New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review.
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ABSTRACT:
SUBMITTER: Bao Y
PROVIDER: S-EPMC4594588 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Nerve injury often causes debilitating chronic pain, referred to as neuropathic pain, which is refractory to currently available analgesics including morphine. Many reports indicate that activated spinal microglia evoke neuropathic pain. The P2X4 receptor (P2X4R), a subtype of ionotropic ATP receptors, is upregulated in spinal microglia after nerve injury by several factors, including CC chemokine receptor CCR2, the extracellular matrix protein fibronectin in the spinal cord, interferon regulatory factor 8 (IRF8) and IRF5. Inhibition of P2X4R function suppresses neuropathic pain, indicating that microglial P2X4R play a key role in evoking neuropathic pain.
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Project description:Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain-inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/?-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-? and regulated the NR2B glutamate receptor and Ca2+-dependent signals through the ?-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.
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Project description:Inflammation plays a central role in the manner that the nervous system responds to injury. These effects include vasodilatation, increased vascular permeability, plasma extravasation, cell migration, and pain. Extracellular signals associated with inflammation may also lead to increased levels of pro-nociceptive chemokines/receptors that directly contribute to persistent or chronic pain behavior. To date, research focused on improving the treatment of chronic pain has largely ignored the role of inflammation-associated transcription factors such as nuclear transcription factor in activated T cells (NFAT). Herein we discuss the idea that activation of this transcription factor may be responsible for the production of chemokines receptors in both neuronal and non-neuronal cells of the peripheral nervous system. Taken together, a better understanding of the transcription of these pro-nociceptive genes may lead to the development of novel analgesic targets.
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Project description:Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain's immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor γ-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils.
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Project description:PURPOSE:This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations. RECENT FINDINGS:Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome.
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Project description:BackgroundHyperglycemia-induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear.ObjectiveTo investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia-induced neuroinflammation and DNP and to explore potential therapeutic interventions.Method and resultsHere, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA-sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia-induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high-glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy-lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia-induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia-induced Sirt3 downregulation.ConclusionHyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP.
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Project description:Pain treatment is a critical aspect of pancreatic cancer patient clinical care. This study investigated the role of trypsin-protease activated receptor-2 (PAR-2) in pancreatic cancer pain. Pancreatic tissue samples were collected from pancreatic cancer (n=22) and control patients (n=22). Immunofluorescence analyses confirmed colocalization of PAR-2 and neuronal markers in pancreatic cancer tissues. Trypsin levels and protease activities were higher in pancreatic cancer tissue specimens than in the controls. Supernatants from cultured human pancreatic cancer tissues (PC supernatants) induced substance P and calcitonin gene-related peptide release in dorsal root ganglia (DRG) neurons, and FS-NH2, a selective PAR-2 antagonist, inhibited this effect. A BALB/c nude mouse orthotopic tumor model was used to confirm the role of PAR-2 signaling in pancreatic cancer visceral pain, and male Sprague-Dawley rats were used to assess ambulatory pain. FS-NH2 treatment decreased hunch scores, mechanical hyperalgesia, and visceromotor reflex responses in tumor-bearing mice. In rats, subcutaneous injection of PC supernatant induced pain behavior, which was alleviated by treatment with FS-NH2 or FUT-175, a broad-spectrum serine protease inhibitor. Our findings suggest that trypsin-PAR-2 signaling contributes to pancreatic cancer pain in vivo. Treatment strategies targeting PAR-2 or its downstream signaling molecules might effectively relieve pancreatic cancer pain.
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Project description:Neuropathic pain is a common and often incapacitating clinical problem for which little useful therapy is presently available. Painful peripheral neuropathies can have many etiologies, among which are trauma, viral infections, exposure to radiation or chemotherapy, and metabolic or autoimmune diseases. Sufferers generally experience both pain at rest and exaggerated, painful sensitivity to light touch. Spontaneous firing of injured nerves is believed to play a critical role in the induction and maintenance of neuropathic pain syndromes. Using a well characterized nerve ligation model in the rat, we demonstrate that hyperpolarization-activated, cyclic nucleotide-modulated (HCN) "pacemaker" channels play a previously unrecognized role in both touch-related pain and spontaneous neuronal discharge originating in the damaged dorsal root ganglion. HCN channels, particularly HCN1, are abundantly expressed in rat primary afferent somata. Nerve injury markedly increases pacemaker currents in large-diameter dorsal root ganglion neurons and results in pacemaker-driven spontaneous action potentials in the ligated nerve. Pharmacological blockade of HCN activity using the specific inhibitor ZD7288 reverses abnormal hypersensitivity to light touch and decreases the firing frequency of ectopic discharges originating in Abeta and Adelta fibers by 90 and 40%, respectively, without conduction blockade. These findings suggest novel insights into the molecular basis of pain and the possibility of new, specific, effective pharmacological therapies.
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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN.In this study we investigated the effect of reparixin, an inhibitor of CXCR1/CXCR2, in suppressing the development of paclitaxel-induced nociception in rats. Moreover, reparixin activity in reversing the neurotoxic effects induced by paclitaxel or GRO/KC in F11 cells was also analyzed.Reparixin administered by continuous infusion ameliorated paclitaxel-induced mechanical and cold allodynia in rats. In F11 cells, reparixin was able to inhibit the increase of acetyladed α-tubulin induced both by paclitaxel and GRO/KC. The subsequent experiments were performed in order to dissect the signal transduction pathways under GRO/KC control, eventually modulated by paclitaxel and/or reparixin. To this aim we found that reparixin significantly counteracted p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation induced either by paclitaxel or GRO/KC.Overall the present results have identified IL-8/CXCR1/2 pathway as a mechanism involved in paclitaxel-induced peripheral neuropathy. In particular, the obtained data suggest that the inhibition of CXCR1/2 combined with standard taxane therapy, in addition to potentiating the taxane anti-tumor activity can reduce chemotherapy-induced neurotoxicity, thus giving some insight for the development of novel treatments.
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Project description:Allergic diseases are associated with central and peripheral nervous system diseases such as autism spectrum disorders and eosinophilic granulomatosis with polyangiitis, which frequently causes mononeuritis multiplex. Thus, it is possible that patients with an atopic constitution might develop multifocal inflammation in central and peripheral nervous system tissues. In a previous study in Japan, we reported a rare form of myelitis with persistent neuropathic pain (NeP) in patients with allergic disorders. However, the underlying mechanism of allergic inflammation-related NeP remains to be elucidated. First, we analyzed the effect of allergic inflammation on the nociceptive system in the spinal cord. Mice with atopy showed microglial and astroglial activation in the spinal cord and tactile allodynia. In a microarray analysis of isolated microglia from the spinal cord, endothelin receptor type B (EDNRB) was the most upregulated cell surface receptor in mice with atopy. Immunohistochemical analysis demonstrated EDNRB expression was upregulated in microglia and astroglia. The EDNRB antagonist BQ788 abolished glial activation and allodynia. These findings indicated that allergic inflammation induced widespread glial activation through the EDNRB pathway and NeP. Second, we investigated whether autoantibody-mediated pathogenesis underlies allergic inflammation-related NeP. We detected specific autoantibodies to small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients with allergic disorders. An analysis of IgG subclasses revealed a predominance of IgG2. These autoantibodies were mostly colocalized with isolectin B4- and P2X3-positive unmyelinated C-fiber type small DRG neurons. By contrast, immunostaining for S100?, a myelinated DRG neuron marker, showed no colocalization with patient IgG. Immunoprecipitation and liquid chromatography-tandem mass spectrometry identified plexin D1 as a target autoantigen. Patients with anti-plexin D1 antibodies often present with burning pain and thermal hyperalgesia. Immunotherapies, including plasma exchange, are effective for NeP management. Therefore, anti-plexin D1 antibodies may be pathogenic for immune-mediated NeP, especially under allergic inflammation conditions. Thus, allergic inflammation may induce NeP through glial inflammation in the spinal cord and the anti-plexin D1 antibody-mediated impairment of small DRG neurons.
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