RESUMO
Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor prognosis and lack of effective treatments and therapies. Bone tumors are often accompanied by skeletal complications such as bone destruction and cancer-induced bone pain. However, the mechanisms involved in bone cancer progression, bone metastasis and skeletal complications remain unclear. Lysophosphatidic acid (LPA), an intercellular lipid signaling molecule that exerts a wide range of biological effects mainly through specifically binding to LPA receptors (LPARs), has been found to be present at high levels in the ascites of bone tumor patients. Numerous studies have suggested that LPA plays a role in primary malignant bone tumors, bone metastasis, and skeletal complications. In this review, we summarize the role of LPA signaling in primary bone cancer, bone metastasis and skeletal complications. Modulating LPA signaling may represent a novel avenue for future therapeutic treatments for bone cancer, potentially improving patient prognosis and quality of life.
Assuntos
Neoplasias Ósseas , Lisofosfolipídeos , Receptores de Ácidos Lisofosfatídicos , Transdução de Sinais , Humanos , Lisofosfolipídeos/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Transdução de Sinais/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , AnimaisRESUMO
Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.
Assuntos
Histamina , Microglia , Camundongos , Animais , Histamina/metabolismo , Microglia/metabolismo , Prurido/induzido quimicamente , Prurido/metabolismo , Camundongos Transgênicos , Cloroquina/farmacologia , Transdução de Sinais , DorRESUMO
The gene cell migration inducing hyaluronidase 1 (CEMIP) is on chromosome 15q25 and codes for a 150-kDa protein with an N-terminal secretion signal, a G8 domain, 2 GG domains, and several repeats. It was first described as a specific protein in the inner ear relating to nonsyndromic hearing loss. Recently, increasing research detected its association in various cancers, determining the progression, metastasis, and prognosis by influencing the proliferation and invasion of the cells. This relation is accomplished through various interacting pathways, such as the Wnt/ß-catenin signaling pathway and the epidermal growth factor receptor signaling pathway. Thus, CEMIP could be a novel and potential focus for tumor diagnosis and treatment, but further studies on the regulatory role of CEMIP in vivo and in vitro are still needed. Herein, we summarize the process in recent studies of CEMIP, especially in cancer research.
Assuntos
Hialuronoglucosaminidase , Via de Sinalização Wnt , Humanos , Movimento CelularRESUMO
Serotonin (5-HT) participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), but its effects have not been completely clarified. Therefore, we observed the distribution features and potential effects of 5-HT in the cerebrum of G93A SOD1 transgenic (TG) and wild-type (WT) mice by fluorescence immunohistochemistry, Western blotting, ELISA, as well as motor function measurements. Both 5-HT and tryptophan hydroxylase-2 (TPH2) were mainly present in the limbic systems of the cerebrum, such as the glomerular layer of the olfactory bulb, nucleus accumbens, cingulate, fimbria of the hippocampus, mediodorsal thalamic nucleus, habenular nucleus, ventromedial hypothalamus nucleus, lateral hypothalamus area, dorsal raphe nucleus, and piriform cortex. TPH2 and 5-HT were expressed in cell bodies in the dorsal raphe nucleus and piriform cortex, while in other regions they were distributed as filaments and clump shapes in axons. The TPH2 distribution in the cerebrum of TG was significantly lower than that in WT in preset, onset, and progression stages. TPH2 expression in the fimbria of the hippocampus, mediodorsal thalamic nucleus, habenular nucleus, ventromedial hypothalamus nucleus and lateral hypothalamus area was increased in the onset stage and decreased in the progression stage, gradually decreased in the cingulate with disease progression and significantly decreased in the glomerular layer of the olfactory bulb and nucleus accumbens in the onset stage in TG. The number of mammalian achaete-scute homolog-1 in the subventricular zone (SVZ) in TG was significantly lower than that in WT, which was correlated with the TPH2 distribution. Double immunofluorescence staining showed that TPH2, mammalian achaete-scute homolog-1 and 5-HT were mainly expressed in neurons but rarely expressed in microglia or astrocytes in the piriform cortex. The relative fluorescence density of TPH2 in the cingulate region was negatively correlated with the disease severity. Our findings suggest that 5-HT plays a protective role in ALS, likely by regulating neural stem cells in the subventricular zone that might be involved in neuron development in the piriform cortex.
Assuntos
Esclerose Lateral Amiotrófica , Cérebro , Camundongos , Animais , Camundongos Transgênicos , Serotonina/metabolismo , Superóxido Dismutase-1/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Cérebro/metabolismo , Mamíferos/metabolismoRESUMO
BACKGROUND: Abnormal white matter is a common neurobiological change in bipolar disorder, and dysregulation of myelination in oligodendrocytes (OLs) is the cause. Transmembrane protein 108 (Tmem108), as a susceptible gene of bipolar disorder, is expressed higher in OL lineage cells than any other lineage cells in the central nervous system. Moreover, Tmem108 mutant mice exhibit mania-like behaviors, belonging to one of the signs of bipolar disorder. However, it is unknown whether Tmem108 regulates the myelination of the OLs. RESULTS: Tmem108 expression in the corpus callosum decreased with the development, and OL progenitor cell proliferation and OL myelination were enhanced in the mutant mice. Moreover, the mutant mice exhibited mania-like behavior after acute restraint stress and were susceptible to drug-induced epilepsy. CONCLUSIONS: Tmem108 inhibited OL progenitor cell proliferation and mitigated OL maturation in the corpus callosum, which may also provide a new role of Tmem108 involving bipolar disorder pathogenesis.
Assuntos
Corpo Caloso , Substância Branca , Animais , Linhagem da Célula , Proliferação de Células , Mania , Camundongos , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismoRESUMO
Lightly stroking the lips or gently poking some skin regions can evoke mechanical itch in healthy human subjects. Sensitization of mechanical itch and persistent spontaneous itch are intractable symptoms in chronic itch patients. However, the underlying neural circuits are not well defined. We identified a subpopulation of excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) in the dorsal spinal cord as a central node in the pathway that transmits acute mechanical itch and mechanical itch sensitization as well as persistent spontaneous itch under chronic itch conditions. This population receives peripheral inputs from Toll-like receptor 5-positive (TLR5+) Aß low-threshold mechanoreceptors and is directly innervated by inhibitory interneurons expressing neuropeptide Y::Cre (NPY+) in the dorsal spinal cord. Reduced synaptic inhibition and increased intrinsic excitability of Ucn3+ neurons lead to chronic itch sensitization. Our study sheds new light on the neural basis of chronic itch and unveils novel avenues for developing mechanism-specific therapeutic advancements.
Assuntos
Interneurônios/fisiologia , Mecanorreceptores/fisiologia , Vias Neurais/fisiopatologia , Prurido/fisiopatologia , Pele/inervação , Medula Espinal/fisiopatologia , Animais , Sensibilização do Sistema Nervoso Central/fisiologia , Ácido Glutâmico/metabolismo , Interneurônios/metabolismo , Mecanorreceptores/metabolismo , Camundongos , Inibição Neural/fisiologia , Neuropeptídeo Y/metabolismo , Estimulação Física , Medula Espinal/citologia , Receptor 5 Toll-Like/metabolismo , Urocortinas/metabolismoRESUMO
Recent studies have made significant progress in identifying distinct populations of peripheral neurons involved in itch transmission, whereas the cellular identity of spinal interneurons that contribute to itch processing is still a debate. Combining genetic and pharmacological ablation of spinal excitatory neuronal subtypes and behavioral assays, we demonstrate that spinal somatostatin-positive (SOM) excitatory interneurons transmit pruritic sensation. We found that the ablation of spinal SOM/Lbx1 (SOM) neurons caused significant attenuation of scratching responses evoked by various chemical pruritogens (chemical itch). In an attempt to identify substrates of spinal itch neural circuit, we observed that spinal SOM neurons partially overlapped with neurons expressing natriuretic peptide receptor A (Npra), the receptor of peripheral itch transmitter B-type natriuretic peptide. Spinal SOM neurons, however, did not show any overlap with itch transmission neurons expressing gastrin-releasing peptide receptor in the dorsal spinal cord, and the gastrin-releasing peptide-triggered scratching responses were intact after ablating spinal SOM neurons. Dual ablation of SOM and Npra neurons in the spinal cord reduced chemical itch responses to a greater extent than ablation of SOM or Npra neurons alone, suggesting the existence of parallel spinal pathways transmitting chemical itch. Furthermore, we showed that SOM peptide modulated itch processing through disinhibition of somatostatin receptor 2A-positive inhibitory interneuron. Together, our findings reveal a novel spinal mechanism for sensory encoding of itch perception.
Assuntos
Interneurônios/metabolismo , Prurido/induzido quimicamente , Prurido/patologia , Somatostatina/metabolismo , Medula Espinal/patologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Inibidores da Angiogênese/farmacologia , Animais , Cloroquina/toxicidade , Modelos Animais de Doenças , Técnicas In Vitro , Interneurônios/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Nitrobenzoatos/farmacologia , Técnicas de Patch-Clamp , Proteínas Proto-Oncogênicas c-fos/metabolismo , Somatostatina/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , p-Metoxi-N-metilfenetilamina/toxicidade , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Long-term potentiation (LTP) of synaptic transmission in the central nervous system is a key form of cortical plasticity. The insular cortex (IC) is known to play important roles in pain perception, aversive memory and mood disorders. LTP has been recently reported in the IC, however, the signaling pathway for IC LTP remains unknown. Here, we investigated the synaptic mechanism of IC LTP. We found that IC LTP induced by the pairing protocol was N-methyl-D-aspartate receptors (NMDARs) dependent, and expressed postsynaptically, since paired-pulse ratio (PPR) was not affected. Postsynaptic calcium is important for the induction of post-LTP, since the postsynaptic application of BAPTA completely blocked the induction of LTP. Calcium-activated adenylyl cyclase subtype 1 (AC1) is required for potentiation. By contrast, AC8 is not required. Inhibition of Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) or protein kinase M zeta (PKMζ) reduced the expression of LTP. Our results suggest that calcium-stimulated AC1, but not AC8, can be a trigger of the induction and maintenance of LTP in the IC.
RESUMO
Adverse early-life experience such as depriving the relationship between parents and children induces permanent phenotypic changes, and impairs the cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanism remains unclear. In this work, we used rat neonatal maternal separation (NMS) model to illuminate whether and how NMS in early life affects cognitive functions, and what the underlying cellular and molecular mechanism is. We showed that rat pups separated from their dam 3 h daily during the first 3 postnatal weeks alters medial prefrontal cortex (mPFC) myelination and impairs mPFC-dependent behaviors. Myelination appears necessary for mPFC-dependent behaviors, as blockade of oligodendrocytes (OLs) differentiation or lysolecithin-induced demyelination, impairs mPFC functions. We further demonstrate that histone deacetylases 1/2 (HDAC1/2) are drastically reduced in NMS rats. Inhibition of HDAC1/2 promotes Wnt activation, which negatively regulates OLs development. Conversely, selective inhibition of Wnt signaling by XAV939 partly rescue myelination arrestment and behavior deficiency caused by NMS. These findings indicate that NMS impairs mPFC cognitive functions, at least in part, through modulation of oligodendrogenesis and myelination. Understanding the mechanism of NMS on mPFC-dependent behaviors is critical for developing pharmacological and psychological interventions for child neglect and abuse.
Assuntos
Transtornos Cognitivos/etiologia , Doenças Desmielinizantes/patologia , Privação Materna , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Animais Recém-Nascidos , Ansiedade/etiologia , Transtornos Cognitivos/patologia , Doenças Desmielinizantes/etiologia , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Lipopolissacarídeos/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Neurogênese/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/ultraestrutura , Ratos , Ratos Sprague-Dawley , Ácido Valproico/farmacologia , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Given that lysophosphatidic acid (LPA) and the tetrodotoxin-resistant sodium channel Nav1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA1 (also known as EDG2) and Nav1.8 in the dorsal root ganglion (DRG) contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in naïve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Nav1.8 expression in L4-6 DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Nav1.8 expression in ipsilateral L4-6 DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Nav1.8 and LPA remarkably enhanced Nav1.8 currents in DRG neurons, and this was blocked by either a protein kinase C (PKC) inhibitor or a PKCε inhibitor. Overall, we demonstrated the modulation of Nav1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.
Assuntos
Neoplasias Ósseas/complicações , Dor do Câncer/etiologia , Dor do Câncer/metabolismo , Carcinoma/complicações , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisofosfolipídeos/toxicidade , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Animais , Biofísica , Dor do Câncer/patologia , Modelos Animais de Doenças , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Isoxazóis/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Medição da Dor , Técnicas de Patch-Clamp , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/metabolismoRESUMO
BACKGROUND: Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Nav1.8 currents in acutely dissociated small-diameter DRG neurons. RESULTS: Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Nav1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2A-AR antagonist BRL44408 but not α2B-AR antagonist imiloxan blocked the inhibition of Nav1.8 currents by DEX. Immunohistochemistry results showed that Nav1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2A-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Nav1.8 currents was prevented by intracellular application of G-protein inhibitor GDPß-s or Gi/o proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Nav1.8 currents. CONCLUSIONS: We established a functional link between α2-AR and Nav1.8 in primary sensory neurons utilizing the Gi/o/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.
Assuntos
Dexmedetomidina/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Gânglios Espinais/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neurônios/metabolismo , Tetrodotoxina/farmacologia , Potenciais de Ação , Animais , Gânglios Espinais/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos alfa 2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: It has been demonstrated that lysophosphatidic acid (LPA) released from injury tissue and transient receptor potential vanilloid 1 (TRPV1) receptor are implicated in the induction of chronic pain. In the present study we examined whether an interaction between LPA receptor LPA(1) and TRPV1 in dorsal root ganglion (DRG) neurons contributes to the development of bone cancer pain. RESULTS: Bone cancer was established by injection of mammary gland carcinoma cells into the rat tibia. Following the development of bone cancer pain, the TRPV1 expression and capsaicin-evoked currents were up-regulated in rat DRG neurons at L(4-6) segments. Immunohistochemistry staining revealed a high co-localization of LPA(1) with TRPV1 in DRG neurons. In isolated DRG neurons, whole-cell patch recording showed that capsaicin-induced currents were potentiated by LPA in a dose-dependent manner. The potentiation was blocked by either LPA(1) antagonist, protein kinase C (PKC) inhibitor or PKCε inhibitor, but not by protein kinase A (PKA) inhibitor or Rho inhibitor. In the behavioral tests, both mechanical allodynia and thermal hyperalgesia in bone cancer rats were attenuated by LPA(1) antagonist. CONCLUSION: LPA potentiates TRPV1 current via a PKCε-dependent pathway in DRG neurons of rats with bone cancer, which may be a novel peripheral mechanism underlying the induction of bone cancer pain.
Assuntos
Neoplasias Ósseas/patologia , Gânglios Espinais/patologia , Lisofosfolipídeos/análise , Dor/etiologia , Proteína Quinase C-épsilon/metabolismo , Canais de Cátion TRPV/análise , Animais , Hiperalgesia/tratamento farmacológico , Imuno-Histoquímica , Lisofosfolipídeos/antagonistas & inibidores , Lisofosfolipídeos/farmacologia , Neoplasias Experimentais , Neurônios/patologia , Ratos , Canais de Cátion TRPV/metabolismoRESUMO
AIMS: Lysophosphatidic acid (LPA) is released from injured tissue and cancer cells and is involved in the induction of neuropathic pain. The present study explores whether LPA plays a role in the development of osteocarcinoma-induced pain. MAIN METHODS: The bone cancer model was established using the Walker 256 mammary gland carcinoma cell line, and cancer-related behavioral and physiological changes were observed using von Frey, X-ray and immunohistochemical methods. The role of LPA in the bone cancer model and related mechanisms were examined by using in vitro single fiber recording and western blot. KEY FINDINGS: Rats exhibited severe hyperalgesia 2weeks after the cancer cell implantation. Several changes were observed at this time point including: ipsilateral dorsal root ganglion (DRG) neurons were labeled by injured neurons marker ATF3; LPA(1) receptor expression in DRG neurons was increased; sural C-fibers were more sensitive to LPA stimuli, and this response could be blocked by LPA receptor and substance P receptor antagonists. SIGNIFICANCE: These data indicate that LPA is involved in the induction of bone cancer pain through mechanisms of peripheral C-fibers sensitization. LPA and its downstream molecules possibly are promising therapeutic targets for treatment of cancer pain.
Assuntos
Neoplasias Ósseas/complicações , Hiperalgesia/fisiopatologia , Lisofosfolipídeos/metabolismo , Dor/fisiopatologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica , Hiperalgesia/etiologia , Transplante de Neoplasias , Fibras Nervosas Amielínicas/metabolismo , Neurônios/metabolismo , Dor/etiologia , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais , Nervo Sural/metabolismoRESUMO
Fractalkine, a chemokine binding to only one known receptor CX3CR1, has recently been proposed to be a neuron-to-glia signal in the spinal cord leading to microglial activation and glially dependent pain facilitation. The previous studies explored that blockade of endogenous fractalkine, using anti-CX3CR1 neutralizing antibody, dose-dependently attenuated neuropathic pain. The present study examined the role of endogenous fractalkine in inflammatory pain. Intra-articular injection of complete Freund's adjuvant (CFA)-induced rat ankle joint monoarthritis (MA) model was used. Western blot analysis revealed that CX3CR1 expression in the spinal cord was significantly increased following CFA-induced MA. Intrathecal injection of anti-CX3CR1 neutralizing antibody both delayed the development of mechanical allodynia and thermal hyperalgesia, and reversed established pain facilitation. Furthermore, blockade of CX3CR1 significantly suppressed activation of spinal glia, especially microglia, evoked by MA. These data provided new evidence for the contribution of endogenous fractalkine to the initiation and early maintenance of inflammatory pain facilitation via activating spinal microglia.