The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.

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BackgroundDoxorubicin, a widely used anti‐tumour drug, is known to cause muscle loss in cancer patients.MethodsFollowing an acute dose of doxorubicin injection (2.5 mg/kg per body weight), we examined macrophage distribution in rat soleus muscle challenged by eccentric exercise (downhill running). Long‐term doxorubicin treatment (one injection every 3 days) on muscle mass and survival were also determined.ResultsUnder non‐exercised condition, increased tumour necrosis factor (TNF)‐alpha mRNA and decreased IL‐10 mRNA were observed in soleus muscle of doxorubicin‐treated rats, compared with saline‐treated control rats. However, increases in inflammation score (leukocyte infiltration), nitrotyrosine level, and M1 macrophage (CD68+) invasion in exercised soleus muscle were absent in doxorubicin‐treated rats, whereas increased M2 macrophage (CD163+) localization in exercised muscle was less affected by doxorubicin. Despites coenzyme Q (Q10) supplementation significantly elevated TNF‐alpha mRNA, nitrotyrosine, and anti‐oxidant gamma‐glutamylcysteine synthetase (GCS) levels in non‐exercised soleus muscle, these pro‐inflammatory responses were also abolished in doxorubicin‐treated rats. Results from long‐term doxorubicin treatment show a significant muscle loss followed by an accelerated death, which cannot be reversed by Q10 supplementation.Conclusions(i) Doxorubicin impairs inflammation mechanism by depleting M1 macrophage in exercised skeletal muscle; (ii) Muscle loss and accelerated death during prolonged doxorubicin treatment cannot be reversed by Q10 supplementation.

Aims: Neuropeptide substance P (SP) is produced and released by a subset of peripheral sensory neurons that respond to tissue damage (nociceptors). SP exerts excitatory effects in the central nervous system, but peripheral SP actions are still poorly understood; therefore, here, we aimed at investigating these peripheral mechanisms. Results: SP acutely inhibited T-type voltage-gated Ca2+ channels in nociceptors. The effect was mediated by neurokinin 1 (NK1) receptor-induced stimulation of intracellular release of reactive oxygen species (ROS), as it can be prevented or reversed by the reducing agent dithiothreitol and mimicked by exogenous or endogenous ROS. This redox-mediated T-type Ca2+ channel inhibition operated through the modulation of CaV3.2 channel sensitivity to ambient zinc, as it can be prevented or reversed by zinc chelation and mimicked by exogenous zinc. Elimination of the zinc-binding site in CaV3.2 rendered the channel insensitive to SP-mediated inhibition. Importantly, peripherally applied SP significantly reduced bradykinin-induced nociception in rats in vivo; knock-down of CaV3.2 significantly reduced this anti-nociceptive effect. This atypical signaling cascade shared the initial steps with the SP-mediated augmentation of M-type K+ channels described earlier. Innovation: Our study established a mechanism underlying the peripheral anti-nociceptive effect of SP whereby this neuropeptide produces ROS-dependent inhibition of pro-algesic T-type Ca2+ current and concurrent enhancement of anti-algesic M-type K+ current. These findings will lead to a better understanding of mechanisms of endogenous analgesia. Conclusion: SP modulates T-type channel activity in nociceptors by a redox-dependent tuning of channel sensitivity to zinc; this novel modulatory pathway contributes to the peripheral anti-nociceptive effect of SP. Antioxid. Redox Signal. 25, 233–251.

The importance of H2S as a physiological signaling molecule continues to develop, and ion channels are emerging as a major family of target proteins through which H2S exerts many actions. The purpose of the present study was to investigate its effects on T-type Ca(2+) channels. Using patch-clamp electrophysiology, we demonstrate that the H2S donor, NaHS (10 μM-1 mM) selectively inhibits Cav3.2 T-type channels heterologously expressed in HEK293 cells, whereas Cav3.1 and Cav3.3 channels were unaffected. The sensitivity of Cav3.2 channels to H2S required the presence of the redox-sensitive extracellular residue H191, which is also required for tonic binding of Zn(2+) to this channel. Chelation of Zn(2+) with N,N,N',N'-tetra-2-picolylethylenediamine prevented channel inhibition by H2S and also reversed H2S inhibition when applied after H2S exposure, suggesting that H2S may act via increasing the affinity of the channel for extracellular Zn(2+) binding. Inhibition of native T-type channels in 3 cell lines correlated with expression of Cav3.2 and not Cav3.1 channels. Notably, H2S also inhibited native T-type (primarily Cav3.2) channels in sensory dorsal root ganglion neurons. Our data demonstrate a novel target for H2S regulation, the T-type Ca(2+) channel Cav3.2, and suggest that such modulation cannot account for the pronociceptive effects of this gasotransmitter.

CEA ratio was found to be a reliable prognostic factor in stage IV CRC, and was highly correlated with the imaging survey according to RECIST criteria. Further prospective studies are essential to validate these findings.

Intestinal crypt epithelial cells synthesize glucocorticoids, steroid hormones that protect against inflammatory bowel disease. To investigate how intestinal glucocorticoids are regulated during chronic inflammation, we induced chronic colitis in mice by exposing them to the chemical dextran sulfate sodium (DSS). We found that intestinal glucocorticoid secretion and expression of the genes Cyp11a1 and Cyp11b1 (which encode enzymes that synthesize glucocorticoids) were initially stimulated, but declined during the chronic phase, whereas tumor necrosis factor (TNF) and inflammatory cytokines secreted by T helper type 1 (TH1) and TH17 cells continuously increased in abundance in the inflamed colon. This suggested that inadequate intestinal glucocorticoid synthesis is a feature of chronic intestinal inflammation. We screened for cytokines that regulated intestinal glucocorticoid synthesis and found that TNF suppressed corticosterone secretion and Cyp11a1 and Cyp11b1 expression in an intestinal crypt epithelial cell line. TNF suppressed steroidogenesis by activating the transcription factors c-Jun and nuclear factor κB (NF-κB), which both interacted with the transcription factor NR5A2 and repressed Cyp11a1 reporter activity. This repression was relieved by expression of a dominant-negative form of c-Jun amino-terminal kinase 1 (JNK1), inhibitor of NF-κB, or by a JNK inhibitor. Furthermore, the dominant-negative TNF inhibitor XPro1595 inhibited c-Jun and NF-κB activation in mice, restored intestinal Cyp11a1 and Cyp11b1 expression, reduced colonic cell death, and rescued chronic colitis caused by DSS. Thus, during chronic colitis, TNF suppresses intestinal steroidogenic gene expression by inhibiting the activity of NR5A2, thus decreasing glucocorticoid synthesis and sustaining chronic inflammation.