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Background The G protein-coupled receptor 40 (GPR40), broadly expressed in various tissues such as the spinal cord, exerts multiple physiological functions including pain regulation. This study aimed to elucidate the mechanisms underlying GPR40 activation-induced antinociception in neuropathic pain, particularly related to the spinal glial expression of IL-10 and subsequent β-endorphin. Methods Spinal nerve ligation-induced neuropathic pain model was used in this study. β-Endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Double immunofluorescence staining of β-endorphin with glial and neuronal cellular biomarkers was also detected in the spinal cord and cultured primary microglia, astrocytes, and neurons. Results GPR40 was expressed on microglia, astrocytes, and neurons in the spinal cords and upregulated by spinal nerve ligation. Intrathecal injection of the GPR40 agonist GW9508 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in neuropathic rats, with E max values of 80% and 100% MPE and ED 50 values of 6.7 and 5.4 μg, respectively. Its mechanical antiallodynia was blocked by the selective GPR40 antagonist GW1100 but not GPR120 antagonist AH7614. Intrathecal GW9508 significantly enhanced IL-10 and β-endorphin immunostaining in spinal microglia and astrocytes but not in neurons. GW9508 also markedly stimulated gene and protein expression of IL-10 and β-endorphin in cultured primary spinal microglia and astrocytes but not in neurons, originated from 1-day-old neonatal rats. The IL-10 antibody inhibited GW9508-stimulated gene expression of the β-endorphin precursor proopiomelanocortin (POMC) but not IL-10, whereas the β-endorphin antibody did not affect GW9508-stimulated IL-10 or POMC gene expression. GW9508 increased phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and its stimulatory effects on IL-10 and POMC expression were blocked by each MAPK isoform inhibitor. Spinal GW9508-induced mechanical antiallodynia was completely blocked by intrathecal minocycline, IL-10 neutralizing antibody, β-endorphin antiserum, and μ-opioid receptor-preferred antagonist naloxone. Conclusions Our results illustrate that GPR40 activation produces antinociception via the spinal glial IL-10/β-endorphin antinociceptive pathway. Electronic supplementary material The online version of this article (10.1186/s12974-019-1457-9) contains supplementary material, which is available to authorized users.

Background: Cinobufagin is the major bufadienolide of Bufonis venenum (Chansu), which has been traditionally used for the treatment of chronic pain especially cancer pain. The current study aimed to evaluate its antinociceptive effects in bone cancer pain and explore the underlying mechanisms. Methods: Rat bone cancer model was used in this study. The withdrawal threshold evoked by stimulation of the hindpaw was determined using a 2290 CE electrical von Frey hair. The β-endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Results: Cinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected E max of 90% MPE and ED 50 of 6.4 μg. Intrathecal cinobufagin also stimulated the gene and protein expression of IL-10 and β-endorphin (but not dynorphin A) in the spinal cords of bone cancer pain rats. In addition, treatment with cinobufagin in cultured primary spinal microglia but not astrocytes or neurons stimulated the mRNA and protein expression of IL-10 and β-endorphin, which was prevented by the pretreatment with the IL-10 antibody but not β-endorphin antiserum. Furthermore, spinal cinobufagin-induced mechanical antiallodynia was inhibited by the pretreatment with intrathecal injection of the microglial inhibitor minocycline, IL-10 antibody, βendorphin antiserum and specific μ-opioid receptor antagonist CTAP. Lastly, cinobufagin-and the specific α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist PHA-543613-induced microglial gene expression of IL-10/βendorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine. Conclusions: Our results illustrate that cinobufagin produces mechanical antiallodynia in bone cancer pain through spinal microglial expression of IL-10 and subsequent β-endorphin following activation of α7-nAChRs. Our results also highlight the broad significance of the recently uncovered spinal microglial IL-10/β-endorphin pathway in antinociception.

Increasing evidence indicates an interaction between dysbiosis of the microbiota and the pathogenesis of schizophrenia. However, limited information is available on the specific microbial communities associated with symptoms of schizophrenia. Therefore, this study aimed to investigate gut microbiota dysbiosis and its relationship with psychopathologies in schizophrenia. We recruited 126 participants and divided them into three groups according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria—acute group (patients with acute schizophrenia), remission group (patients with schizophrenia in remission), and control group (healthy controls). Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale. Microbiota compositions, diversity and community structure were evaluated using 16S rRNA sequencing. Pearson's correlation analysis was used to evaluate the association between bacterial taxa and psychotic symptoms. The beta-diversity of microbiota composition in the acute group was distinct from that in the remission and control groups (PC1 = 21.11% vs. PC2 = 12.86%, P = 0.021). Furthermore, Pearson's correlation analysis revealed that abundance of Haemophilus was positively correlated with negative psychiatric symptoms (r = 0.303, P = 0.021), while abundance of Coprococcus was negatively correlated with negative psychiatric symptoms (r = −0.285, P = 0.025). Moreover, abundance of Haemophilus was positively correlated with cognition (r = 0.428, P = 0.009), excitement (r = 0.266, P = 0.037), and depression (r = 0.295, P = 0.020). The study findings suggest that alterations in certain gut microbiota may interfere with psychological symptoms in schizophrenia. Our results provide evidence that may help in the development of therapeutic strategies using microbial-based targets. The data that support the findings of this study have been deposited in the NCBI (https://submit.ncbi.nlm.nih.gov/) with accession number SUB9453991.