RESUMO
Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy.
Assuntos
Analgésicos/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/genética , Dor/fisiopatologia , Vasopressinas/uso terapêutico , Animais , Animais Recém-Nascidos , Capsaicina/efeitos adversos , Desamino Arginina Vasopressina/uso terapêutico , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peso Molecular , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Limiar da Dor/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Receptores de Vasopressinas/deficiência , Receptores de Vasopressinas/genética , Fatores Sexuais , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologiaRESUMO
Polyuria, hypernatremia, and hypovolemia are the major clinical signs of inherited nephrogenic diabetes insipidus (NDI). Hypernatremia is commonly considered a secondary sign caused by the net loss of water due to insufficient insertion of aquaporin-2 water channels into the apical membrane of the collecting duct cells. In the present study, we employed transcriptome-wide expression analysis to study gene expression in V2 vasopressin receptor (Avpr2)-deficient mice, an animal model for X-linked NDI. Gene expression changes in NDI mice indicate increased proximal tubular sodium reabsorption. Expression of several key genes including Na+-K+-ATPase and carbonic anhydrases was increased at the mRNA levels and accompanied by enhanced enzyme activities. In addition, altered expression was also observed for components of the eicosanoid and thyroid hormone pathways, including cyclooxygenases and deiodinases, in both kidney and hypothalamus. These effects are likely to contribute to the clinical NDI phenotype. Finally, our data highlight the involvement of the renin-angiotensin-aldosterone system in NDI pathophysiology and provide clues to explain the effectiveness of diuretics and indomethacin in the treatment of NDI.
Assuntos
Diabetes Insípido Nefrogênico/fisiopatologia , Hipotálamo/fisiologia , Túbulos Renais Proximais/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Vasopressinas/genética , Equilíbrio Hidroeletrolítico/fisiologia , Animais , Diabetes Insípido Nefrogênico/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/fisiologia , Perfilação da Expressão Gênica , Homeostase/fisiologia , Hipernatremia/metabolismo , Hipernatremia/fisiopatologia , Camundongos , Receptores de Vasopressinas/deficiência , Transdução de Sinais/fisiologia , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response. However, acoustic startle response was not significantly correlated to the PPI of the startle reflex in V1bR KO mice. V1bR KO mice also showed a decrease in basal levels of extracellular dopamine (DA) in the medial prefrontal cortex, which is thought to be an important brain region for PPI. Moreover, PPI deficits observed in the V1bR KO mice are significantly reversed by atypical antipsychotics such as risperidone and clozapine but not by a typical neuroleptic haloperidol, like in schizophrenic patients. By contrast, we did not observe any significant differences between V1bR KO mice and wild-type mice in the open-field, light/dark, elevated plus maze, and forced swimming tests. The results of the present study indicate that V1bR may be involved in the regulation of PPI of the startle reflex. The V1bR has been considered an important molecular target for the development of antipsychotic drugs.