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1.
FASEB J ; 31(1): 224-237, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27702770

RESUMEN

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.


Asunto(s)
Regulación Enzimológica de la Expresión Génica/fisiología , Nocicepción/fisiología , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo , Trastornos Somatosensoriales/metabolismo , Animales , Membrana Celular/enzimología , Femenino , Heterocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Factores Sexuales , Trastornos Somatosensoriales/genética
2.
Neurobiol Dis ; 54: 194-205, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23313320

RESUMEN

Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile inflammation associated with systemic injury and non-infectious diseases via binding of endogenous ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in nervous system injury and especially in injury-elicited pain and sterile inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9 ligands in the functional outcomes of SCI, including pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe contusion SCI, diminishes injury-induced heat hypersensitivity. Investigations on the potential mechanisms underlying the reduction in pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in tumor necrosis factor-α (TNF-α) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist, CpG ODN 1826, increased inflammatory cell numbers and TNF-α expression in the epicenter. The CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum cytokine levels. We propose that CpG ODN 2088 dampens injury-induced heat hypersensitivity by suppressing the inflammatory response and TNF-α expression. This investigation defines a previously unreported therapeutic role for CpG ODN 2088 in SCI-induced pain.


Asunto(s)
Hiperalgesia/etiología , Oligodesoxirribonucleótidos/farmacología , Traumatismos de la Médula Espinal/complicaciones , Médula Espinal/efectos de los fármacos , Receptor Toll-Like 9/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Hiperalgesia/patología , Inmunohistoquímica , Inflamación/etiología , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Traumatismos de la Médula Espinal/patología
3.
J Spine Surg ; 3(2): 163-167, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28744496

RESUMEN

BACKGROUND: The modulus of elasticity of an assortment of materials used in spinal surgery, as well as cortical and cancellous bones, is determined by direct measurements and plotting of the appropriate curves. When utilized in spine surgery, the stiffness of a surgical implant can affect its material characteristics. The modulus of elasticity, or Young's modulus, measures the stiffness of a material by calculating the slope of the material's stress-strain curve. While many papers and presentations refer to the modulus of elasticity as a reason for the choice of a particular spinal implant, no peer-reviewed surgical journal article has previously been published where the Young's modulus values of interbody implants have been measured. METHODS: Materials were tested under pure compression at the rate of 2 mm/min. A maximum of 45 kilonewtons (kN) compressive force was applied. Stress-strain characteristics under compressive force were plotted and this plot was used to calculate the elastic modulus. RESULTS: The elastic modulus calculated for metals was more than 50 Gigapascals (GPa) and had significantly higher modulus values compared to poly-ether-ether-ketone (PEEK) materials and allograft bone. CONCLUSIONS: The data generated in this paper may facilitate surgeons to make informed decisions on their choices of interbody implants with specific attention to the stiffness of the implant chosen.

4.
J Neurotrauma ; 31(21): 1800-6, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-24936867

RESUMEN

Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due to alterations in the inflammatory milieu. These findings indicate that the TLR9 antagonist has beneficial effects not only in reducing sensory deficits, but also on bladder dysfunction and tissue preservation. Thus, modulation of innate immune receptor signaling in the spinal cord can impact the effects of SCI.


Asunto(s)
Oligodesoxirribonucleótidos/uso terapéutico , Traumatismos de la Médula Espinal/complicaciones , Receptor Toll-Like 9/antagonistas & inhibidores , Vejiga Urinaria/efectos de los fármacos , Retención Urinaria/tratamiento farmacológico , Sustancia Blanca/efectos de los fármacos , Animales , Femenino , Ratones , Oligodesoxirribonucleótidos/farmacología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Vejiga Urinaria/patología , Vejiga Urinaria/fisiopatología , Retención Urinaria/etiología , Retención Urinaria/patología , Retención Urinaria/fisiopatología , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología
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