RESUMO
Current evidence indicates that rises in systemic levels of estrogen create in the uterus an inhibitory environment for sympathetic nerves. However, molecular insights of these changes are far from complete. We evaluated if semaphorin 3F mRNA, a sympathetic nerve repellent, was produced by the rat uterus and if its expression was modulated by estrogen. We also analyzed whether uterine nerves express the semaphorin 3F binding receptor, neuropilin-2. Uterine levels of semaphorin 3F mRNA were measured using real time reverse transcriptase-polymerase chain reaction in prepubertal rat controls and following chronic estrogen treatment. Localization of semaphorin 3F transcripts was determined by in situ hybridization and the expression of neuropilin-2 was assessed by immunohistochemistry. These studies showed that: (1) chronic estrogen treatment led to a 5-fold induction of semaphorin 3F mRNA in the immature uterus; (2) estrogen provoked a tissue-specific induction of semaphorin 3F which was particularly localized in the connective tissue that borders muscle bundles and surrounds intrauterine blood vessels; (3) two major cell-types were recognized in the areas where transcripts were concentrated, fibroblast-like cells and infiltrating eosinophil leukocytes; and (4) some delicate nerve terminal profiles present in the estrogenized uterus were immunoreactive for neuropilin-2. Temporal and spatial expression patterns of semaphorin 3F/neuropilin-2 are consistent with a possible role of this guidance cue in the remodeling of uterine sympathetic innervation by estrogen. Though correlative in its nature, these data support a model whereby semaphorin 3F, in combination with other inhibitory molecules, converts the estrogenized myometrium to an inhospitable environment for sympathetic nerves.
Assuntos
Estrogênios/fisiologia , Miométrio/inervação , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/biossíntese , Fibras Simpáticas Pós-Ganglionares/metabolismo , Regulação para Cima/fisiologia , Útero/inervação , Animais , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/agonistas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Miométrio/fisiologia , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Ratos , Ratos Wistar , Útero/fisiologiaRESUMO
We have recently demonstrated that s.c.-injected 5-hydroxytryptamine (5-HT) induces nociception by an indirect action on the primary afferent nociceptor in addition to its previously described direct action. Although the mechanisms mediating hyperalgesia can be quite separate and distinct from those mediating nociception, the aim of this study was to test the hypothesis that 5-HT induces mechanical hyperalgesia by mechanisms similar to those mediating nociception. s.c. injection of 5-HT induced a dose-dependent mechanical hyperalgesia measured by the mechanical paw withdrawal nociceptive threshold test in the rat. 5-HT-induced hyperalgesia was significantly reduced by local blockade of the 5-HT(3) receptor by tropisetron, by the nonspecific selectin inhibitor fucoidan, by the cyclooxygenase inhibitor indomethacin, by guanethidine depletion of norepinephrine in the sympathetic terminals, and by local blockade of the beta(1)- or beta(2)-adrenergic receptor by atenolol or ICI 118,551, respectively. Taken together, these findings indicate that like nociception, hyperalgesia induced by the injection of 5-HT in the s.c. tissue is also mediated by an indirect action of 5-HT on the primary afferent nociceptor. This indirect hyperalgesic action of 5-HT is mediated by a combination of mechanisms involved in inflammation such as neutrophil migration and the local release of prostaglandin and norepinephrine. However, in contrast to nociception, hyperalgesia induced by 5-HT in the s.c. tissue is mediated by a norepinephrine-dependent mechanism that involves the activation of peripheral beta(2) adrenoceptors.
Assuntos
Vias Aferentes/metabolismo , Hiperalgesia/metabolismo , Nociceptores/metabolismo , Células Receptoras Sensoriais/metabolismo , Serotonina/metabolismo , Pele/inervação , Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Nociceptores/efeitos dos fármacos , Nociceptores/fisiopatologia , Norepinefrina/metabolismo , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Prostaglandinas/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Selectinas/efeitos dos fármacos , Selectinas/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiopatologia , Serotonina/farmacologia , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/farmacologia , Pele/fisiopatologia , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Fibras Simpáticas Pós-Ganglionares/metabolismoRESUMO
Chronic stress affects brain areas involved in learning and emotional responses. Although most studies have concentrated on the effect of stress on limbic-related brain structures, in this study we investigated whether chronic stress might induce impairments in diencephalic structures associated with limbic components of the stress response. Specifically, we analyzed the effect of chronic immobilization stress on the expression of sympathetic markers in the rat epithalamic pineal gland by immunohistochemistry and western blot, whereas the plasma melatonin concentration was determined by radioimmunoassay. We found that chronic stress decreased the expression of three sympathetic markers in the pineal gland, tyrosine hydroxylase, the p75 neurotrophin receptor and alpha-tubulin, while the same treatment did not affect the expression of the non-specific sympathetic markers Erk1 and Erk2, and glyceraldehyde-3-phosphate dehydrogenase. Furthermore, these results were correlated with a significant increase in plasma melatonin concentration in stressed rats when compared with control animals. Our findings indicate that stress may impair pineal sympathetic inputs, leading to an abnormal melatonin release that may contribute to environmental maladaptation. In addition, we propose that the pineal gland is a target of glucocorticoid damage during stress.
Assuntos
Melatonina/sangue , Glândula Pineal/metabolismo , Estresse Psicológico/sangue , Sistema Nervoso Simpático/metabolismo , Animais , Biomarcadores/metabolismo , Doença Crônica , Regulação para Baixo/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gliceraldeído 3-Fosfato/metabolismo , Imuno-Histoquímica , Masculino , Melatonina/metabolismo , Atividade Motora/fisiologia , Glândula Pineal/inervação , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural/metabolismo , Restrição Física , Estresse Psicológico/fisiopatologia , Fibras Simpáticas Pós-Ganglionares/metabolismo , Fibras Simpáticas Pós-Ganglionares/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Tubulina (Proteína)/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/fisiologiaRESUMO
The pre-synaptic sympathetic modulator role of adenosine was assessed by studying transmitter release following electrical depolarization of nerve endings from the rat mesenteric artery. Mesentery perfusion with exogenous adenosine exclusively inhibited the release of norepinephrine (NA) but did not affect the overflow of neuropeptide Y (NPY), establishing the basis for a differential pre-synaptic modulator mechanism. Several adenosine structural analogs mimicked adenosine's effect on NA release and their relative order of potency was: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride = 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-d-ribofuranuronamide = 5'-(N-ethylcarboxamido)adenosine >> adenosine > N(6)-cyclopentyladenosine. The use of selective receptor subtype antagonists confirmed the involvement of A(2A) and A(3) adenosine receptors. The modulator role of adenosine is probably due to the activation of both receptors; co-application of 1 nM 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride plus 1 nM 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide caused additive reductions in NA released. Furthermore, while 1 nM of an A(2A) or A(3) receptor antagonist only partially reduced the inhibitory action of adenosine, the combined co-application of the two antagonists fully blocked the adenosine-induced inhibition. Only the simultaneous blockade of the adenosine A(2A) plus A(3) receptors with selective antagonists elicited a significant increase in NA overflow. H 89 reduced the release of both NA and NPY. We conclude that pre-synaptic A(2A) and A(3) adenosine receptor activation modulates sympathetic co-transmission by exclusively inhibiting the release of NA without affecting immunoreactive (ir)-NPY and we suggest separate mechanisms for vesicular release modulation.
Assuntos
Neuropeptídeo Y/metabolismo , Norepinefrina/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptor A3 de Adenosina/metabolismo , Receptores A2 de Adenosina/metabolismo , Fibras Simpáticas Pós-Ganglionares/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Agonistas do Receptor A3 de Adenosina , Antagonistas do Receptor A3 de Adenosina , Animais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Isoquinolinas/farmacologia , Masculino , Artérias Mesentéricas/inervação , Artérias Mesentéricas/fisiologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismoRESUMO
We studied the effect of thyrotropin-releasing hormone (TRH) applied centrally on the sympathetic activity of the ovary in female rats. Intracerebroventricular (i.c.v.) administration of a dose of 25 ng/kg weight produced an increase in noradrenaline (NA) content at the ovary after 5 days of hormone administration. However, higher doses in a range up to 500 ng/kg weight decreased NA content at the ovary. At the celiac ganglia (where the cell bodies of sympathetic neurons projecting to the ovary originate) there was an accumulation of NA in spite of a decrease in tyrosine hydroxylase activity (T-OH). After cold exposure, opposite effects on T-OH activity and no effects on NA in ganglia and in ovary were obtained. Besides, i.v. injection of TRH only induced a decrease in ovarian NA. In contrast to the increase in T(3) plasma levels obtained after the cold-stress procedure, none of the i.c.v. doses of TRH used produced changes in T(3) plasma levels, strongly suggesting that the effect on sympathetic activity is mediated by a central effect of TRH acting as a putative activator of ovarian sympathetic nerves.
Assuntos
Vias Autônomas/metabolismo , Ovário/inervação , Hormônio Liberador de Tireotropina/fisiologia , Glândulas Suprarrenais/metabolismo , Animais , Temperatura Baixa , Feminino , Gânglios Simpáticos/metabolismo , Norepinefrina/metabolismo , Ovário/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Fibras Simpáticas Pós-Ganglionares/metabolismoRESUMO
OBJECTIVES: The aim of the present work was to study the effect of long-term cyclosporine (CSA) administration on norepinephrine (NE) metabolism and adrenergic-evoked secretion in the rat submandibular gland (SMG). METHODS: Dose-response curves to adrenergic agonists (methoxamine, isoproterenol, NE) were performed in control and CSA (10 and 30 mg/kg every 2 days for 1 month)-treated rats after SMG duct cannulation. In SMG tissue neuronal NE uptake, release, synthesis and endogenous content were determined. In addition phosphoinositide intracellular signaling was also investigated. RESULTS: CSA administration caused an increase in salivary secretion evoked by methoxamine (alpha-adrenergic agonist) and NE but failed to modify salivation evoked by beta-adrenergic stimulation (isoproterenol). Long-term CSA administration decreased NE release and synthesis whereas it enhanced the amine uptake and phosphoinositide hydrolysis in the SMG. CONCLUSIONS: The administration of CSA for 30 days induced salivary gland sensitization likely mediated by diminished adrenergic input. Present results suggest that the decreased sympathetic activity evoked by long-term CSA administration in the rat SMG may lead to sensitization of the gland supported by increased phosphoinositide hydrolysis and enhanced adrenergic-evoked salivation.