Scorpion toxin BmKI directly activates Nav1.8 in primary sensory neurons to induce neuronal hyperexcitability in rats

Voltage-gated sodium channels （VGSCs） in primary sensory neurons play a key role in transmitting pain signals to the central nervous system. BmK I, a site-3 sodium channel-specific toxin from scorpion Buthus martensi Karsch, induces pain behaviors in rats. How- ever, the subtypes of VGSCs targeted by BmK I were not entirely clear. We therefore investigated the effects of BmK I on the current amplitude, gating and kinetic properties of Nav1.8, which is associated with neuronal hyperexcitability in DRG neurons. It was found that BmK I dose-dependently increased Nav1.8 current in small- sized （〈25 μm） acutely dissociated DRG neurons, which correlated with its inhibition on both fast and slow in- activation. Moreover, voltage-dependent activation and steady-state inactivation curves of Nay1.8 were shifted in a hyperpolarized direction. Thus, BmK I reduced the threshold of neuronal excitability and increased action potential firing in DRG neurons. In conclusion, our data clearly demonstrated that BmK I modulated Nav1.8 re- markably, suggesting BmK I as a valuable probe for studying Nay1.8. And Navl.8 is an important target re- lated to BmK I-evoked pain.

Satellite glial cells in sensory ganglia play a wider role in chronic pain via multiple mechanisms

Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons.An increasing body of evidence suggests that in the presence of inflammation and nerve damage,a significant number of satellite glial cells become activated,thus triggering a series of functional changes.This suggests that satellite glial cells are closely related to the occurrence of chronic pain.In this review,we first summarize the morphological structure,molecular markers,and physiological functions of satellite glial cells.Then,we clarify the multiple key roles of satellite glial cells in chronic pain,including gap junction hemichannel Cx43,membrane channel Pannexin1,K channel subunit 4.1,ATP,purinergic P2 receptors,and a series of additional factors and their receptors,including tumor necrosis factor,glutamate,endothelin,and bradykinin.Finally,we propose that future research should focus on the specific sorting of satellite glial cells,and identify genomic differences between physiological and pathological conditions.This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.

Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway

Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.

Peripheral mechanisms of itch

Detection of environmental stimuli that provoke an aversive response has been shown to involve many receptors in the periphery. Probably the least-studied of these stimuli are those that induce the perception of itch （pruritus）, an often-experienced unpleasant stimulus. This review covers the ligands and their receptors which are known to cause primary sensory neuron activation and initiate itch sensation. Also covered are several itch-inducing substances which may act indirectly by activating other cell types in the periphery which then signal to primary neurons. Finally, progress in identifying candidate neurotransmitters that sensory neurons use to propagate the itch signal is discussed.