RESUMO
BACKGROUND: Regulation of pain states is, in part, dependent upon plastic changes in neurones within the superficial dorsal horn. There is also compelling evidence that pain states are under the control of descending projections from the brainstem. While a number of transcription factors including Methyl-CpG-binding protein 2 (MeCP2), Zif268 and Fos have been implicated in the regulation of dorsal horn neurone sensitization following injury, modulation of their activity by descending controls has not been investigated. RESULTS: Here, we describe how descending controls regulate MeCP2 phosphorylation (P-MeCP2), known to relieve transcriptional repression by MeCP2, and Zif268 and Fos expression in the rat superficial dorsal horn, after CFA injection into the hind paw. First, we report that CFA significantly increased P-MeCP2 in Lamina I and II, from 30 min post injection, with a maximum reached after 1 h. The increase in P-MeCP2 paralleled that of Zif268 and Fos, and P-MeCP2 was expressed in large sub-populations of Zif268 and Fos expressing neurones. Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively. Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA. CONCLUSION: We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.
Assuntos
Mediadores da Inflamação/administração & dosagem , Proteína 2 de Ligação a Metil-CpG/metabolismo , Células do Corno Posterior/metabolismo , Células do Corno Posterior/patologia , Serotonina/fisiologia , Medula Espinal/metabolismo , Medula Espinal/patologia , 5,7-Di-Hidroxitriptamina/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Adjuvante de Freund/administração & dosagem , Masculino , Proteína 2 de Ligação a Metil-CpG/biossíntese , Proteína 2 de Ligação a Metil-CpG/genética , Fosforilação , Ratos , Ratos Sprague-Dawley , Serotonina/efeitos adversosRESUMO
The effects of bergamot essential oil (BEO; Citrus bergamia, Risso) on brain damage caused by permanent focal cerebral ischemia in rat were investigated. Administration of BEO (0.1-0.5 ml/kg but not 1 ml/kg, given intraperitoneally 1 h before occlusion of the middle cerebral artery, MCAo) significantly reduced infarct size after 24 h permanent MCAo. The most effective dose (0.5 ml/kg) resulted in a significant reduction of infarct extension throughout the brain, especially in the medial striatum and the motor cortex as revealed by TTC staining of tissue slices. Microdialysis experiments show that BEO (0.5 ml/kg) did not affect basal amino acid levels, whereas it significantly reduced excitatory amino acid, namely aspartate and glutamate, efflux in the frontoparietal cortex typically observed following MCAo. Western blotting experiments demonstrated that these early effects were associated, 24 h after permanent MCAo, to a significant increase in the phosphorylation and activity of the prosurvival kinase, Akt. Indeed, BEO significantly enhanced the phosphorylation of the deleterious downstream kinase, GSK-3beta, whose activity is negatively regulated via phosphorylation by Akt.
Assuntos
Infarto Encefálico/prevenção & controle , Isquemia Encefálica/fisiopatologia , Ácido Glutâmico/biossíntese , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Óleos Voláteis/uso terapêutico , Óleos de Plantas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/biossíntese , Animais , Isquemia Encefálica/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacosRESUMO
(-)-Linalool is a natural compound with anti-inflammatory and antinociceptive properties. The antinociceptive action of linalool has been reported in several models of inflammatory pain. However, its effects in neuropathic pain have not been investigated. Here, we used the spinal nerve ligation (SNL) model of neuropathic pain and studied the effects of acute and chronic administration of an established antinociceptive dose of linalool on mechanical and thermal sensitivity induced by the nerve injury in mice. Linalool did not affect pain behavior triggered by mechanical or thermal stimuli when administered as a single dose before SNL. However, mechanical allodynia was reduced transiently in neuropathic animals when linalool was administered for 7 consecutive days, while no changes were seen in the sensitivity to noxious radiant heat. We investigated the possible involvement of the PI3K/Akt pathway in linalool antinociceptive effect by western blot analysis. Linalool did not induce significant changes in Akt expression and phopshorylation though a trend toward an increased ratio of phosphorylated versus total Akt was observed in SNL animals treated with linalool, in comparison to SNL alone or sham. We then wondered whether linalool could modulate inflammatory processes and investigated spinal glia activation and IL-1beta contents following linalool treatment in SNL animals. The data suggest that mechanisms other than an action on inflammatory processes may mediate linalool ability to reduce mechanical allodynia in this model of neuropathic pain.
Assuntos
Dor/tratamento farmacológico , Nervos Espinhais/lesões , Monoterpenos Acíclicos , Animais , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-1beta/metabolismo , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos/farmacologia , Inflamação Neurogênica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Medula Espinal/metabolismoRESUMO
Abnormal expression of matrix metalloproteinases (MMPs) has been implicated in the pathophysiology of neuroinflammatory processes that accompany most central nervous system disease. In particular, early upregulation of the gelatinases MMP-2 and MMP-9 has been shown to contribute to disruption of the blood-brain barrier and to death of neurons in ischemic stroke. In situ zymography reveals a significant increase in gelatinolytic MMPs activity in the ischemic brain hemisphere after 2-h middle cerebral artery occlusion (MCAo) followed by 2-h reperfusion in rat. Accordingly, gel zymography demonstrates that expression and activity of MMP-2 and MMP-9 are enhanced in cortex and striatum ipsilateral to the ischemic insult. The latter effect appears to be instrumental for development of delayed brain damage since administration of a broad spectrum, highly specific MMPs inhibitor, GM6001, but not by its negative control, results in a significant (50%) reduction in ischemic brain volume. Increased gelatinase activity in the ischemic cortex coincides with elevation (166% vs sham) of mature interleukin-1beta (IL-1beta) after 2-h reperfusion and this does not appear to implicate a caspase-1-dependent processing of pro(31kDa)-IL-1beta to yield mature (17kDa) IL-1beta. More importantly, when administered at a neuroprotective dose GM6001 abolishes the early IL-1beta increase in the ischemic cortex and reduces the cleavage of the cytokine proform supporting the deduction that MMPs may initiate IL-1beta processing. In conclusion, development of tissue damage that follows transient ischemia implicates a crucial interplay between MMPs and mediators of neuroinflammation (e.g., IL-1beta), and this further underscores the therapeutic potential of MMPs inhibitors in the treatment of stroke.