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Neuropathic pain is a devastating disease that affects millions of people worldwide. Serotonin (5-hydroxytryptamine, 5-HT) is involved in pain modulation. Several lines of evidence have indicated that 5-HT1F receptor agonists are potent inducers of mitochondrial biogenesis. In this study, we tested the hypothesis that 5-HT1F receptor agonists ameliorate mechanical allodynia in neuropathic pain via the induction of mitochondrial biogenesis and suppression of neuroinflammation. Male Sprague–Dawley rats were used to establish a neuropathic pain model via spared nerve injury (SNI). The paw withdrawal threshold (PWT) was used to evaluate mechanical allodynia. Real-time polymerase chain reaction was used to examine the mitochondrial DNA (mtDNA) copy number. Western blotting and immunofluorescence were used to examine the expression of target proteins. Our results showed that mitochondrial biogenesis was impaired in the spinal cord of rats with SNI. Moreover, activation of PGC-1α, the master regulator of mitochondrial biogenesis, attenuates established mechanical allodynia in rats with neuropathic pain. In addition, the neuronal 5-HT1F receptor is significantly downregulated in the spinal cord of rats with neuropathic pain. Furthermore, the selective 5-HT1F receptor agonist lasmiditan attenuated established mechanical allodynia in rats with neuropathic pain. Finally, lasmiditan (Las) treatment restored mitochondrial biogenesis and suppressed neuroinflammation in the spinal cord of rats with SNI. These results provide the first evidence that lasmiditan ameliorates mechanical allodynia in neuropathic pain by inducing mitochondrial biogenesis and suppressing neuroinflammation in the spinal cord. Inducers of mitochondrial biogenesis may be an encouraging therapeutic option for the management of neuropathic pain.

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] GTPγS 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.