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1.
Pain ; 161(8): 1730-1743, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32701834

RESUMO

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.

2.
Pain ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32229764

RESUMO

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.

3.
Brain Res ; 1727: 146567, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31783002

RESUMO

New findings on neural regulation of immunity are allowing the design of novel pharmacological strategies to control inflammation and nociception. Herein, we report that choline, a 7-nicotinic acetylcholine receptor (α7nAChRs) agonist, prevents carrageenan-induced hyperalgesia without affecting inflammatory parameters (neutrophil migration or cytokine/chemokines production) or inducing sedation or even motor impairment. Choline also attenuates prostaglandin-E2 (PGE2)-induced hyperalgesia via α7nAChR activation and this antinociceptive effect was abrogated by administration of LNMMA (a nitric oxide synthase inhibitor), ODQ (an inhibitor of soluble guanylate cyclase; cGMP), andglibenclamide(an inhibitor of ATP-sensitive potassium channels). Furthermore, choline attenuates long-lasting Complete Freund's Adjuvant and incision-induced hyperalgesia suggesting its therapeutic potential to treat pain in rheumatoid arthritis or post-operative recovery, respectively. Our results suggest that choline modulates inflammatory hyperalgesia by activating the nitric oxide/cGMP/ATP-sensitive potassium channels without interfering in inflammatory events, and could be used in persistent pain conditions.

4.
Pharmacol Res ; 151: 104580, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786317

RESUMO

Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil's functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.

5.
J Leukoc Biol ; 106(3): 541-551, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31150565

RESUMO

The development of neuropathic pain after peripheral nerve injury involves neuroimmune-glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2-deficient mice. These results suggest that blood-circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2-expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.

6.
Neurol Res ; 41(7): 633-643, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31002029

RESUMO

Objective: Animal models of chronic pain have demonstrated that glial cells are promising target for development of analgesic drugs. However, preclinical studies on glial response under chronic pain conditions vary depending on the cellular markers, the species used, the experimental design and model. Therefore, we investigate the expression profile of GFAP and Iba-1 during the behavioral manifestation of sensory disorder in inflammatory and neuropathic pain models. Methods: the expression profile of fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) were quantitated in the spinal dorsal horn of Balb/C mice submitted to six models of chronic pain. Protein analysis was performed by western blot and the results colligated with pain-related behavior. Results: Using the same method to quantitate proteins we observed that while GFAP is upregulated after axotomy, partial nerve injury and cutaneous inflammation, its expression is not changed during muscle inflammation, non-inflammatory muscle pain, and in a viral-associated pain. Differently, Iba-1 is downregulated after axotomy but upregulated after partial lesion of peripheral nerve as well as after virus inoculation and during non-inflammatory muscle pain. Cutaneous and muscle inflammation induced no change in Iba-1 expression in the dorsal horn.In spite of a marked time-dependent variation in protein expression, mechanical allodynia was present at any time of all the models investigated. Discussion: Under distinct pain conditions, GFAP and Iba-1 expression is dependent on the origin of the stimulus, disease progression and tissue affected. Moreover, their expression and is not necessarily associated to the behavior manifestation of pain.


Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Dor Crônica/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Inflamação/metabolismo , Proteínas dos Microfilamentos/biossíntese , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Camundongos , Músculos/fisiopatologia , Nervo Isquiático/lesões , Pele/fisiopatologia , Regulação para Cima
7.
Mol Neurobiol ; 56(8): 5715-5728, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30674034

RESUMO

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.


Assuntos
Hipersensibilidade/patologia , Inflamação/patologia , Nociceptores/patologia , Peptídeos/metabolismo , Animais , Dinoprostona/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Hipersensibilidade/complicações , Hipersensibilidade/fisiopatologia , Inflamação/complicações , Inflamação/fisiopatologia , Lectinas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Fibras Nervosas Amielínicas/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Dor/complicações , Dor/fisiopatologia , Saporinas/farmacologia
8.
Pain ; 160(1): 102-116, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30169421

RESUMO

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1ß). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.


Assuntos
Macrófagos/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Transplante de Medula Óssea , Carragenina/toxicidade , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Neuralgia/genética , Neuralgia/cirurgia , Fármacos Neuroprotetores/uso terapêutico , Proteína Adaptadora de Sinalização NOD2/genética , RNA Interferente Pequeno/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Xantinas/uso terapêutico
9.
Front Immunol ; 10: 3059, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32047492

RESUMO

Neuroimmune-glia interactions have been implicated in the development of neuropathic pain. Interleukin-27 (IL-27) is a cytokine that presents regulatory activity in inflammatory conditions of the central nervous system. Thus, we hypothesized that IL-27 would participate in the neuropathic pain process. Here, we found that neuropathic pain caused by peripheral nerve injury (spared nerve injury model; SNI), was enhanced in IL-27-deficient(-/-) mice, whereas nociceptive pain is similar to that of wild-type mice. SNI induced an increase in the expression of IL-27 and its receptor subunit (Wsx1) in the sensory ganglia and spinal cord. IL-27 receptor was expressed mainly in resident macrophage, microglia, and astrocytes of the sensory ganglia and spinal cord, respectively. Finally, we identify that the antinociceptive effect of IL-27 was not observed in IL-10-/- mice. These results provided evidence that IL-27 is a cytokine produced after peripheral nerve injury that counteracts neuropathic pain development through induction of the antinociceptive cytokine IL-10. In summary, our study unraveled the role of IL-27 as a regulatory cytokine that counteracts the development of neuropathic pain after peripheral nerve damage. In conclusion, they indicate that immunotherapies based on IL-27 could emerge as possible therapeutic approaches for the prevention of neuropathic pain development after peripheral nerve injury.

10.
Mol Neurobiol ; 56(8): p. 5715–5728, 2019.
Artigo | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib16117

RESUMO

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

11.
Cell Rep ; 21(6): 1681-1691, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29117570

RESUMO

Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.


Assuntos
Nociceptividade/efeitos dos fármacos , Ocitocina/farmacologia , Canais de Cátion TRPV/genética , Animais , Cálcio/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Células Cultivadas , Potenciais Evocados/efeitos dos fármacos , Feminino , Gânglios Espinais/citologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estrutura Quaternária de Proteína , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
12.
Sci Rep ; 6: 26955, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27230787

RESUMO

Peripheral neuropathic pain is a consequence of an injury/disease of the peripheral nerves. The mechanisms involved in its pathophysiology are not entirely understood. To better understand the mechanisms involved in the development of peripheral nerve injury-induced neuropathic pain, more experimental models are required. Here, we developed a novel peripheral neuropathic pain model in mice by using a minimally invasive surgery and medial plantar nerve ligation (MPNL). After MPNL, mechanical allodynia was established, and mice quickly recovered from the surgery without any significant motor impairment. MPNL causes an increased expression of ATF-3 in the sensory neurons. At 14 days after surgery, gabapentin was capable of reversing the mechanical allodynia, whereas anti-inflammatory drugs and opioids were ineffective. MPNL-induced neuropathic pain was mediated by glial cells activation and the production of TNF-α and IL-6 in the spinal cord. These results indicate MPNL as a reasonable animal model for the study of peripheral neuropathic pain, presenting analgesic pharmacological predictivity to clinically used drugs. The results also showed molecular phenotypic changes similar to other peripheral neuropathic pain models, with the advantage of a lack of motor impairment. These features indicate that MPNL might be more appropriate for the study of neuropathic pain than classical models.


Assuntos
Modelos Animais de Doenças , Hiperalgesia/fisiopatologia , Atividade Motora/fisiologia , Neuralgia/fisiopatologia , Nervo Tibial/fisiopatologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Aminas/farmacologia , Analgésicos/farmacologia , Animais , Ácidos Cicloexanocarboxílicos/farmacologia , Gabapentina , Regulação da Expressão Gênica , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/prevenção & controle , Interleucina-6/genética , Interleucina-6/metabolismo , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Nervo Tibial/efeitos dos fármacos , Nervo Tibial/lesões , Nervo Tibial/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ácido gama-Aminobutírico/farmacologia
13.
Sci Rep ; 5: 14648, 2015 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-26511791

RESUMO

The assessment of articular nociception in experimental animals is a challenge because available methods are limited and subject to investigator influence. In an attempt to solve this problem, the purpose of this study was to establish the use of dynamic weight bearing (DWB) as a new device for evaluating joint nociception in an experimental model of antigen-induced arthritis (AIA) in mice. AIA was induced in Balb/c and C57BL/6 mice, and joint nociception was evaluated by DWB. Western Blotting and real-time PCR were used to determine protein and mRNA expression, respectively. DWB detected a dose- and time-dependent increase in joint nociception during AIA and was able to detect the dose-response effects of different classes of analgesics. Using DWB, it was possible to evaluate the participation of spinal glial cells (microglia and astrocytes) and cytokines (IL-1ß and TNFα) for the genesis of joint nociception during AIA. In conclusion, the present results indicated that DWB is an effective, objective and predictable test to study both the pathophysiological mechanisms involved in arthritic nociception in mice and for evaluating novel analgesic drugs against arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Astrócitos/imunologia , Microglia/imunologia , Nociceptividade , Analgésicos/farmacologia , Animais , Artrite Experimental/patologia , Astrócitos/patologia , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/patologia , Fator de Necrose Tumoral alfa/imunologia , Suporte de Carga
14.
Pain ; 156(3): 504-13, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25687543

RESUMO

Treatment of neuropathic pain is a clinical challenge likely because of the time-dependent changes in many neurotransmitter systems, growth factors, ionic channels, membrane receptors, transcription factors, and recruitment of different cell types. Conversely, an increasing number of reports have shown the ability of extended and regular physical exercise in alleviating neuropathic pain throughout a wide range of mechanisms. In this study, we investigate the effect of swim exercise on molecules associated with initiation and maintenance of nerve injury-induced neuropathic pain. BALB/c mice were submitted to partial ligation of the sciatic nerve followed by a 5-week aerobic exercise program. Physical training reversed mechanical hypersensitivity, which lasted for an additional 4 weeks after exercise interruption. Swim exercise normalized nerve injury-induced nerve growth factor, and brain-derived neurotrophic factor (BDNF) enhanced expression in the dorsal root ganglion, but had no effect on the glial-derived neurotrophic factor. However, only BDNF remained at low levels after exercise interruption. In addition, exercise training significantly reduced the phosphorylation status of PLCγ-1, but not CREB, in the spinal cord dorsal horn in response to nerve injury. Finally, prolonged swim exercise reversed astrocyte and microglia hyperactivity in the dorsal horn after nerve lesion, which remained normalized after training cessation. Together, these results demonstrate that exercise therapy induces long-lasting analgesia through various mechanisms associated with the onset and advanced stages of neuropathy. Moreover, the data support further studies to clarify whether appropriate exercise intensity, volume, and duration can also cause long-lasting pain relief in patients with neuropathic pain.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Terapia por Exercício/métodos , Neuralgia/reabilitação , Neuroglia/metabolismo , Regulação para Cima/fisiologia , Adaptação Fisiológica , Animais , Proteína de Ligação a CREB/metabolismo , Citrato (si)-Sintase , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Coração/fisiopatologia , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/fisiopatologia , Neuralgia/complicações , Neuralgia/patologia , Neuroglia/patologia , Medição da Dor , Limiar da Dor/fisiologia , Fosfolipase C gama/metabolismo , Fosforilação , Fatores de Tempo
15.
J Pain ; 14(10): 1162-72, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23816950

RESUMO

UNLABELLED: The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate-responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase γ-1 (PLCγ-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCγ-1 but not extracellular signal-regulated kinase (ERK1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury-induced CREB and PLCγ-1 phosphorylation but had no effect on ERK1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCγ-1/CREB-signaling pathway. PERSPECTIVE: This article demonstrates that long-term treatment with imipramine reverses some of the marked effects induced by peripheral nerve injury in the spinal dorsal horn that contribute to long-term maintenance of sensory disorder, providing a new view to the mechanisms of action of these drugs.


Assuntos
Antidepressivos/uso terapêutico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Fosfolipase C gama/metabolismo , Células do Corno Posterior/metabolismo , Animais , Antidepressivos Tricíclicos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Western Blotting , Imipramina/uso terapêutico , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Medição da Dor/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ciática/tratamento farmacológico , Ciática/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Mol Pain ; 7: 17, 2011 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-21385380

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNAs that inhibit translation of target genes by binding to their mRNAs. The expression of numerous brain-specific miRNAs with a high degree of temporal and spatial specificity suggests that miRNAs play an important role in gene regulation in health and disease. Here we investigate the time course gene expression profile of miR-1, -16, and -206 in mouse dorsal root ganglion (DRG), and spinal cord dorsal horn under inflammatory and neuropathic pain conditions as well as following acute noxious stimulation. RESULTS: Quantitative real-time polymerase chain reaction analyses showed that the mature form of miR-1, -16 and -206, is expressed in DRG and the dorsal horn of the spinal cord. Moreover, CFA-induced inflammation significantly reduced miRs-1 and -16 expression in DRG whereas miR-206 was downregulated in a time dependent manner. Conversely, in the spinal dorsal horn all three miRNAs monitored were upregulated. After sciatic nerve partial ligation, miR-1 and -206 were downregulated in DRG with no change in the spinal dorsal horn. On the other hand, axotomy increases the relative expression of miR-1, -16, and 206 in a time-dependent fashion while in the dorsal horn there was a significant downregulation of miR-1. Acute noxious stimulation with capsaicin also increased the expression of miR-1 and -16 in DRG cells but, on the other hand, in the spinal dorsal horn only a high dose of capsaicin was able to downregulate miR-206 expression. CONCLUSIONS: Our results indicate that miRNAs may participate in the regulatory mechanisms of genes associated with the pathophysiology of chronic pain as well as the nociceptive processing following acute noxious stimulation. We found substantial evidence that miRNAs are differentially regulated in DRG and the dorsal horn of the spinal cord under different pain states. Therefore, miRNA expression in the nociceptive system shows not only temporal and spatial specificity but is also stimulus-dependent.


Assuntos
MicroRNAs/genética , Dor/genética , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células do Corno Posterior/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Rev. Odontol. Araçatuba (Online) ; 31(1): 9-15, jan.-jun. 2010. ilus
Artigo em Português | BBO - Odontologia | ID: biblio-856870

RESUMO

As funções fisiológicas sofrem um retardo gradual que se inicia por volta de 25-30 anos e se estende até a morte. Além disso, esta alteração afeta mais gravemente as atividades mais complexas e as respostas mais intrincadas às tensões ou estresse. O propósito deste trabalho foi estudar histologicamente em ratos idosos o efeito do estresse crônico sobre a reação do tecido conjuntivo subcutâneo. Para tanto, 60 ratos, divididos em quatro grupos (GI (controle), GII (estressado), GIII (idoso) e GIV (Idoso/Estressado) receberam implante subcutâneo, bilateral e dorsal, de tubos de polietileno contendo soro fisiológico. Em grupos de cinco, os animais foram sacrificados aos 7,14 e 28 dias pós-operatórios. Os resultados obtidos permitiram observar reação inflamatória mais intensa e organização do tecido conjuntivo mais tardia nos animais idosos submetidos ao estresse


Physiological functions undergo a gradual retardation that begins around 25-30 years and extends to the death. Moreover, this change affects most severely the activities more complex and more intricate responses to tensions or stress. The purpose of this study was to evaluate histologically in aged rats the effect of chronic stress on the reaction of subcutaneous connective tissue. The purpose of this study was to evaluate histologically in aged rats the effect of chronic stress on the reaction of subcutaneous connective tissue. For this purpose, 60 rats were divided into four groups (GI (control), GII (stressed), GIII (elderly) and GIV (aged / stressed) received dorsal subcutaneous implants of polyethylene tubes containing saline solution. In groups of four animals were sacrificed at 7,14 and 28 days postoperatively. The results allowed to observe more intense inflammatory reaction and tissue organization later in the aged animals subjected to stress


Assuntos
Animais , Ratos , Envelhecimento , Assistência Odontológica para Idosos , Doença , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Cicatrização
18.
Rev. Odontol. Araçatuba (Online) ; 31(1): 28-33, jan.-jun. 2010. ilus
Artigo em Português | BBO - Odontologia | ID: biblio-856873

RESUMO

Sistemas indiretos de resina composta têm sido rotineiramente indicados para confecção de restaurações em pacientes estressados. O propósito deste trabalho foi estudar histologicamente em ratos o efeito do estresse crônico sobre a reação do tecido conjuntivo subcutâneo ao implante de Artglass®. Para tanto, 60 ratos, divididos em quatro grupos (GI (controle), GII (estressado), GIII (Artglass®) e GIV (Artglass®/Estressado) receberam implante subcutâneo, bilateral e dorsal, de tubos de polietileno contendo soro fisiológico (Grupos I e II) ou Artglass® (Grupos III e IV). Em grupos de cinco, os animais foram sacrificados aos 7,14 e 28 dias pós-operatórios. Os resultados obtidos permitiram observar reação inflamatória mais intensa e organização do tecido conjuntivo mais tardia nos animais submetidos ao estresse


Indirect composite resin systems have been routinely recommended for making restorations in distressed patients. The purpose of this study was to evaluate histologically in rats the effect of chronic stress on the reaction of subcutaneous connective tissue after implant of Artglass™. For this purpose, 60 rats were divided into four groups (GI (control), GII (stressed), GIII (Artglass™) and GIV (Artglass™/ stressed) received dorsal subcutaneous implants of polyethylene tubes containing saline solution (GI and GII) or Artglass™ (GIII and GIV). In groups of four animals were sacrificed at 7,14 and 28 days postoperatively. The results allowed to observe more intense inflammatory reaction and tissue organization later in the animals subjected to stress


Assuntos
Animais , Ratos , Materiais Biocompatíveis , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Cicatrização , Ratos Wistar
19.
Rev. Odontol. Araçatuba (Online) ; 31(1): 66-72, jan.-jun. 2010. ilus
Artigo em Português | BBO - Odontologia | ID: biblio-856880

RESUMO

Aceita-se o estresse como um fator ambiental capaz de predispor o indivíduo à depressão. Os benzodiazepínicos têm sido prescritos como drogas eficazes nessas situações. O propósito deste trabalho foi estudar histologicamente o efeito do estresse crônico e drogas benzodiazepínicas sobre o reparo ósseo. Cavidades ósseas foram criadas em ambas as tíbias de 40 ratos machos, divididos em 2 grupos: Controle e Tratado. Neste, o estímulo estressor foi aplicado nos 40 dias pré-operatórios e em todos os dias pós-operatórios até o sacrifício, pela manhã por 2 horas, por meio da imobilização por contenção. Esses animais também receberam benzodiazepínico do grupo Diazepam, diariamente, na concentração de 5mg/Kg/peso corporal nos 15 dias pré-operatórios. Em grupos de cinco, os animais foram sacrificados aos 7, 14, 30 e 60 dias pós-operatórios. Aos 7 dias pós-operatórios, enquanto o grupo controle exibia tecido conjuntivo rico em fibroblastos, o grupo tratado mostrava tecido conjuntivo neoformado, com escassos fibroblastos e vasos capilares ao lado de linfócitos e macrófagos. Aos 14 dias pós-operatórios, o Grupo Controle exibiu trabeculado ósseo neoformado enquanto o Grupo Tratado evoluiu para trabéculas ósseas delgadas, com numerosos osteoblastos em suas bordas. Aos 30 dias pós-operatórios a reparação óssea está completa em ambos os grupos. Aos 60 dias pós-operatórios as características observadas nos grupos controle e tratado são semelhantes ao período anterior, porém com osteogênese mais avançada


Stress is an environmental factor that may predispose individuals to depression. Benzodiazepines have been prescribed as effective drugs in these situations. The purpose of this study was histological evaluate of the effect of chronic stress and benzodiazepine drugs on bone healing. Bone cavities were created in both tibias of 40 male rats were divided into two groups: Control and Treaty. In this, the stressor stimulus was applied 40 days pre-operative and all post-operative days until sacrifice in the morning for 2 hours, by immobilizing restraint. These animals also received diazepam benzodiazepine group, daily, at a concentration of 5mg/Kg/peso body within 15 days of preoperative. In groups of five animals were sacrificed at 7, 14, 30 and 60 days post-surgery. At 7 days postoperatively, while the control group exhibited tissue rich in fibroblasts, the treated group showed newly formed tissue with few fibroblasts and capillaries along with lymphocytes and macrophages. At 14 days postsurgery, the control group showed newly formed trabecular bone while the treated group progressed to thin trabecular bone with numerous osteoblasts on their borders. At 30 days post-operative bone healing is complete in both groups. At 60 days post-operative characteristics observed in the treated and control groups are similar to the previous period, but with more advanced osteogenesis


Assuntos
Animais , Ratos , Benzodiazepinonas , Moduladores GABAérgicos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Cicatrização
20.
Rev. Odontol. Araçatuba (Online) ; 30(2): 14-18, jul.-dez. 2009. ilus
Artigo em Português | BBO - Odontologia | ID: biblio-856858

RESUMO

Os benzodiazepínicos respondem como uma das drogas mais prescritas e consumidas. O propósito deste trabalho foi estudar histologicamente o efeito de drogas benzodiazepínicas sobre o reparo ósseo. Cavidades ósseas foram criadas em ambas as tíbias de 40 ratos machos, divididos em dois grupos: controle e tratado. No grupo tratado, a droga foi administrada diariamente, na concentração de 5mg/Kg/peso corporal nos 15 dias pré-operatórios. Em grupos de cinco, os animais foram sacrificados aos 7,14,30 e 60 dias pós-operatórios. Aos 7 dias pós-operatórios a cavidade cirúrgica mostra-se preenchida por tecido conjuntivo denso, permeado por delicadas trabéculas ósseas neoformadas nos grupo controle e tratado. Aos 14 dias pós-operatórios as lojas cirúrgicas encontram-se totalmente preenchidas por tecido ósseo neoformado no grupo controle e parcialmente no grupo tratado. Aos 30 dias pós-operatórios a reparação óssea está completa e as lojas cirúrgicas encontram-se preenchidas por tecido ósseo secundário em ambos os grupos. Aos 60 dias pós-operatórios, tecido ósseo maduro e bem diferenciado ocupa todos os espécimes de ambos os grupos. Com base nos resultados obtidos conclui-se que o uso de drogas benzodiazepínicas não interferiu nos estádios de organização do coágulo de fibrina e ossificação da reparação óssea


Benzodiazepines respond as one of the most commonly prescribed drugs and consumed. The purpose of this study was to evaluate histologically the effect of benzodiazepine drugs on bone healing. Bone cavities were created in both tibias of 32 male rats were divided into two groups: control and treated. In the treated group, the drug was administered daily at a concentration of 5mg/Kg/peso body within 15 days of preoperative period. In groups of four animals were sacrificed at 7, 14, 30 and 60 days postoperatively. At 7 days postoperatively, while the control group showed connective tissue rich in fibroblasts, the treated group showed neoformed tissue with numerous fibroblasts and capillaries along with lymphocytes and macrophages. At 14 days postoperatively, the control group evolved into newly formed trabecular bone and the group treated for thin trabecular bone with numerous osteoblasts on their borders. At 30 days post-operative bone healing is complete surgical and shops are filled by secondary bone tissue in both groups. At 60 days post-surgery, bone tissue and well differentiated occupies all specimens of both groups. Based on the results it is concluded that the use of benzodiazepine drugs did not interfere in bone repair


Assuntos
Animais , Ratos , Benzodiazepinas , Benzodiazepinas/efeitos adversos , Moduladores GABAérgicos , Cicatrização , Ratos Wistar
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