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1.
Sci Rep ; 11(1): 19877, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615939

RESUMO

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.


Assuntos
Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X3/metabolismo , Distúrbios Somatossensoriais/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Ratos , Receptores Purinérgicos P2X3/genética , Distúrbios Somatossensoriais/tratamento farmacológico , Distúrbios Somatossensoriais/etiologia
2.
Continuum (Minneap Minn) ; 26(5): 1130-1160, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002996

RESUMO

PURPOSE OF REVIEW: Neuroanatomic localization and pattern recognition can be used to diagnose both focal lesions and generalized disorders of the peripheral nervous system. This article describes the nature and pattern of sensory and motor deficits associated with lesions of specific spinal nerve roots, plexus, or peripheral nerves. It also describes the patterns of sensory and motor deficits that suggest multifocal or generalized disorders of the motor neurons, sensory neurons, and peripheral nerves. RECENT FINDINGS: The pattern of sensory and motor deficits may be used to distinguish lesions of the peripheral nervous system from those of the central nervous system. The spinal roots, nerve plexus, and peripheral nerves supply specific muscles and receive sensory input from distinctive cutaneous regions. Focal lesions of these structures therefore produce characteristic patterns of sensory and motor deficits. Multifocal or generalized disorders of the peripheral nervous system may be distinguished by categorizing their sensory and motor involvement, proximal and distal predominance, and degree of symmetry. Serum tests, CSF analysis, electrodiagnostic studies, MRI, ultrasound, nerve biopsy, and skin biopsy have unique roles in the diagnosis of suspected neuromuscular disorders. SUMMARY: A structured approach to the diagnosis of nerve and motor neuron disorders can lead to hypothesis-driven diagnostic testing. Ancillary tests should be reserved for cases in which confirming or refuting a diagnosis will change patient management.


Assuntos
Doença dos Neurônios Motores/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Distúrbios Somatossensoriais/diagnóstico , Adulto , Feminino , Humanos , Masculino , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/fisiopatologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia , Distúrbios Somatossensoriais/fisiopatologia , Adulto Jovem
3.
Diabetes ; 67(8): 1650-1662, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29875100

RESUMO

The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the Ins2+/Akita mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in Ins2+/Akita mechanonociceptors compared with wild-type littermates, whereas the function of low-threshold A-fibers was essentially intact. Studies of isolated sensory neurons demonstrated a markedly reduced heat responsiveness in Ins2+/Akita dorsal root ganglion (DRG) neurons, but a mostly unchanged function of cold-sensitive neurons. Restoration of normal glucose control by islet transplantation produced a rapid recovery of nociception, which occurred before normoglycemia had been achieved. Islet transplantation also restored Ins2+/Akita intraepidermal nerve fiber density to the same level as wild-type mice, indicating that restored insulin production can reverse both sensory and anatomical abnormalities of diabetic neuropathy in mice. The reduced rate of action potential discharge in nociceptive fibers and the impaired heat responsiveness of Ins2+/Akita DRG neurons suggest that ionic sensory transduction and transmission mechanisms are modified by diabetes.


Assuntos
Neuropatias Diabéticas/metabolismo , Epiderme/inervação , Gânglios Espinais/metabolismo , Insulina/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Distúrbios Somatossensoriais/metabolismo , Termorreceptores/metabolismo , Potenciais de Ação , Substituição de Aminoácidos , Animais , Comportamento Animal , Células Cultivadas , Diabetes Mellitus/sangue , Diabetes Mellitus/cirurgia , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/prevenção & controle , Epiderme/metabolismo , Epiderme/patologia , Epiderme/fisiopatologia , Gânglios Espinais/patologia , Gânglios Espinais/fisiopatologia , Heterozigoto , Insulina/genética , Transplante das Ilhotas Pancreáticas , Rim , Masculino , Mecanorreceptores/metabolismo , Mecanorreceptores/patologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fibras Nervosas Amielínicas/patologia , Medição da Dor , Distúrbios Somatossensoriais/complicações , Distúrbios Somatossensoriais/fisiopatologia , Distúrbios Somatossensoriais/prevenção & controle , Termorreceptores/patologia , Termorreceptores/fisiopatologia , Transplante Heterotópico
4.
Int J Biol Macromol ; 110: 30-38, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29223756

RESUMO

Human skin is made up of multiple layers and is designed to protect the human body. The stratum corneum (SC), specifically, is a keratinized layer of skin through which molecules heavier than 500 Da cannot penetrate. Traditional methods of transdermal drug delivery through the SC, such as hypodermic needles, are less than ideal because their size and appearance can cause fear and pain, creating hesitation, limiting self-administration, and preventing their use in some patients altogether. A new technology has been developed to address these limitations, in which an array of needles, each microns in diameter and length, called microneedles, are able to pierce the skin's SC to deliver therapeutic agents without stimulating the proprioceptive pain nerves. These needles provide a strong advantage because they are capable of being incorporated into patches that can be conveniently self-administered by patients, while also offering the same bioabsorption and bioavailability currently provided by hypodermic needles. There have been many advancements in microneedle fabrication, and there are currently many variations of microneedle technology. Therefore, the purpose of this review is to provide a broad, introductory summary of current microneedle technology.


Assuntos
Agulhas , Neuralgia/tratamento farmacológico , Pele/metabolismo , Distúrbios Somatossensoriais/tratamento farmacológico , Administração Cutânea , Animais , Humanos , Neuralgia/metabolismo , Neuralgia/patologia , Autoadministração/instrumentação , Autoadministração/métodos , Pele/patologia , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia
5.
FASEB J ; 31(1): 224-237, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27702770

RESUMO

Plasma membrane calcium ATPase 2 (PMCA2) is a calcium pump that plays important roles in neuronal function. Although it is expressed in pain-associated regions of the CNS, including in the dorsal horn (DH), its contribution to pain remains undefined. The present study assessed the role of PMCA2 in pain responsiveness and the link between PMCA2 and glutamate receptors, GABA receptors (GABARs), and glutamate transporters that have been implicated in pain processing in the DH of adult female and male PMCA2+/+ and PMCA2+/- mice. Behavioral assays evaluated mechanical and thermal pain responsiveness. Mechanical sensitivity was significantly increased by 52% and heat sensitivity was reduced by 29% in female, but not male, PMCA2+/- mice compared with PMCA2+/+ controls. There were female-specific changes in metabotropic glutamate receptor 1, NMDA receptor 2A, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1, GABABR1, and GABABR2 levels, whereas metabotropic glutamate receptor 5, NMDA receptor 2B, GluR2, and GABAARα2 levels were not altered. Glutamate aspartate transporter levels were higher and glial glutamate transporter 1 levels were lower in the DH of female, but not male, PMCA2+/- mice. These findings indicate a novel role for PMCA2 in modality- and sex-dependent pain responsiveness. Female-specific molecular changes potentially account for the altered pain responses.-Khariv, V., Ni, L., Ratnayake, A., Sampath, S., Lutz, B. M., Tao, X.-X., Heary, R. F., Elkabes, S. Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Nociceptividade/fisiologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Distúrbios Somatossensoriais/metabolismo , Animais , Membrana Celular/enzimologia , Feminino , Heterozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Fatores Sexuais , Distúrbios Somatossensoriais/genética
6.
Exp Neurol ; 283(Pt A): 73-84, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27264357

RESUMO

Although previous studies have identified several strategies to stimulate regeneration of CNS axons, extensive regeneration and functional recovery have remained a major challenge, particularly for large diameter myelinated axons. Within the CNS, myelin is thought to inhibit axon regeneration, while modulating activity of the mTOR pathway promotes regeneration of injured axons. In this study, we examined NT-3 mediated regeneration of sensory axons through the dorsal root entry zone in a triple knockout of myelin inhibitory proteins or after activation of mTOR using a constitutively active (ca) Rheb in DRG neurons to determine the influence of environmental inhibitory or activation of intrinsic growth pathways could enhance NT-3-mediate regeneration. Loss of myelin inhibitory proteins showed modest enhancement of sensory axon regeneration. In mTOR studies, we found a dramatic age related decrease in the mTOR activation as determined by phosphorylation of the downstream marker S6 ribosomal subunit. Expression of caRheb within adult DRG neurons in vitro increased S6 phosphorylation and doubled the overall length of neurite outgrowth, which was reversed in the presence of rapamycin. In adult female rats, combined expression of caRheb in DRG neurons and NT-3 within the spinal cord increased regeneration of sensory axons almost 3 fold when compared to NT-3 alone. Proprioceptive assessment using a grid runway indicates functionally significant regeneration of large-diameter myelinated sensory afferents. Our results indicate that caRheb-induced increase in mTOR activation enhances neurotrophin-3 induced regeneration of large-diameter myelinated axons.


Assuntos
Regulação da Expressão Gênica/fisiologia , Regeneração Nervosa/fisiologia , Neurotrofina 3/metabolismo , Transdução de Sinais/fisiologia , Distúrbios Somatossensoriais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Associada a Mielina/deficiência , Glicoproteína Associada a Mielina/genética , Neurotrofina 3/genética , Neurotrofina 3/uso terapêutico , Proteínas Nogo/deficiência , Proteínas Nogo/genética , Ratos , Ratos Sprague-Dawley , Sirolimo/farmacologia , Distúrbios Somatossensoriais/patologia , Distúrbios Somatossensoriais/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia
7.
Br J Pharmacol ; 172(4): 1020-33, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25297838

RESUMO

BACKGROUND AND PURPOSE: Elevation of glutamate, an excitatory amino acid, during inflammation and injury plays a crucial role in the reception and transmission of sensory information via ionotropic and metabotropic receptors. This study aimed to investigate the mechanisms underlying the biphasic effects of metabotropic glutamate mGlu5 receptor activation on responses to noxious heat. EXPERIMENTAL APPROACH: We assessed the effects of intraplantar quisqualate, a non-selective glutamate receptor agonist, on heat and mechanical pain behaviours in mice. In addition, the effects of quisqualate on the intracellular calcium response and on membrane currents mediated by TRPV1 channels, were examined in cultured dorsal root ganglion neurons from mice. KEY RESULTS: Activation of mGlu5 receptors in hind paw transiently increased, then decreased, the response to noxious heat. In sensory neurons, activation of mGlu5 receptors potentiated TRPV1-mediated intracellular calcium elevation, while terminating activation of mGlu5 receptors depressed it. TRPV1-induced currents were potentiated by activation of mGlu5 receptors under voltage clamp conditions and these disappeared after washout. However, voltage-gated calcium currents were inhibited by the mGlu5 receptor agonist, even after washout. CONCLUSIONS AND IMPLICATIONS: These results suggest that, in sensory neurons, mGlu5 receptors biphasically modulate TRPV1-mediated intracellular calcium response via transient potentiation of TRPV1 channel-induced currents and persistent inhibition of voltage-gated calcium currents, contributing to heat hyper- and hypoalgesia.


Assuntos
Cálcio/metabolismo , Ácido Quisquálico/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Distúrbios Somatossensoriais/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Canais de Cálcio/fisiologia , Capsaicina/farmacologia , Células Cultivadas , Gânglios Espinais/citologia , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Glutamato Metabotrópico 5/agonistas , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPV/fisiologia
8.
PLoS One ; 9(6): e99828, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24925072

RESUMO

The discovery of heat-sensitive Transient Receptor Potential Vanilloid ion channels (ThermoTRPVs) greatly advanced our molecular understanding of acute and injury-evoked heat temperature sensation. ThermoTRPV channels are activated by partially overlapping temperatures ranging from warm to supra-threshold noxious heat. TRPV1 is activated by noxious heat temperature whereas TRPV3 can be activated by warm as well as noxious heat temperatures. Loss-of-function studies in single TRPV1 and TRPV3 knock-out mice have shown that heat temperature sensation is not completely abolished suggesting functional redundancies among these two channels and highlighting the need of a detailed analysis of TRPV1::TRPV3 double knock-out mice (V1V3dKO) which is hampered by the close proximity of the loci expressing the two channels. Here we describe the generation of a novel mouse model in which trpv1 and trpv3 genes have been inactivated using bacterial artificial chromosome (BAC)-based homologous recombination in embryonic stem cells. In these mice, using classical thermosensory tests such hot plate, tail flick and the thermotaxis gradient paradigms, we confirm that TRPV1 is the master channel for sensing noxious heat temperatures and identify a cooperative role of TRPV1 and TRPV3 for sensing a well-defined window of acute moderate heat temperature. Using the dynamic hot plate assay, we unravel an intriguing and unexpected pronounced escape behavior in TRPV1 knock-out mice that was attenuated in the V1V3dKO. Together, and in agreement with the temperature activation overlap between TRPV1 and TRPV3 channels, our data provide in vivo evidence of a cooperative role between skin-derived TRPV3 and primary sensory neurons-enriched TRPV1 in modulation of moderate and noxious heat temperature sensation and suggest that other mechanisms are required for heat temperature sensation.


Assuntos
Temperatura Alta , Distúrbios Somatossensoriais/genética , Canais de Cátion TRPV/genética , Sensação Térmica/genética , Animais , Aprendizagem da Esquiva , Comportamento Animal , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/metabolismo , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia , Canais de Cátion TRPV/metabolismo
9.
Endocrinology ; 151(10): 4908-15, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20858768

RESUMO

Adrenomedullin (AM) is a regulatory peptide, coded by the adm gene, which is involved in numerous physiological processes, including pain sensitivity. Previous studies have shown that intrathecal injection of AM induced hyperalgesia in the rat. Here, we explore pain sensitivity in a mouse conditional knockout for adm in neurons of the central nervous system, including the spinal cord and dorsal root ganglia. Double immunofluorescence in wild-type (WT) animals shows that AM immunoreactivity is found in calcitonin gene-related peptide-positive neurons of the dorsal root ganglia but not in neurons that bind isolectin B4. Mice lacking adm had modified expression of canonical sensorial neuropeptides, having significantly more calcitonin gene-related peptide and less substance P and enkephalin than their WT littermates. Furthermore, the spinal cord of adm knockout mice expressed higher levels of the AM receptor components, suggesting a compensation attempt to deal with the lack of afferent AM signaling. Behavioral nociceptive tests also found differences between genotypes. In the tail-flick test, which measures mostly spinal reflexes, the adm-null animals had a longer latency than their WT counterparts. On the other hand, in the hotplate test, which requires encephalic processing, mice lacking adm had shorter latencies than normal littermates. These results suggest that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels. This study confirms the important role of AM in pain sensitivity processing but unveils a more complex scenario than previously surmised.


Assuntos
Adrenomedulina/genética , Sistema Nervoso Central/metabolismo , Dor/genética , Adrenomedulina/deficiência , Adrenomedulina/metabolismo , Animais , Comportamento Animal/fisiologia , Sistema Nervoso Central/patologia , Gânglios Espinais/metabolismo , Hiperalgesia/genética , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neuropeptídeos/metabolismo , Especificidade de Órgãos/genética , Dor/metabolismo , Medição da Dor , Receptores de Adrenomedulina , Receptores de Peptídeos/metabolismo , Reflexo/genética , Reflexo/fisiologia , Distúrbios Somatossensoriais/genética , Distúrbios Somatossensoriais/metabolismo , Medula Espinal/metabolismo
10.
Int J Psychophysiol ; 69(2): 96-100, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18436318

RESUMO

Hypertension and risk for hypertension have been associated with reduced pain sensitivity. It has been hypothesised that endogenous opioids contribute to this hypertensive hypoalgesia. The nociceptive flexion reflex can be used as a tool to investigate modulation of nociceptive transmission at spinal level. The current study employed a double-blind placebo-controlled design to compare the effects of naltrexone, an opioid antagonist, and placebo on nociceptive flexion reflex thresholds and nociceptive responding in unmedicated patients with essential hypertension and normotensive individuals. Neither nociceptive flexion reflex thresholds nor nociceptive responding differed between hypertensives and normotensives during placebo or naltrexone. These data provide no support for the hypothesis that essential hypertension is characterised by higher levels of endogenous opioids in the central nervous system and reveal no association between blood pressure status and nociceptive flexion reflex responses.


Assuntos
Hipertensão/complicações , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Limiar da Dor/efeitos dos fármacos , Distúrbios Somatossensoriais/complicações , Adulto , Método Duplo-Cego , Feminino , Humanos , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos Opioides/metabolismo , Medição da Dor , Valores de Referência , Reflexo/efeitos dos fármacos , Distúrbios Somatossensoriais/metabolismo
11.
Neurosci Lett ; 433(1): 43-7, 2008 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-18248898

RESUMO

The sensory deficit in TrkB deficient mice was evaluated by counting the neuronal loss in lumbar dorsal root ganglia (DRG), the absence of sensory receptors (cutaneous--associated to the hairy and glabrous skin - muscular and articular), and the percentage and size of the neurocalcin-positive DRG neurons (a calcium-binding protein which labels proprioceptive and mechanoceptive neurons). Mice lacking TrkB lost 32% of neurons, corresponding to the intermediate-sized and neurocalcin-positive ones. This neuronal lost was accomplished by the absence of Meissner corpuscles, and reduction of hair follicle-associated sensory nerve endings and Merkel cells. The mutation was without effect on Pacinian corpuscles, Golgi's organs and muscle spindles. Present results further characterize the sensory deficit of the TrkB-/- mice demonstrating that the intermediate-sized neurons in lumbar DRG, as well as the cutaneous rapidly and slowly adapting sensory receptors connected to them, are under the control of TrkB for survival and differentiation. This study might serve as a baseline for future studies in experimentally induced neuropathies affecting TrkB positive DRG neurons and their peripheral targets, and to use TrkB ligands in the treatment of neuropathies in which cutaneous mechanoreceptors are primarily involved.


Assuntos
Gânglios Espinais/metabolismo , Mecanorreceptores/metabolismo , Neurônios Aferentes/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Receptor trkB/deficiência , Distúrbios Somatossensoriais/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Tamanho Celular , Sobrevivência Celular/genética , Modelos Animais de Doenças , Gânglios Espinais/citologia , Gânglios Espinais/fisiopatologia , Imuno-Histoquímica , Mecanorreceptores/fisiopatologia , Células de Merkel/metabolismo , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/metabolismo , Neurocalcina/metabolismo , Neurônios Aferentes/citologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Propriocepção/genética , Receptor trkB/genética , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiopatologia , Distúrbios Somatossensoriais/genética , Distúrbios Somatossensoriais/fisiopatologia , Tato/genética
12.
J Clin Gastroenterol ; 41 Suppl 2: S160-2, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17575516

RESUMO

Emerging information on physiology and pathophysiology of gastroesophageal reflux disease raises the question of whether our thought process should go beyond mucosal injury and consider 2 parallel tracks that may cross each other at some time, but at other times they may indeed remain parallel, that is, neurally mediated effects of reflux events beyond the esophageal wall and inflammation mediated effect of reflux within the esophageal wall. In this process, intraesophageal events with and without causing mucosal injury may induce changes in the neural function on a temporary or long-term basis resulting in symptoms at different organs and various levels not completely in lock-step with esophageal mucosal injury. Emerging data also suggest the influence of liminal and subliminal esophageal acid exposure on cerebral cortical networks involved in motor function such as swallowing in addition to its effect on sensory centers. These observations suggest the existence of a more extensive influence of esophageal sensory input to the cerebral cortical processing mechanisms than previously thought and may provide new avenues for research in pathophysiology of reflux disease.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Córtex Cerebral/fisiopatologia , Esôfago/fisiopatologia , Ácido Gástrico/metabolismo , Refluxo Gastroesofágico/fisiopatologia , Distúrbios Somatossensoriais/fisiopatologia , Vias Aferentes/metabolismo , Vias Aferentes/fisiopatologia , Animais , Córtex Cerebral/patologia , Deglutição , Esôfago/inervação , Esôfago/metabolismo , Esôfago/patologia , Refluxo Gastroesofágico/metabolismo , Refluxo Gastroesofágico/patologia , Humanos , Imageamento por Ressonância Magnética , Mucosa/metabolismo , Mucosa/fisiopatologia , Neurônios Aferentes/metabolismo , Limiar Sensorial , Índice de Gravidade de Doença , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia
13.
Psychopharmacology (Berl) ; 189(2): 237-47, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17016710

RESUMO

RATIONALE: Clinical observations have shown that pain sensitivity is altered in some schizophrenic patients. OBJECTIVES: To study alterations in pain sensitivity, the ketamine model in schizophrenia research was employed. MATERIALS AND METHODS: Rats were subchronically injected with the dissociative anaesthetic ketamine (Ket, ten injections of 30 mg/kg, one injection per day over a period of 10 days). Two weeks after treatment completion, the animals' pain sensitivity was assayed in the hot plate test and they were subjected to electrical stimulation of the tail root. In addition, the effect of morphine was studied. RESULTS: In group-housed animals, there was no difference between Ket-injected animals and control rats as measured in both nociceptive tests. In singly housed Ket-injected rats, pain threshold was increased in the electrical stimulation test. This suggests that stress due to single housing might be essential for modifications of pain sensitivity. Moreover, the antinociceptive effect of morphine was modified after single housing. Interestingly, the effect of morphine on locomotor activity was similar in both groups. In group-housed rats, mu receptor binding was unchanged in the frontal cortex, whereas Ket-injected animals had decreased levels in the hippocampus. In singly housed animals, mu receptor binding in Ket-injected rats increased in the frontal cortex and decreased in the hippocampus. (35)S-GTPgamma-S binding increased in the frontal cortex in both singly housed groups, but remained unchanged in the hippocampus. CONCLUSIONS: The data suggest that the ketamine model might be useful for studying altered pain sensitivity in schizophrenia. Moreover, the data suggest that modifications in mu opioid receptor binding contribute to this phenomenon.


Assuntos
Ketamina/farmacologia , Limiar da Dor/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Medição da Dor/métodos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/fisiopatologia , Estresse Psicológico/fisiopatologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
14.
Neurobiol Dis ; 20(2): 372-83, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16242642

RESUMO

Discovery of various mutations in the tau gene among frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) families suggests gain-of-toxic function of wild-type or mutant tau as the mechanism for extensive neuronal loss. We thus generated transgenic nematode (Caenorhabditis elegans) expressing wild-type or mutant (P301L and R406W) tau in the touch (mechanosensory) neurons. Whereas the worm expressing wild-type tau showed a small decrease in the touch response across the lifespan, the worm expressing mutant tau displayed a large and progressive decrease. When the touch neurons lost their function, neuritic abnormalities were found prominent, and microtubular loss became remarkable in the later stage. A substantial fraction of degenerating neurons developed tau accumulation in the cell body and neuronal processes. This neuronal dysfunction is not related to the apoptotic process because little recovery from touch abnormality was observed in the ced-3 or ced-4-deficient background. Expression of GSK3 brought about slight deterioration in the touch response, while expression of HSP70 led to some improvement.


Assuntos
Caenorhabditis elegans/metabolismo , Degeneração Neural/metabolismo , Sistema Nervoso/metabolismo , Tauopatias/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Imuno-Histoquímica , Mecanorreceptores/metabolismo , Mecanorreceptores/patologia , Mecanorreceptores/ultraestrutura , Microscopia Eletrônica de Transmissão , Microtúbulos/metabolismo , Microtúbulos/patologia , Microtúbulos/ultraestrutura , Mutação/genética , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Sistema Nervoso/patologia , Sistema Nervoso/fisiopatologia , Neuritos/metabolismo , Neuritos/patologia , Neuritos/ultraestrutura , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Estresse Oxidativo/genética , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia , Distúrbios Somatossensoriais/fisiopatologia , Tauopatias/patologia , Tauopatias/fisiopatologia , Tato/genética , Proteínas tau/genética , Proteínas tau/metabolismo
15.
Expert Opin Ther Targets ; 9(4): 685-98, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16083337

RESUMO

Neuropathic pain (NeP) is initiated by a lesion or dysfunction in the nervous system. Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. NeP encompasses a wide range of pain syndromes of diverse aetiologies which together account for > 12 million sufferers in the US. Currently, there are a number of therapies available for NeP, including gabapentin, pregabalin, anticonvulsants (tiagabine HCl), tricyclic antidepressants (amitriptyline, nortriptyline) and acetaminophen/opioid combination products (Vicodin, Tylenol #3). However, these products do not provide sufficient pain relief and a significant proportion of sufferers are refractory (60%). Therefore, there is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding of the basic mechanisms contributing to the generation of NeP in preclinical animal models has greatly improved. Together with the completion of the various genome sequencing projects and significant advances in microarray and target validation strategies, new therapeutic approaches are being rigourously pursued. This article reviews the rationale behind a number of these mechanism-based approaches, briefly discusses specific challenges that they face, and finally, speculates on the potential of emerging technologies as alternative therapeutic strategies to the traditional 'small-molecule' approach.


Assuntos
Analgésicos/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Distúrbios Somatossensoriais/tratamento farmacológico , Distúrbios Somatossensoriais/metabolismo , Animais , Humanos , RNA Interferente Pequeno/farmacologia , Especificidade por Substrato
16.
Expert Opin Ther Targets ; 9(4): 699-713, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16083338

RESUMO

Peripheral nerve injury produces neuropathic pain as well as phosphorylation of mitogen activated protein kinase (MAPK) family in dorsal root ganglia (DRG) and dorsal horn. Following nerve injury, phosphorylation of extracellular signal-regulated protein kinase (ERK), an important member of this family, is sequentially increased in neurons, microglia and astrocytes of the dorsal horn and gracile nucleus, and in injured large DRG neurons. Nerve injury-induced phosphorylation of ERK occurs early and is long-lasting. In several animal models of neuropathic pain, MEK inhibitors, known to suppress the synthesis of ERK, have proven effective to alleviate pain at various time points. Thus, the regulation of ERK/MAPK can be considered as a promising therapeutic target for the treatment of neuropathic pain.


Assuntos
Analgésicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Distúrbios Somatossensoriais/tratamento farmacológico , Analgésicos/uso terapêutico , Animais , Humanos , Dor/enzimologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/enzimologia , Doenças do Sistema Nervoso Periférico/metabolismo , Distúrbios Somatossensoriais/enzimologia , Distúrbios Somatossensoriais/metabolismo
17.
Muscle Nerve ; 32(2): 230-5, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15803482

RESUMO

A 22-year-old man, with a past history of generalized tonic-clonic seizures treated with phenobarbital, presented with spinocerebellar ataxia. The electrophysiological studies revealed a demyelinating motor-sensory neuropathy. The serum vitamin E level was low. Sural nerve biopsy revealed loss of large myelinated fibers with evidence of remyelination. Vitamin E supplementation led to clinical and electrophysiological recovery of sensory conduction and evoked potentials. Motor nerve conduction, however, showed only partial recovery. Vitamin E deficiency leading to a demyelinating neuropathy, as in the present case, suggests that the full spectrum of the disease entity is not fully defined.


Assuntos
Doenças Desmielinizantes/etiologia , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/etiologia , Ataxias Espinocerebelares/etiologia , Deficiência de Vitamina E/complicações , Adulto , Biópsia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/fisiopatologia , Eletrodiagnóstico , Humanos , Masculino , Debilidade Muscular/etiologia , Debilidade Muscular/metabolismo , Debilidade Muscular/fisiopatologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Fibras Nervosas Mielinizadas/patologia , Condução Nervosa/fisiologia , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Convulsões/etiologia , Distúrbios Somatossensoriais/etiologia , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/fisiopatologia , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/fisiopatologia , Nervo Sural/metabolismo , Nervo Sural/patologia , Nervo Sural/fisiopatologia , Vitamina E/uso terapêutico
18.
Pain ; 114(1-2): 7-18, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15733626

RESUMO

The transmission of nociceptive information occurs along non-myelinated, or thinly myelinated, primary afferent axons. These axons are generally classified as peptidergic (CGRP-expressing) or non-peptidergic (IB4-binding), although there is a sub-population that is both CGRP-positive and IB4-binding. During neuronal development and following injury, trophic factors and their respective receptors regulate their survival and repair. Recent reports also show that the carbohydrate-binding protein galectin-1 (Gal1), which is expressed by nociceptive primary afferent neurons during development and into adulthood, is involved in axonal pathfinding and regeneration. Here we characterize anatomical differences in dorsal root ganglia (DRG) of Gal1 homozygous null mutant mice (Gal1(-/-)), as well as behavioural differences in tests of nociception. Gal1(-/-) mice have a significantly reduced proportion of IB4-binding DRG neurons, an increased proportion of NF200-immunoreactive DRG neurons, increased depth of central terminals of IB4-binding and CGRP-immunoreactive axons in the dorsal horn, and a reduced number of Fos-positive second order neurons following thermal (cold or hot) stimulation. While there is no difference in the total number of axons in the dorsal root of Gal1(-/-) mice, there are an increased number of myelinated axons, suggesting that in the absence of Gal1, neurons that are normally destined to become IB4-binding instead become NF200-expressing. In addition, mice lacking Gal1 have a decreased sensitivity to noxious thermal stimuli. We conclude that Gal1 is involved in nociceptive neuronal development and that the lack of this protein results in anatomical and functional deficits in adulthood.


Assuntos
Galectina 1/deficiência , Gânglios Espinais/metabolismo , Células do Corno Posterior/metabolismo , Limiar Sensorial/fisiologia , Distúrbios Somatossensoriais/genética , Vias Aferentes/metabolismo , Vias Aferentes/patologia , Animais , Temperatura Baixa , Citotoxinas/metabolismo , Galectina 1/biossíntese , Galectina 1/genética , Temperatura Alta , Lectinas/metabolismo , Camundongos , Camundongos Knockout , Medição da Dor/métodos , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia
19.
Eur J Pain ; 8(2): 129-33, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-14987622

RESUMO

Vulvodynia is characterised by painful burning sensation, allodynia and hyperalgesia in the region of the vulval vestibulus. While in many patients the cause of vulvodynia remains uncertain, we and others have previously shown increased intraepithelial and papillary innervation in vulvodynia. The vanilloid receptor VR1 (TRPV1) is expressed by nociceptors, and is triggered by capsaicin, noxious heat, protons, and chemicals produced during inflammation. In the present study we show increased papillary VR1 fibres by immunostaining and image analysis in vulvodynia tissues compared to controls (p<0.002). VR1 expression was found to be significantly increased when the percentage area immunostained was expressed as a ratio of VR1 to PGP 9.5, a pan-neuronal marker (P=0.01). VR1-positive fine epidermal fibres also appeared to be increased in vulvodynia tissues, by inspection. Fibres immunoreactive to the voltage-gated sodium channel SNS1/PN3 (Nav1.8), also expressed by nociceptors, were relatively scarce in both vulvodynia and control tissues. We hypothesize that increased expression of VR1 by nociceptors could mediate some of the symptoms in vulvodynia, for which systemic or topical specific VR1 antagonists may provide novel treatment.


Assuntos
Receptores de Droga/metabolismo , Canais de Sódio/metabolismo , Distúrbios Somatossensoriais/metabolismo , Vulva/metabolismo , Doenças da Vulva/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Epiderme/inervação , Epiderme/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.8 , Ubiquitina Tiolesterase/metabolismo , Vulva/inervação
20.
J Neurosci Res ; 67(2): 167-73, 2002 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11782960

RESUMO

Mice heterozygously deficient in the major myelin component P0 are an established model of an inherited neuropathy and show signs of myelin degeneration in motor nerves. Unlike the case in patients, the sensory nerves are only mildly affected in the mouse mutants and do not show features indicative of myelin degeneration. Unexpectedly, by applying established behavioral tests, we found sensory deficits, as reflected by raised withdrawal thresholds to mechanical and thermal stimuli, whereas behavioral signs of a painful neuropathy were not detectable. By electron microscopy of longitudinal sections of sensory nerves, we found abnormalities in nodes of Ranvier comprising enlarged nodal gaps and poorly developed nodal Schwann cell microvilli. These alterations might be causally linked to the sensory deficits in the absence of profound myelin degeneration in the sensory nerves of the mutants.


Assuntos
Proteína P0 da Mielina/deficiência , Bainha de Mielina/patologia , Doenças do Sistema Nervoso Periférico/genética , Nós Neurofibrosos/patologia , Células de Schwann/patologia , Distúrbios Somatossensoriais/genética , Degeneração Walleriana/genética , Animais , Feminino , Genótipo , Heterozigoto , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Transtornos dos Movimentos/patologia , Proteína P0 da Mielina/genética , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Compressão Nervosa , Condução Nervosa/genética , Limiar da Dor/fisiologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Estimulação Física , Nós Neurofibrosos/metabolismo , Nós Neurofibrosos/ultraestrutura , Células de Schwann/metabolismo , Células de Schwann/ultraestrutura , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Distúrbios Somatossensoriais/metabolismo , Distúrbios Somatossensoriais/patologia , Degeneração Walleriana/metabolismo , Degeneração Walleriana/patologia
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