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Management of bone cancer pain (BCP) is difficult because of its complex mechanisms, which has a major impact on the quality of patients' daily life. Recent studies have indicated that endoplasmic reticulum (ER) stress is involved in many neurological and inflammatory pathways associated with pain. However, the factors that contribute to ER stress and its causes in bone cancer pain are still unknown. In this study, we examined whether the ER stress response is involved in caspase signaling pathway-dependent apoptosis in neurons in the spinal dorsal horn of tumor-38 bearing rats and whether it thereby induces bone cancer pain.
Learn More >Bone Morphogenetic Protein-2/4 (BMP2/4) have been recognized as promoters of astrocyte activity. Substantial evidence suggests BMP2/4 may be elevated and play a critical role in astrocyte activation upon spinal cord injury. Although neuropathic pain (NP) is similarly associated with astrocyte activation, the participation of BMP2/4 in this regard still remains unclear. A rat model of NP achieved by spinal nerve ligation (SNL) at L5 was used to evaluate the expression of glial fibrillary acidic protein (GFAP) and BMP2/4 in the spinal cord in days 1, 4, 7, 10 and 14. Next, normal rats received intrathecal exogenous BMP2/4 and the antagonist Noggin to assess the effect of BMP2/4 on astrocyte activation. In both experiments, von Frey filaments were used to evaluate changes in paw withdrawal threshold (PWT). In addition, Western blotting and immunofluorescence were performed to assess the expression of glial fibrillary acidic protein (GFAP), BMP2/4, p-Smad 1/5/8, p-STAT3 in the spinal cord. Firstly, SNL caused a significant increase in the expression of BMP4, while BMP2 levels remained unchanged. Secondly, exogenous BMP4 but not BMP2 induced a significant decrease in PWT, along with upregulation of GFAP. Moreover, exogenous BMP4 stimulated both p-Smad 1/5/8 and p-STAT3, while BMP2 only upregulated p-Smad 1/5/8. Finally, exogenous Noggin alleviated the decrease in PWT induced by BMP4, and reduced astrocyte activation, as well as p-STAT3 upregulation. Our results indicate only BMP4-and not BMP2-intervened in allodynia in rats by eliciting glial activation, probably through both p-Smad 1/5/8 andp-STAT3 signaling.
Learn More >Mechanosensation is central to a wide range of functions, including tactile and pain perception, hearing, proprioception, and control of blood pressure, but identifying the molecules underlying mechanotransduction has proved challenging. In , the avoidance response to gentle body touch is mediated by 6 touch receptor neurons (TRNs), and is dependent on MEC-4, a DEG/ENaC channel. We show that hemichannels containing the innexin protein UNC-7 are also essential for gentle touch in the TRNs, as well as harsh touch in both the TRNs and the PVD nociceptors. UNC-7 and MEC-4 do not colocalize, suggesting that their roles in mechanosensory transduction are independent. Heterologous expression of in touch-insensitive chemosensory neurons confers ectopic touch sensitivity, indicating a specific role for UNC-7 hemichannels in mechanosensation. The touch defect can be rescued by the homologous mouse gene gene, thus, innexin/pannexin proteins may play broadly conserved roles in neuronal mechanotransduction.
Learn More >There is a major unmet need to develop new therapies for migraine. We have previously demonstrated the therapeutic potential of the acid sensing ion channel (ASIC) blockade in migraine, via an ASIC1 mechanism. ASIC3 is expressed in the trigeminal ganglion and its response is potentiated by nitric oxide that can trigger migraine attacks in patients, and thus we sought to explore the potential therapeutic effect of ASIC3 blockade in migraine.
Learn More >We have developed an experimental fibromyalgia (FM)-like mouse model using intermittent cold stress (ICS), where chronic pain is generalized, female-predominant and abolished in type 1 lysophosphatidic acid receptor-KO (LPA1-/-) mice, but is not reversed by systemic or brain treatment with morphine. In the present study, we investigated two issues whether both chronic pain mechanisms and lack of brain morphine analgesia are associated to each other in the ICS model, and what mechanisms are involved in the lack of morphine analgesia. The hyperalgesia was not affected in μ-opioid receptor-KO (MOPr-/-) mice, while the lack of brain morphine analgesia remained unchanged in LPA1-/- mice, which completely abolish the hyperalgesia in the ICS model. On the other hand, the lack of morphine analgesia was abolished in NR2A-NMDA receptor-KO (NR2A-/-) mice, and blocked by intracerebroventricular (i.c,v,) injection of (R)-CPP, an NR2A antagonist or by microinjection of siRNA for NR2A into PAG region, while no change was observed with Ro 04-5595, an NR2B antagonist (i.c.v.). The lack of morphine analgesia was also reversed by the concomitant treatment with 1 mg/kg (i.p.) of dextromethorphan possessing NMDA receptor antagonist activity, which has no analgesic activity. Finally, the hyperalgesia was completely reversed by methadone possessing MOPr agonist and NMDA receptor antagonist activity. Indeed, the methadone analgesia was abolished in MOPr-/- mice. All these results suggest that chronic pain status and lack of morphine analgesia are independent to each other, and the lack of morphine analgesia is mediated by an activation of NR2A-NMDA receptor system. SIGNIFICANCE STATEMENT: This study describes that a type of stress-induced wide-spread pain has chronic pain independent of endogenous opioid-mediated pain inhibitory system and lack of morphine analgesia independent of chronic pain status. This study describes that the lack of morphine analgesia is possibly mediated by endogenous opioid-induced analgesic tolerance and thereby reversed by anti-opioid NMDA receptor system. The latter view is evidenced by the findings that NMDA receptor blockades recover the morphine analgesia.
Learn More >Major depressive disorders (MDD) and chronic pain (CP) affect significant portion of the world's population and have high comorbidity rate. Social defeat stress (SDS) model was standardized in mice and can trigger depressive-like behavior and chronic pain. Based especially on clinical trials showing an effective preventive and therapeutic effect of physical exercise on CP and symptoms associated with MDD, this study aimed to investigate if the voluntary running wheel exercise can exert these effects in mice submitted to the 10-day SDS protocol, using fluoxetine as positive control. For this, we ran two set of experiments: in the first set mice started performing voluntary running wheel exercise after submitted to SDS and, in the second set, mice performed voluntary running wheel exercise before and during SDS. Mechanical and chemical hyperalgesia was analyzed through electronic von Frey and capsaicin test, respectively. Depressive-like behavior was assessed through social interaction test. Our results showed that the voluntary running wheel exercise was more effective than fluoxetine reversing the SDS-induced persistent hyperalgesia and both, fluoxetine and voluntary running wheel exercise, was effective reversing SDS-induced social avoidance. Also, voluntary running wheel exercise is an effective tool preventing both hyperalgesia and social avoidance induced by SDS. To the best of our knowledge, this was the first study using physical exercise as a therapeutic and preventive tool for chronic pain and depressive-like behavior simultaneously induced by social stress.
Learn More >NrCAM, a neuronal cell adhesion molecule in the L1 family of the immunoglobulin superfamily, is subjected to extensively alternative splicing and is involved in neural development and some disorders. The aim of this study was to explore the role of Nrcam mRNA alternative splicing in neuropathic pain. A next generation RNA sequencing analysis of dorsal root ganglions (DRGs) showed the differential expression of two splicing variants of Nrcam, Nrcam and Nrcam, in the injured DRG after the fourth lumbar spinal nerve ligation (SNL). SNL increased the exon 10 insertion, resulting in an increase in the amount of Nrcam and a corresponding decrease in the level of Nrcam in the injured DRG. An antisense oligonucleotide (ASO) that specifically targeted exon 10 of Nrcam gene (Nrcam ASO) repressed RNA expression of Nrcam while increased Nrcam in in vitro DRG cell culture. Either DRG microinjection or intrathecal injection of Nrcam ASO attenuated SNL-induced the development of mechanical allodynia, thermal hyperalgesia, or cold allodynia. Nrcam ASO also relieved SNL- or chronic compression of DRG (CCD)-induced the maintenance of pain hypersensitivities in male and female mice. PERSPECTIVE: We conclude that the relative levels of alternatively spliced Nrcam variants are critical for neuropathic pain genesis. Targeting Nrcam alternative splicing via the antisense oligonucleotides may be a new potential avenue in neuropathic pain management.
Learn More >Functional dyspepsia (FD) is a common functional gastrointestinal disorder. Gastric hypersensitivity (GHS) is a hallmark of this disorder but the cellular mechanisms remain largely unknown. Stressors during gestational period could have effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of this study was to test whether prenatal maternal stress (PMS) induces GHS and to investigate role of acid-sensing ion channel (ASIC)/ nuclear factor-κB (NF-κB) signaling by examining Asic1 methylation status in adult offspring rats. GHS in response to gastric distention was examined by electromyography recordings. Changes in neuronal excitability were determined by whole-cell patch-clamp recording techniques. Demethylation of CpG islands of Asic1 was determined by methylation-specific PCR and bisulfite sequencing assay. PMS produced GHS in adult offspring rats. Treatment with Amiloride, an inhibitor of ASICs, significantly attenuated GHS and reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI. Expression of ASIC1 and NF-κBp65 were markedly enhanced in T7-T10 DRGs. Furthermore, PMS led to a significant demethylation of CpG islands in the Asic1 promoter. A chromatin immunoprecipitation assay showed that PMS also enhanced the ability of NF-κBp65 to bind the promoter of Asic1 gene. Blockade of NF-κB using lentiviral-p65shRNA reversed upregulation of ASIC1 expression, GHS and the hyperexcitability of DRG neurons. These data suggest that upregulation of ASIC1 expression is attributed to Asic1 promoter DNA demethylation and NF-κB activation, and that the enhanced interaction of the Asic1 and NF-κBp65 contributes to GHS induced by PMS.
Learn More >Burn injuries and associated complications present a major public health challenge. Many burn patients develop clinically intractable complications, including pain and other sensory disorders. Recent evidence has shown that dendritic spine neuropathology in spinal cord sensory and motor neurons accompanies central nervous system (CNS) or peripheral nervous system (PNS) trauma and disease. However, no research has investigated similar dendritic spine neuropathologies following a cutaneous thermal burn injury. In this retrospective investigation, we analyzed dendritic spine morphology and localization in alpha-motor neurons innervating a burn-injured area of the body (hind paw). To identify a molecular regulator of these dendritic spine changes, we further profiled motor neuron dendritic spines in adult mice treated with romidepsin, a clinically approved Pak1-inhibitor, or vehicle control at two postburn time points: Day 6 immediately after treatment, or Day 10 following drug withdrawal. In control treated mice, we observed an overall increase in dendritic spine density, including structurally mature spines with mushroom-shaped morphology. Pak1-inhibitor treatment reduced injury-induced changes to similar levels observed in animals without burn injury. The effectiveness of the Pak1-inhibitor was durable, since normalized dendritic spine profiles remained as long as 4 days despite drug withdrawal. This study is the first report of evidence demonstrating that a second-degree burn injury significantly affects motor neuron structure within the spinal cord. Furthermore, our results support the opportunity to study dendritic spine dysgenesis as a novel avenue to clarify the complexities of neurological disease following traumatic injury.
Learn More >Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ET) and B (ET) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague-Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ET/ET receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ET receptor antagonism. Intrathecal administration of an ET receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ET receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ET receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.
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