Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naive animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems

Evolução da mortalidade por neoplasias malignas no Rio Grande do Sul, 1979-1995 Time trends in cancer mortality in Rio Grande do Sul, Brazil, 1979-1995

Foi analisada a mortalidade por câncer no Rio Grande do Sul (RS), entre 1979 e 1995. As variáveis consideradas foram sexo, idade, ano de ocorrência do óbito e causa básica da morte. Para análise da tendência das taxas padronizadas de mortalidade (método direto, população padrão: RS-1996) foi utilizada a regressão linear simples. As localizações mais freqüentes do tumor foram: pulmão, esôfago, próstata, estômago e cólon/reto, nos homens, e mama, colo do útero/útero não especificado, pulmão, cólon/reto e estômago, nas mulheres. A tendência temporal das taxas padronizadas de mortalidade, em cada sexo, do ponto de vista estatístico, foi de estabilidade, bem como por câncer de cólon/reto feminino e de colo do útero/útero não especificado. Verificou-se tendência estatisticamente significativa de crescimento da mortalidade por câncer de pulmão, em ambos os sexos, mama feminina, próstata e cólon/reto masculino; e, da mesma forma, decréscimo por câncer de estômago, para ambos os sexos, e esôfago, para os homens.<br>The aim of this study was to analyze cancer mortality in Rio Grande do Sul (RS), Brazil, during the period from1979 to 1995. Study variables were sex, age, year and underlying cause of death. The simple linear regression technique was used to evaluate the trend of standardized death rates (direct method, using the population of RS in 1996 as the standard). The most frequent sites of tumors in males were lung, esophagus, prostate, stomach and colon/rectum; in females they were breast, cervix of the uterus, lung, colon/rectum and stomach. Standardized death rates presented a stable trend for all malignant neoplasms in both sexes, as did cancer of cervix of the uterus/ non-specified uterus and colon/rectum tumors in females. A significant rising trend was observed in mortality rates due to lung cancer in both sexes, breast cancer in females, prostate and colon/rectum cancer in males. The rates of stomach cancer presented a significant decreasing trend in both sexes as did esophagus cancer rates in men