and hyperalgesia in CCI mice in a dose-associated manner (3, 10 and 30 mg·kg-1 ). These pain-relieving effects seem serotonergically dependent, because (I) the antihyperalgesia and antiallodynia were attenuated by chemical depletion of 5-HT with p-chlorophenylalanine (PCPA), but potentiated by 5-hydroxytryptophan (5-HTP), (II) apigenin-treated CCI mice displayed increased level of spinal 5-HT, with diminished MAO activity. In vivo antagonist tests revealed that apigenin-evoked antiallodynia and antihyperalgesia were offset by 5-HT1A receptor antagonist WAY-100635 delivered spinally or systematically. In vitro, apigenin behaved as a positive allosteric modulator (PAM) to increase the efficacy (stimulation of [35 S] GTPγS binding) of the 5-HT1A receptor agonist 8-OH-DPAT. Beneficially, apigenin confered neuroprotection by attenuating neuronal derangement of sciatic nerve in CCI mice, without causing hypertensive crisis.
CONCLUSIONS AND IMPLICATIONS: These findings demonstrate the antiallodynic and antihyperalgesic efficacies of apigenin against neuropathic pain, with spinal 5-HT1A receptors being crucially involved.
PMID:34030210 | DOI:10.1111/bph.15574
