Pannexin-1 Up-regulation in the Dorsal Root Ganglion Contributes to Neuropathic Pain Development

Pannexin-1 (Panx1) is a large-pore membrane channel involved in the release of ATP and other signaling mediators. Little is known about the expression and functional role of Panx1 in the dorsal root ganglion (DRG) in the development of chronic neuropathic pain. In this study, we determined the epigenetic mechanism involved in increased Panx1 expression in the DRG after nerve injury. Spinal nerve ligation in rats significantly increased the mRNA and protein levels of Panx1 in the DRG but not in the spinal cord. Immunocytochemical labeling showed that Panx1 was primarily expressed in a subset of medium and large DRG neurons in control rats and that nerve injury markedly increased the number of Panx1-immunoreactive DRG neurons. Nerve injury significantly increased the enrichment of two activating histone marks (H3K4me2 and H3K9ac) and decreased the occupancy of two repressive histone marks (H3K9me2 and H3K27me3) around the promoter region of Panx1 in the DRG. However, nerve injury had no effect on the DNA methylation level around the Panx1 promoter in the DRG. Furthermore, intrathecal injection of the Panx1 blockers or Panx1-specific siRNA significantly reduced pain hypersensitivity induced by nerve injury. In addition, siRNA knockdown of Panx1 expression in a DRG cell line significantly reduced caspase-1 release induced by neuronal depolarization. Our findings suggest that nerve injury increases Panx1 expression levels in the DRG through altered histone modifications. Panx1 up-regulation contributes to the development of neuropathic pain and stimulation of inflammasome signaling.     

Fascin-1 Contributes to Neuropathic Pain by Promoting Inflammation in Rat Spinal Cord

Neuropathic pain is a complicated clinical syndrome caused by heterogeneous etiology. Despite the fact that the underlying mechanisms remain elusive, it is well accepted that neuroinflammation plays a critical role in the development of neuropathic pain. Fascin-1, an actin-bundling protein, has been proved to be involved in the processing of diverse biological events including cellular development, immunity, and tumor invasion etc. Recent studies have shown that Fascin-1 participates in antigen presentation and the regulation of pro-inflammatory agents. However, whether Fascin-1 is involved in neuropathic pain has not been reported. In the present study we examined the potential role of Fascin-1 by using a rodent model of chronic constriction injury (CCI). Our results showed that Fascin-1 increased rapidly in dorsal root ganglions (DRG) and spinal cord (SC) after CCI. The increased Fascin-1 widely expressed in DRG, however, it localized predominantly in microglia, seldom in neuron, and hardly in astrocyte in the SC. Intrathecal injection of Fascin-1 siRNA not only suppressed the activation of microglia and the release of pro-inflammatory mediators, but also attenuated the mechanical allodynia and thermal hyperalgesia induced by CCI.     

Spinal Astrocytic Activation Contributes to Mechanical Allodynia in a Rat Chemotherapy-Induced Neuropathic Pain Model

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain enigmatic. Accumulating evidence implicates the involvement of spinal glia in some neuropathic pain models. In this study, using a vincristine-evoked CNP rat model with obvious mechanical allodynia, we found that spinal astrocyte rather than microglia was dramatically activated. The mechanical allodynia was dose-dependently attenuated by intrathecal administratration of L-α-aminoadipate (astrocytic specific inhibitor); whereas minocycline (microglial specific inhibitor) had no such effect, indicating that spinal astrocytic activation contributes to allodynia in CNP rat. Furthermore, oxidative stress mediated the development of spinal astrocytic activation, and activated astrocytes dramatically increased interleukin-1β expression which induced N-methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal neurons to strengthen pain transmission. Taken together, our findings suggest that spinal activated astrocytes may be a crucial component of the pathophysiology of CNP and “Astrocyte-Cytokine-NMDAR-neuron” pathway may be one detailed neural mechanisms underlying CNP. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for treating CNP.     

糖尿病大鼠脊髓内高迁移率族蛋白-1参与调节机械性痛敏的机制

目的:观察高迁移率族蛋白-1(high mobility group box-1,HMGB1)在糖尿病大鼠脊髓内的表达变化,探索其参与糖尿病性机械性痛觉过敏的具体机制,进一步阐明糖尿病性痛的机制,为糖尿病疼痛的治疗提供新的思路。方法:(1)36只SD大鼠随机分成6组(n=6),分别为正常大鼠组、糖尿病大鼠对照组、糖尿病7 d组、14 d、21 d和28 d组。通过Real-time PCR法检测各组大鼠脊髓内HMGB1 m RNA的表达情况。(2)24只SD大鼠分成4组(n=6)制作糖尿病大鼠模型,在造模后第28 d鞘内给予生理盐水、HMGB1的中和抗体10、30和100μg,检测糖尿病大鼠模型在各时间点的机械性缩足阈值。(3)30只SD大鼠随机分成5组(n=6),其中4组给予链尿佐菌素制作糖尿病大鼠模型。模型制作28 d后鞘内给予生理盐水、HMGB1的中和抗体10、30和100μg。另一组大鼠腹腔给予生理盐水,作为糖尿病大鼠的对照组。检测各组大鼠脊髓的TNF-α、IL-1β和IL-6 m RNA的表达。结果:(1)糖尿病大鼠模型制作21 d和28 d,脊髓内HMGB1 m RNA的表达显著上调(P0.05)。(2)糖尿病大鼠鞘内给予HMGB1中和抗体30和100μg后,可以在长达24 h的时间内扭转模型大鼠的机械性痛敏(P0.05)。(3)糖尿病大鼠造模28 d后,鞘内给予HMGB1的中和抗体30和100μg可以明显逆转糖尿病大鼠脊髓内的TNF-α、IL-1β和IL-6 m RNA的表达(P0.05)。结论:糖尿病大鼠脊髓内HMGB1显著上调,鞘内给予HMGB1的中和抗体可以通过抑制脊髓内TNF-α等细胞因子的表达而扭转糖尿病大鼠的机械性痛敏。以上结果提示,脊髓HMGB1可能参与了糖尿病机械性痛敏状态的维持过程。我们的研究对脊髓HMGB1参与糖尿病大鼠的疼痛的机制进行初步的探讨,为糖尿病性痛的治疗提供新的思路。     

Macrophage-Colony Stimulating Factor Derived from Injured Primary Afferent Induces Proliferation of Spinal Microglia and Neuropathic Pain in Rats

Peripheral nerve injury induces proliferation of microglia in the spinal cord, which can contribute to neuropathic pain conditions. However, candidate molecules for proliferation of spinal microglia after injury in rats remain unclear. We focused on the colony-stimulating factors (CSFs) and interleukin-34 (IL-34) that are involved in the proliferation of the mononuclear phagocyte lineage. We examined the expression of mRNAs for macrophage-CSF (M-CSF), granulocyte macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF) and IL-34 in the dorsal root ganglion (DRG) and spinal cord after spared nerve injury (SNI) in rats. RT-PCR and in situ hybridization revealed that M-CSF and IL-34, but not GM- or G-CSF, mRNAs were constitutively expressed in the DRG, and M-CSF robustly increased in injured-DRG neurons. M-CSF receptor mRNA was expressed in naive rats and increased in spinal microglia following SNI. Intrathecal injection of M-CSF receptor inhibitor partially but significantly reversed the proliferation of spinal microglia and in early phase of neuropathic pain induced by SNI. Furthermore, intrathecal injection of recombinant M-CSF induced microglial proliferation and mechanical allodynia. Here, we demonstrate that M-CSF is a candidate molecule derived from primary afferents that induces proliferation of microglia in the spinal cord and leads to induction of neuropathic pain after peripheral nerve injury in rats.     

趋化因子介导的神经炎症反应和神经病理性疼痛

各种疾病引起的神经系统的损伤或功能障碍致使全球数以百万计的人们患有神经性病理性疼痛。目前的方法对神经病理性疼痛的疗效不佳且有副作用,需要开发有效的治疗方法。近年来人们逐渐认识到,脊髓中胶质细胞（如小胶质细胞和星形胶质细胞）能通过释放强效的神经调质,如促炎细胞因子和趋化因子,在神经性病理性疼痛的产生和维持中起重要作用。近期的证据显示,趋化因子是疼痛调控中的新成员。该文综述了一些趋化因子和受体（如CCL2／CCR2、CXCL1／CXCR2、CX3CL1／CX3CR1、CCL21／CXCR3）作为神经元和胶质细胞相互调控的介质参与神经病理性疼痛的调节。靶向趋化因子介导的神经炎症反应将成为治疗神经病理性疼痛的新方向。     

Locomotor Dysfunction and Pain: The Scylla and Charybdis of Fiber Sprouting After Spinal Cord Injury

Injury to the spinal cord (SCI) can produce a constellation of problems including chronic pain, autonomic dysreflexia, and motor dysfunction. Neuroplasticity in the form of fiber sprouting or the lack thereof is an important phenomenon that can contribute to the deleterious effects of SCI. Aberrant sprouting of primary afferent fibers and synaptogenesis within incorrect dorsal horn laminae leads to the development and maintenance of chronic pain as well as autonomic dysreflexia. At the same time, interruption of connections between supraspinal motor control centers and spinal cord output cells, due to lack of successful regenerative sprouting of injured descending fiber tracts, contributes to motor deficits. Similarities in the molecular control of axonal growth of motor and sensory fibers have made the development of cogent therapies difficult. In this study, we discuss recent findings related to the degradation of inhibitory barriers and promotion of sprouting of motor fibers as a strategy for the restoration of motor function and note that this may induce primary afferent fiber sprouting that can contribute to chronic pain. We highlight the importance of careful attentiveness to off-target molecular- and circuit-level modulation of nociceptive processing while moving forward with the development of therapies that will restore motor function after SCI.     

Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice

Oxidation products of the naturally occurring phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), which are known as OxPAPC, accumulate in atherosclerotic lesions and at other sites of inflammation in conditions such as septic inflammation and acute lung injury to exert pro- or anti-inflammatory effects. It is currently unknown whether OxPAPC also contributes to inflammatory pain and peripheral neuronal excitability in these conditions. Here, we observed that OxPAPC dose-dependently and selectively activated human TRPA1 nociceptive ion channels expressed in HEK293 cells in vitro, without any effect on other TRP channels, including TRPV1, TRPV4 and TRPM8. OxPAPC agonist activity was dependent on essential cysteine and lysine residues within the N-terminus of the TRPA1 channel protein. OxPAPC activated calcium influx into a subset of mouse sensory neurons which were also sensitive to the TRPA1 agonist mustard oil. Neuronal OxPAPC responses were largely abolished in neurons isolated from TRPA1-deficient mice. Intraplantar injection of OxPAPC into the mouse hind paw induced acute pain and persistent mechanical hyperalgesia and this effect was attenuated by the TRPA1 inhibitor, HC-030031. More importantly, we found levels of OxPAPC to be significantly increased in inflamed tissue in a mouse model of chronic inflammatory pain, identified by the binding of an OxPAPC-specific antibody. These findings suggest that TRPA1 is a molecular target for OxPAPC and OxPAPC may contribute to chronic inflammatory pain through TRPA1 activation. Targeting against OxPAPC and TRPA1 signaling pathway may be promising in inflammatory pain treatment.     

The Contribution of TRPM8 and TRPA1 Channels to Cold Allodynia and Neuropathic Pain

Cold allodynia is a common feature of neuropathic pain however the underlying mechanisms of this enhanced sensitivity to cold are not known. Recently the transient receptor potential (TRP) channels TRPM8 and TRPA1 have been identified and proposed to be molecular sensors for cold. Here we have investigated the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG) and examined the cold sensitivity of peripheral sensory neurons in the chronic construction injury (CCI) model of neuropathic pain in mice.In behavioral experiments, chronic constriction injury (CCI) of the sciatic nerve induced a hypersensitivity to both cold and the TRPM8 agonist menthol that developed 2 days post injury and remained stable for at least 2 weeks. Using quantitative RT-PCR and in situ hybridization we examined the expression of TRPM8 and TRPA1 in DRG. Both channels displayed significantly reduced expression levels after injury with no change in their distribution pattern in identified neuronal subpopulations. Furthermore, in calcium imaging experiments, we detected no alterations in the number of cold or menthol responsive neurons in the DRG, or in the functional properties of cold transduction following injury. Intriguingly however, responses to the TRPA1 agonist mustard oil were strongly reduced.Our results indicate that injured sensory neurons do not develop abnormal cold sensitivity after chronic constriction injury and that alterations in the expression of TRPM8 and TRPA1 are unlikely to contribute directly to the pathogenesis of cold allodynia in this neuropathic pain model.     

钠离子通道NaV1.7与神经病理性疼痛

钠通道NaV1.7是电压门控性钠通道的亚型之一。大多数钠离子通道NaV1.7表达在背根神经节(DRG)小C纤维的伤害性感受器上,具有缓慢开放和缓慢关闭失活的特点。它能够产生大量的斜坡电流,降低感觉神经元中动作电位产生的阈值,放大外来小的缓慢的去极化斜坡电流,从而增加神经元兴奋性,对疼痛的产生、传递、调节具有关键性作用。随着遗传学研究的不断深入,钠离子通道NaV1.7的功能获得性突变和功能缺失性突变,使其成为了新型镇痛疗法中一个的特别有吸引力的药物靶点,受到人们的广泛关注。而研究发现,NaV1.7通道在不同因素引起的神经病理性疼痛中通过不同途径提高神经元兴奋性,参与神经病理性疼痛,给NaV1.7选择性抑制剂研发带来了巨大阻碍。目前,虽然已有的NaV1.7选择性抑制剂具备有效镇痛作用,且无明显副作用或成瘾问题,但寻找NaV1.7选择性配体极其困难。此外,现有的NaV1.7选择性抑制剂也因神经病理性疼痛类型的不同在抑制效力、靶向性、安全性以及可行性等方面存在差异。提示寻找NaV1.7通道作用于不同神经病理性疼痛的普遍机制或NaV1.7通道特有的受体结合位点,可能是未来NaV1.7选择性抑制剂研发的主要方向。本文就NaV1.7通道在不同因素引起的神经病理性疼痛中的主要作用进行简要综述。     

Involvement of the Melanocortin-1 Receptor in Acute Pain and Pain of Inflammatory but Not Neuropathic Origin

Background

Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R.

Methodology and Principal Findings

We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain.

Conclusions

We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.     

The Fragile Fiber1 Kinesin Contributes to Cortical Microtubule-Mediated Trafficking of Cell Wall Components

The cell wall consists of cellulose microfibrils embedded within a matrix of hemicellulose and pectin. Cellulose microfibrils are synthesized at the plasma membrane, whereas matrix polysaccharides are synthesized in the Golgi apparatus and secreted. The trafficking of vesicles containing cell wall components is thought to depend on actin-myosin. Here, we implicate microtubules in this process through studies of the kinesin-4 family member, Fragile Fiber1 (FRA1). In an fra1-5 knockout mutant, the expansion rate of the inflorescence stem is halved compared with the wild type along with the thickness of both primary and secondary cell walls. Nevertheless, cell walls in fra1-5 have an essentially unaltered composition and ultrastructure. A functional triple green fluorescent protein-tagged FRA1 fusion protein moves processively along cortical microtubules, and its abundance and motile density correlate with growth rate. Motility of FRA1 and cellulose synthase complexes is independent, indicating that FRA1 is not directly involved in cellulose biosynthesis; however, the secretion rate of fucose-alkyne-labeled pectin is greatly decreased in fra1-5, and the mutant has Golgi bodies with fewer cisternae and enlarged vesicles. Based on our results, we propose that FRA1 contributes to cell wall production by transporting Golgi-derived vesicles along cortical microtubules for secretion.The cell wall plays a vital role in the life of a plant. In growing cells, the tough but extensible primary wall determines the rate and direction of expansion and overall plant form. In differentiated cells, such as interfascicular fibers and xylem cells, the thick secondary cell wall provides strength to withstand gravity and large negative pressures. Other than mechanics, cell walls feature in essential processes, such as pathogen resistance, signal transduction, and cell-to-cell communication. In addition, cell wall biomass has potential as a feedstock for biofuel production. Therefore, understanding cell wall biogenesis is important fundamentally and practically.Cell walls consist primarily of cellulose, hemicellulose, and pectin along with small amounts of protein. Typical of eukaryotic secretory products, hemicellulose and pectin are synthesized in the Golgi and then delivered to the extracellular space through the secretory system. Atypically, cellulose microfibrils are synthesized de novo at the plasma membrane by cellulose synthase (CESA) complexes, although the CESA complexes themselves are thought to be assembled in the Golgi and trafficked to the plasma membrane (McFarlane et al., 2014). How the various cell wall components are delivered to the plasma membrane and extracellular space to form a functional cell wall remains poorly understood.Among cell wall components, cellulose has perhaps the best understood delivery process, which is influenced by cortical microtubules (Baskin, 2001; Lloyd, 2011). The cortical microtubule array organizes cellulose deposition spatially by targeting the secretion of CESA complexes (Crowell et al., 2009; Gutierrez et al., 2009) and orienting their movement (Gardiner et al., 2003; Paredez et al., 2006). What controls the delivery of other wall components is less clear. Sustained transport of organelles in plants is actin based (Sparkes, 2011), and vesicle trafficking is generally assumed to be independent of microtubules, at least during interphase. Nevertheless, in xylem tracheary cells, cortical microtubule bands have been linked to not only cellulose guidance but also, the targeted exocytosis of hemicellulose and other matrix components (Fukuda, 1997). In seed coat cells, vesicles containing pectin associate with cortical microtubules that line the mucilage secretion pockets (McFarlane et al., 2008). In addition, in maize (Zea mays) roots, vesicles bind cortical microtubules densely (Tian et al., 2004). These and other observations indicate that cortical microtubules might serve as roadways for trafficking secretory vesicles.If microtubules are tracks, then the engines are kinesins, because seed plants lack dyneins (Zhu and Dixit, 2012). Kinesins are molecular motors that move along microtubules and transport various cargo, including organelles, vesicles, and proteins. Kinesins have proliferated in plant lineages, and many are expressed during interphase, which is surprising given that long-distance organelle motility is thought to be actin based. Recently, a particular plant kinesin of the kinesin-4 family, called Fragile Fiber1 (FRA1), was shown to move rapidly and processively (i.e. taking multiple steps) toward microtubule plus ends in vitro (Zhu and Dixit, 2011). This makes FRA1 a candidate for sustained and active vesicle transport.An Arabidopsis (Arabidopsis thaliana) partial loss-of-function mutant, fra1-1, was reported to have altered cellulose organization in fiber cells, despite having evidently undisturbed cortical microtubule organization (Zhong et al., 2002). Those results suggested a function for FRA1 in cell wall organization rather than secretion, and FRA1 has been proposed to link motile CESA complexes in the plasma membrane to cortical microtubules (Zhong et al., 2002; Lloyd and Chan, 2004; Zhu and Dixit, 2011). Strengthening this suggestion, a null mutant of the FRA1 ortholog in rice (Oryza sativa), brittle culm12 (bc12), also was reported to have disorganized sclerenchyma cell walls (Zhang et al., 2010). However, the motility of FRA1 in vivo and its relationship to CESA complexes remain unknown.We have reexamined FRA1 function in cell wall formation. Because the originally characterized allele, fra1-1, is predicted to give rise to a nearly full-length protein, we characterized a transfer DNA (T-DNA)-induced knockout mutant, fra1-5. Using this allele as well as imaging a functional FRA1-3GFP fusion protein, we show here that FRA1 is involved in membrane trafficking that contributes to delivery of cell wall polysaccharides, such as pectin. We propose that FRA1 drives the movement of vesicles containing cell wall cargo along cortical microtubules to facilitate their secretion.     

外周神经源性疼痛的实验模型研究进展

神经源性疼痛是严重困扰人类的临床问题之一。为了探索其发病机理及治疗方法,研究人员建立了多种神经损伤性疼痛模型,其中大鼠部分脊神经结扎,慢性压迫性神经损伤和L5／L6脊神经结扎的外周神经损伤的模型应用最为广泛。细胞模型也显示出了很好的应用前景,原代和永久性感觉神经元,作为研究疼痛发生和发展的分子机理,特别是神经递质的释放和信号转导的研究非常有用。     

Up-Regulation of CX3CL1 via STAT3 Contributes to SMIR-Induced Chronic Postsurgical Pain

Chronic postsurgical pain (CPSP) often occurs after surgery and has a strong impact on patients’ daily lives. However, the underlying mechanism of CPSP remains unknown. Here, we used a skin/muscle incision and retraction (SMIR) model to investigate the role of CX3CL1 in SMIR-induced pain and its underlying mechanism. We found that up-regulation of CX3CL1 in the spinal dorsal horn contributed to SMIR-induced mechanical allodynia. The use of a CX3CL1-neutralizing antibody to block CX3CL1 attenuated mechanical allodynia induced by SMIR surgery. We also found that phospho-STAT3 co-localizes with CX3CL1 in spinal neurons after SMIR surgery and that this contributes to SMIR-induced mechanical allodynia. Intrathecal administration of the STAT3 inhibitor S3I-201 suppressed up-regulation of CX3CL1 at both the protein and mRNA levels after SMIR surgery. Chromatin immunoprecipitation further demonstrated that SMIR promotes the recruitment of STAT3 to the cx3cl1 gene promoter (??1032/??1022). These findings suggest that activation of STAT3 after SMIR mediates the up-regulation of CX3CL1, leading to mechanical allodynia, and that this upregulation may partly be due to the enhanced recruitment of STAT3 to the cx3cl1 gene promoter after SMIR.     

Lipo-Endomorphin-1 Derivatives with Systemic Activity against Neuropathic Pain without Producing Constipation

To enhance the drug-like properties of the endogenous opioid peptide endomorphin-1 (1 = Tyr-Pro-Trp-Phe-NH₂), the N-terminus of the peptide was modified with 2-aminodecanoic acid, resulting in compound 3. Tyr in compound 1 was replaced with 2,6-dimethyltyrosine yielding compound 2. Derivative 2 was also substituted with 2-aminodecanoic acid producing compound, 4. Lipoamino acid-modified derivatives showed improved metabolic stability and membrane permeability while maintaining high μ-opioid (MOP) receptor binding affinity and acting as a potent agonist. In vivo studies showed dose-dependent antinociceptive activity following intravenous (i.v.) administration of compounds 3 and 4 in a chronic constriction injury (CCI)-rat model of neuropathic pain with ED₅₀ values of 1.22 (±0.93) and 0.99 (±0.89) µmol/kg, respectively. Pre-treatment of animals with naloxone hydrochloride significantly attenuated the anti-neuropathic effects of compound 3, confirming the key role of opioid receptors in mediating antinociception. In contrast to morphine, no significant constipation was produced following i.v. administration of compound 3 at 16 µmol/kg. Furthermore, following chronic administration of equi-potent doses of compound 3 and morphine to rats, there was less antinociceptive tolerance for compound 3 compared with morphine.     

突触后致密物与癫痫苔藓纤维出芽

突触后致密物是化学性突触后膜内侧的特化结构,为神经信息传递的重要结构基础,参与突触后信号转导的调节和整合,在学习、记忆和突触可塑性等生理过程中有重要作用。近年来发现,癫痫发作伴有突触后致密物成分的改变,可能参与了癫痫的病理生理过程。     

Platelet-Rich Plasma and the Elimination of Neuropathic Pain

Peripheral neuropathic pain typically results from trauma-induced nociceptive neuron hyperexcitability and their spontaneous ectopic activity. This pain persists until the trauma-induced cascade of events runs its full course, which results in complete tissue repair, including the nociceptive neurons recovering their normal biophysical properties, ceasing to be hyperexcitable, and stopping having spontaneous electrical activity. However, if a wound undergoes no, insufficient, or too much inflammation, or if a wound becomes stuck in an inflammatory state, chronic neuropathic pain persists. Although various drugs and techniques provide temporary relief from chronic neuropathic pain, many have serious side effects, are not effective, none promotes the completion of the wound healing process, and none provides permanent pain relief. This paper examines the hypothesis that chronic neuropathic pain can be permanently eliminated by applying platelet-rich plasma to the site at which the pain originates, thereby triggering the complete cascade of events involved in normal wound repair. Many published papers claim that the clinical application of platelet-rich plasma to painful sites, such as muscle injuries and joints, or to the ends of nerves evoking chronic neuropathic pain, a process often referred to as prolotherapy, eliminates pain initiated at such sites. However, there is no published explanation of a possible mechanism/s by which platelet-rich plasma may accomplish this effect. This paper discusses the normal physiological cascade of trauma-induced events that lead to chronic neuropathic pain and its eventual elimination, techniques being studied to reduce or eliminate neuropathic pain, and how the application of platelet-rich plasma may lead to the permanent elimination of neuropathic pain. It concludes that platelet-rich plasma eliminates neuropathic pain primarily by platelet- and stem cell-released factors initiating the complex cascade of wound healing events, starting with the induction of enhanced inflammation and its complete resolution, followed by all the subsequent steps of tissue remodeling, wound repair and axon regeneration that result in the elimination of neuropathic pain, and also by some of these same factors acting directly on neurons to promote axon regeneration thereby eliminating neuropathic pain.