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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. [ABSTRACT FROM AUTHOR]

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‐HT1A 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−1), 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‐HT1A 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 [35S]GTPγS binding) of the 5‐HT1A 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‐HT1A receptors and indicate it could be used to treat neuropathic pain. [ABSTRACT FROM AUTHOR]

With the aggravation of soil acidification, aluminum toxicity has become one of the important stress factors that affect crop seed germination quality and crop yield. There have been many reports on QTL mapping and candidate gene screening for aluminum tolerance related traits in crops, but few reports on QTL mapping for aluminum tolerance during germination in Brassica napus L. The seed germination test was conducted on the recombinant inbred line population treated with 80 µg mL-1 aluminum solution and with distilled water as control. Germination potential was investigated at 3 d, germination rate was investigated at 7 d, root length, bud length and dry weight were measured, and the relative values of various characters were calculated. Based on 6K SNP chip and combined with high density genetic linkage map, we detected 23 QTLs for five traits in rape germination period. QTLs for relative germination potential, relative germination rate, relative root length, relative bud length and relative dry weight were 9, 1, 4, 5, and 4 respectively, covering A and C genomes, with LOD values from 3.00 to 5.26, and interpretable phenotypic variation from 7.70% to 13.10%. According to the confidence interval sequence of each QTL, 30 candidate genes related to aluminum stress were screened. ALMT1 gene and MATE gene are related to the synthesis and secretion of organic acids, which mainly enhance the aluminum tolerance of plants through the secretion of organic acids such as malic acid, citric acid and oxalic acid. STOP1 gene, NAC gene and RAP2.4 gene all belong to transcription activation factors, which enhance the resistance of plants by inducing the expression of aluminum tolerance genes. ABC transporter, membrane protein transporter, GDSL lipase enhance aluminum tolerance of plants by reducing accumulation of toxic substances on plasma membrane or discharging toxic substances out of body. Peroxidase and cytochrome P450 are genes related to oxidative stress, which have the functions of preventing oxidative damage of plant cells and resisting stress. At the same time, many genes encoding stress proteins were found, which play an important role in various stress reactions. The results of this study provide a theoretical basis for the cultivation of aluminum-tolerant rape varieties and the functional research of subsequent genes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]