Inhibition of Muscular Nociceptive Afferents via the Activation of Cutaneous Nociceptors in a Rat Model of Inflammatory Muscle Pain

Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant(CFA)into the tibialis anterior muscle.CFAinduced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents,and decreased weight-bearing of the hindlimb were relieved by topical application of CAP,PO,or MO on the skin overlying the inflamed muscle.The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg,or when the relevant cutaneous nerve or dorsal root was transected.Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.

Injury of Muscular but not Cutaneous Nerve Drives Acute Neuropathic Pain in Rats

Acute pain is a common complication after injury of a peripheral nerve but the underlying mechanism is obscure.We established a model of acute neuropathic pain via pulling a pre-implanted suture loop to transect a peripheral nerve in awake rats.The tibial(both muscular and cutaneous),gastrocnemius-soleus(muscular only),and sural nerves(cutaneous only)were each transected.Transection of the tibial and gastrocnemius-soleus nerves,but not the sural nerve immediately evoked spontaneous pain and mechanical allodynia in the skin territories innervated by the adjacent intact nerves.Evans blue extravasation and cutaneous temperature of the intact skin territory were also significantly increased.In vivo electrophysiological recordings revealed that injury of a muscular nerve induced mechanical hypersensitivity and spontaneous activity in the nociceptive C-neurons in adjacent intact nerves.Our results indicate that injury of a muscular nerve,but not a cutaneous nerve,drives acute neuropathic pain.

Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer's disease

Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.

Correlations Between Single Nucleotide Polymorphisms,Cognitive Dysfunction,and Postmortem Brain Pathology in Alzheimer's Disease Among Han Chinese

In this study, the distribution of five Alzheimer's disease(AD)-related single nucleotide polymorphisms(SNPs) in the Han population was examined in combination with the evaluation of clinical cognition and brain pathological analysis. The associations among SNPs,clinical daily cognitive states, and postmortem neuropathological changes were analyzed in 110 human brains from the Chinese Academy of Medical Sciences/Peking Union Medical College(CAMS/PUMC) Human Brain Bank.APOE ?4(OR = 4.482, P = 0.004), the RS2305421 GG genotype(adjusted OR = 4.397, P = 0.015), and the RS10498633 GT genotype(adjusted OR = 2.375,P = 0.028) were associated with a higher score on the ABC(Ab plaque score, Braak NFT stage, and CERAD neuritic plaque score) dementia scale. These results advance our understanding of the pathogenesis of AD,the relationship between pathological diagnosis and clinical diagnosis, and the SNPs in the Han population for future research.

Cutaneous Hypersensitivity as an Indicator of Visceral Inflammation via C-Nociceptor Axon Bifurcation

Pain on the body surface can accompany disorders in the deep tissue or internal organs. However, the anatomical and physiological mechanisms are obscure.Here, we provided direct evidence of axon bifurcation in primary C-nociceptive neurons that innervate both the skin and a visceral organ. Double-labeled dorsal root ganglion(DRG) neurons and Evans blue extravasation were observed in 3 types of chemically-induced visceral inflammation(colitis, urocystitis, and acute gastritis) rat models.In the colitis model, mechanical hypersensitivity and spontaneous activity were recorded in vivo from doublelabeled C-nociceptive neurons in S1 or L6 DRGs. These neurons showed significantly enhanced responses to both somatic stimulation and colorectal distension. Our findings suggest that the branching of C-nociceptor axons contribute to cutaneous hypersensitivity in visceral inflammation. Cutaneous hypersensitivity on certain locations of the body surface might serve as an indicator of pathological conditions in the corresponding visceral organ.

Comparison of Reference Genes for Transcriptional Studies in Postmortem Human Brain Tissue Under Different Conditions

Dear Editor Research on neurodegenerative diseases is a hot topic worldwide[1],and MRI,genetics and epigenetics,and animal models have been commonly used.Considering species differences,research on human brain samples is irreplaceable(2)Many countries and regions have built brain banks to collect and store brain tissue from donors.Samples provided by a brain bank can be used to study synaptic structure,protein,DNA,RNA[3,4],and lipids to illuminate the pathological mechanisms underlying neurodegenerative diseases.When brain tissue is used for gene expression research,the quantitative real-time polymerase chain reaction(RT-qPCR)is an accurate method,which simultaneously amplifies and quantifies the expression of target genes by measuring the intensity of fluorescence in each PCR cycle.

Progress in Human Brain Banking in China

Human brain banks collect,preserve,and distribute postmortem and biopsied brain samples for histological,pathological,and molecular research.Different from the western countries,human brain banking in China has remained preliminary over decades.However,joint efforts during the past few years have substantially promoted this key frontier of neuroscience in China.This special topic brings together review and perspective articles on the ethical,administrative,and practical issues of brain banking.Several original studies report molecular and pathological characterizations based on banked human brain samples.