Chronic
neuropathic pain poses a significant health problem, for which effective
therapy is lacking. The current work aimed to investigate the potential antinociceptive efficacy of
isorhynchophylline, an
oxindole alkaloid, against
neuropathic pain and elucidate mechanisms. Male C57BL/6J mice were subjected to chronic constriction injury (CCI) by loose
ligation of their sciatic nerves. Following CCI surgery, the neuropathic mice developed
pain-like behaviors, as shown by
thermal hyperalgesia in the Hargreaves test and
tactile allodynia in the von Frey test. Repetitive treatment of CCI mice with
isorhynchophylline (p.o., twice per day for two weeks) ameliorated behavioral
hyperalgesia and
allodynia in a dose-dependent fashion (5, 15, and 45 mg/kg). The
isorhynchophylline-triggered antinociception seems serotonergically dependent, since its antinociceptive actions on neuropathic
hyperalgesia and
allodynia were totally abolished by chemical depletion of spinal
serotonin by PCPA, whereas potentiated by
5-HTP (a precursor of 5-HT). Consistently,
isorhynchophylline-treated neuropathic mice showed escalated levels of spinal monoamines especially
5-HT, with depressed
monoamine oxidase activity. Moreover, the
isorhynchophylline-evoked antinociception was preferentially counteracted by co-administration of
5-HT1A receptor antagonist
WAY-100635. In vitro,
isorhynchophylline (0.1-10 nM) increased the Emax (stimulation of [35S] GTPĪ³S binding) of
8-OH-DPAT, a
5-HT1A agonist. Of notable benefit,
isorhynchophylline was able to correct co-morbidly behavioral symptoms of depression and anxiety evoked by
neuropathic pain. Collectively, these findings confirm, for the first time, the disease-modifying efficacy of
isorhynchophylline on neuropathic
hypersensitivity, and this effect is dependent on spinal serotonergic system and 5-HT1A receptors.