RESUMEN
Pioglitazone, an agonist at peroxisome proliferator-activated receptor gamma, is FDA-approved for the treatment of insulin resistance in type 2 diabetes. Numerous studies in male rodents suggest that pioglitazone inhibits inflammatory and neuropathic pain, but few included female subjects. To address this gap, we compared the effects of pioglitazone in both sexes in the intraplantar methylglyoxal model (MG) model of chemical pain and painful diabetic neuropathy (PDN), the plantar incision model (PIM) of postoperative pain, the spared nerve injury (SNI) model of traumatic nerve injury, and the ZDF rat and db/db mouse models of PDN. We administered pioglitazone by one-time intrathecal or intraperitoneal injection or by adding it to chow for 6 weeks, followed by measurement of hypersensitivity to non-noxious mechanical, noxious mechanical, heat, and/or cold stimuli. In all mouse models, injection of pioglitazone decreased pain-like behaviors with greater potency and/or efficacy in females as compared to males: heat and mechanical hypersensitivity in the MG model (0.1-10 mg/kg); mechanical hypersensitivity in the PIM model (10 µg); mechanical and cold hypersensitivity in the SNI model (100 mg/kg); and heat hypersensitivity in the db/db model (100 mg/kg). Furthermore, co-administration of low doses of morphine (1 mg/kg) and pioglitazone (10 mg/kg) decreased SNI-induced mechanical and cold hypersensitivity in female but not male mice. In the ZDF rat, pioglitazone (100 mg/kg) decreased heat and mechanical hypersensitivity with no sex difference. In the db/db model, pioglitazone had no effect when given into chow for 6 weeks at 0.3, 3 or 30 mg/kg doses. We conclude that females exhibit greater anti-hyperalgesic responses to pioglitazone in mouse models of chemical-induced nociception, postsurgical pain, neuropathic pain, and PDN. These findings set the stage for clinical trials to determine whether pioglitazone has analgesic properties across a broad spectrum of chronic pain conditions, particularly in women.
Asunto(s)
Analgésicos/farmacología , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Dolor Nociceptivo/tratamiento farmacológico , PPAR gamma/agonistas , Dolor Postoperatorio/tratamiento farmacológico , Pioglitazona/farmacología , Analgésicos/administración & dosificación , Animales , Neuropatías Diabéticas/complicaciones , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Morfina/farmacología , Neuralgia/etiología , Dolor Nociceptivo/inducido químicamente , Dolor Postoperatorio/etiología , Traumatismos de los Nervios Periféricos/complicaciones , Pioglitazona/administración & dosificación , Piruvaldehído/farmacología , Caracteres SexualesRESUMEN
BACKGROUND AND OBJECTIVE: This study evaluated whether the biochemical changes associated with type 2 diabetes modulate the expression of interleukin-1beta, interleukin-6, interleukin-8, and interferon-gamma in sites with chronic periodontitis. MATERIAL AND METHODS: Biopsies were harvested and divided into three groups: group 1, systemically and periodontally healthy subjects (n = 10); group 2, systemically healthy subjects with moderate-to-severe chronic periodontitis (probing depth > 6 mm) (n = 20); and group 3, type 2 diabetic subjects with periodontitis (n = 20). Cytokine levels were assessed in the gingival tissues by enzyme-linked immunosorbent assay analysis. RESULTS: Data analysis demonstrated that the interleukin-1beta, interleukin-6, interleukin-8, and interferon-gamma levels were higher in the presence of periodontal inflammation than in the absence of inflammation, regardless of systemic status. The interleukin-1beta and interleukin-6 levels were higher in diabetic subjects (group 3) than in systemically healthy patients with comparable types of periodontitis (group 2). No difference was observed for the interleukin-8 and interferon-gamma levels between groups 2 and 3. CONCLUSION: Within the limits of this study, it was concluded that type 2 diabetes was associated with increased expression of interleukin-1beta and interleukin-6 in periodontally inflamed tissues of diabetic patients, relative to nondiabetic subjects, and that such overexpression may be involved in the mechanisms by which type 2 diabetes enhances periodontal destruction.
Asunto(s)
Diabetes Mellitus Tipo 2/inmunología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Enfermedades Periodontales/inmunología , Adulto , Enfermedad Crónica , Placa Dental , Diabetes Mellitus Tipo 2/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Encía/inmunología , Encía/cirugía , Humanos , Interferón gamma/metabolismo , Interleucina-8/metabolismo , Masculino , Enfermedades Periodontales/metabolismo , Índice PeriodontalRESUMEN
BACKGROUND AND OBJECTIVE: This study evaluated the effect of smoking on the gene expression of interleukin-1alpha, -1ra, -6, -8 and -10, tumor necrosis factor-alpha, matrix metalloproteinase (MMP)-2 and -8, receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin, in sites with periodontitis. MATERIAL AND METHODS: Gingival biopsies were divided into three groups: the healthy group (periodontally healthy subjects; n=10); the periodontitis group [subjects with severe chronic periodontitis who never smoked (probing depth>or=7 mm) (n=25)]; and the smoking group (subjects diagnosed with severe chronic periodontitis who smoked>or=1 pack per day for at least 10 years; n=25). Gene and protein expressions were analyzed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Data analysis demonstrated that, except for MMP-8 and osteoprotegerin, the levels of all factors were increased by inflammation (p<0.001). The levels of interleukin-1alpha, -1ra, -6 and -8, and RANKL, were higher in smokers with periodontitis compared with controls, whereas the levels of interleukin-10, MMP-8 and osteoprotegerin were lower (p<0.001). Smoking lowered the levels of interleukin-1alpha, -8, -10, tumor necrosis factor-alpha, MMP-8 and osteoprotegerin, and increased the levels of interleukin-6 and -1ra in sites with a comparable type of periodontitis (p<0.001). CONCLUSION: In conclusion, smoking modulates gene expression in the periodontium, and the influence of smoking on periodontal disease may involve effects of interleukin-6:interleukin-10 and RANKL:osteoprotegerin ratios.
Asunto(s)
Interleucinas/biosíntesis , Osteoprotegerina/biosíntesis , Periodontitis/metabolismo , Ligando RANK/biosíntesis , Fumar/efectos adversos , Análisis de Varianza , Estudios de Casos y Controles , Enfermedad Crónica , Ensayo de Inmunoadsorción Enzimática , Femenino , Expresión Génica , Humanos , Masculino , Metaloproteinasas de la Matriz/biosíntesis , Periodontitis/etiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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.
Asunto(s)
Vías Aferentes/metabolismo , Hiperalgesia/metabolismo , Nociceptores/metabolismo , Células Receptoras Sensoriales/metabolismo , Serotonina/metabolismo , Piel/inervación , Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Animales , Quimiotaxis de Leucocito/efectos de los fármacos , Quimiotaxis de Leucocito/fisiología , Inhibidores de la Ciclooxigenasa/farmacología , Relación Dosis-Respuesta a Droga , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Masculino , Nociceptores/efectos de los fármacos , Nociceptores/fisiopatología , Norepinefrina/metabolismo , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Prostaglandinas/metabolismo , Ratas , Ratas Wistar , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Selectinas/efectos de los fármacos , Selectinas/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiopatología , Serotonina/farmacología , Antagonistas del Receptor de Serotonina 5-HT3 , Antagonistas de la Serotonina/farmacología , Piel/fisiopatología , Fibras Simpáticas Posganglionares/efectos de los fármacos , Fibras Simpáticas Posganglionares/metabolismoRESUMEN
The aim of this study was to test the hypothesis that 5-hydroxytryptamine induces nociception by an indirect action on the primary afferent nociceptor in addition to its previously described direct action. Injection of 5-hydroxytryptamine into the s.c. tissue of the hind paw of rats produced nociceptive flinch behavior and inflammatory cell migration, that were significantly reduced by the nonspecific selectin inhibitor fucoidan. 5-Hydroxytryptamine-induced nociception was also significantly reduced by local blockade of the 5-HT3 receptor by tropisetron, by the cyclooxygenase inhibitor indomethacin and by local blockade of the beta1-adrenergic receptor or of the D1 receptor by atenolol or SCH 23390, respectively. Neither guanethidine depletion of norepinephrine in the sympathetic terminals nor local blockade of the beta2-adrenergic receptor by ICI-118,551 significantly reduced 5-hydroxytryptamine-induced nociception. Taken together, these findings indicate that 5-hydroxytryptamine induces nociception by a novel, indirect and norepinephrine-independent mechanism mediated by neutrophil migration and local release of prostaglandin and dopamine. Furthermore, to test whether dopamine acts on beta1-adrenergic and/or D1 receptor to contribute to 5-hydroxytryptamine-induced nociception, dopamine was s.c. injected either alone or combined with atenolol or with SCH 23390. S.c.-injected dopamine also produced a dose-dependent nociceptive behavior that was significantly reduced by both SCH 23390 and atenolol. Based on that it is proposed that dopamine, once released, activates D1 and beta1-adrenergic receptors to contribute to 5-hydroxytryptamine-induced nociception.