RESUMO
Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 µg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.
Assuntos
Colecistocinina/uso terapêutico , Endotoxemia/tratamento farmacológico , Hipotensão/prevenção & controle , Mediadores da Inflamação/sangue , Choque Séptico/tratamento farmacológico , Animais , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Colecistocinina/antagonistas & inibidores , Colecistocinina/sangue , Colecistocinina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Interleucina-10/sangue , Ácido Láctico/sangue , Lipopolissacarídeos , Fígado/enzimologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/biossíntese , Proglumida/farmacologia , Ratos , Ratos Wistar , Choque Séptico/sangue , Choque Séptico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/sangueRESUMO
The purpose of this study was to assess the effect of the non-selective cholecystokinin receptor antagonist proglumide on the antinociceptive activity of ketorolac and meloxicam in non-diabetic and diabetic rats. Streptozotocin (60 mg/kg) injection caused hyperglycemia which was maintained for 2 weeks. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Local peripheral ipsilateral, but not contralateral, administration of ketorolac and meloxicam produced antinociception in non-diabetic and diabetic rats. However, the antinociceptive effect of both drugs was significantly reduced in diabetic animals. Proglumide was ineffective by itself and it did not affect the antinociception induced by the cyclooxygenase inhibitors in non-diabetic rats. Contrariwise, proglumide reduced formalin-induced nociception and it increased ketorolac- or meloxicam-induced antinociception in diabetic rats. These results suggest that peripheral cholecystokinin plays an important role in diabetes-induced sensitization as well as in the reduction of the antinociceptive effects of ketorolac and meloxicam in diabetic rats. The combination of cholecystokinin receptor antagonists and ketorolac or meloxicam may be a useful strategy to reduce nociception in diabetic patients.
Assuntos
Analgésicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Formaldeído/efeitos adversos , Proglumida/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Sinergismo Farmacológico , Cetorolaco/farmacologia , Masculino , Meloxicam , Ratos , Ratos Wistar , Receptores da Colecistocinina/antagonistas & inibidores , Tiazinas/farmacologia , Tiazóis/farmacologiaRESUMO
Systemic administration of cholecystokinin (CCK) fragments produces anxiogenic effects. The dorsal periaqueductal gray (dPAG) has been related to anxiety and panic reactions. The objective of this study was to investigate a possible anxiogenic effect of CCK-8 microinjected into the dPAG. At 10 min after the last microinjection (0.5 microl) into the dPAG male Wistar rats (N=7-17) were tested in the elevated plus-maze, an animal model of anxiety. The following treatments were tested alone or in combination: sulfated CCK-8 (CCK-8s, 0.5-1 microg), PD 135158 (N-methyl-D-glucamine, 0.1 microg), a CCK-2 receptor antagonist, lorglumide (0.1-0.3 microg), a CCK-1 receptor antagonist. In addition, Fos immunohistochemistry was performed in rats (n=3-4) treated with CCK-8s (1 microg) alone or in combination with PD 135158 (0.1 microg). CCK-8s produced anxiogenic-like effect, decreasing the percentage of time spent in open arm (saline=30.3+/-6.6, CCK 0.5 microg=15.2+/-1.8; CCK 1 microg=14.6+/-2.1). This effect was prevented by pretreatment with PD 135158, but not by lorglumide. CCK-8s injected into the dPAG induced Fos immunoreactivity in several brain areas related to defensive behavior, including the PAG, median, and dorsal raphe nuclei, superior colliculus, lateral septal nuclei, medial hypothalamus, and medial amygdala. This effect was also prevented by pretreatment with PD 135,158. These results suggest that CCK-8s, acting on CCK-2 receptors, may modulate anxiety reactions in the dPAG.
Assuntos
Ansiedade/metabolismo , Meglumina/análogos & derivados , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Proglumida/análogos & derivados , Receptor de Colecistocinina B/metabolismo , Sincalida/farmacologia , Análise de Variância , Animais , Ansiolíticos/farmacologia , Depressores do Apetite/farmacologia , Contagem de Células , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações Medicamentosas , Antagonistas de Hormônios/farmacologia , Imuno-Histoquímica/métodos , Indóis/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Meglumina/farmacologia , Microinjeções , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/citologia , Proglumida/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina B/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Fatores de TempoRESUMO
The ventrolateral periaqueductal gray (PAG) is a key structure for the development of opioid tolerance. An increased activity of 'anti-opioids' like cholecystokinin (CCK) has been proposed as a possible mechanism for opioid tolerance. The present study evaluates the role of PAG-located CCK in the opioid tolerance induced by repeated microinjections of morphine (MOR) into PAG. Male rats were implanted with chronic guide cannulae aimed at the PAG. Microinjection of MOR (0.5 microg in 0.5 microl) into PAG caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days (tolerance). However, if each MOR microinjection was preceded (within 15 min) by a microinjection of the non-selective CCK receptor antagonist proglumide (PRO), (0.4 microg in 0.5 microl) into the same PAG site, the microinjections of MOR always produced antinociception and did not induce tolerance. If PRO microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single PRO microinjection into the same PAG site was enough to restore the antinociceptive effect of MOR. On the other hand, if CCK (1 ng in 0.5 microl) was microinjected into PAG, then MOR microinjection administered 15 min later into the same PAG site did not elicit antinociception. These results show that CCK has anti-opioid activity in PAG and that tolerance to MOR in PAG can be prevented or reversed if CCK receptors are blocked with PRO. Finally, opioid tolerance induced by repeated systemic MOR injections (5mg/kg intraperitoneal ) was reversed by a single microinjection of PRO into PAG. This emphasizes the central importance of PAG in the MOR/CCK interactions that lead to opioid tolerance.
Assuntos
Analgésicos Opioides/farmacologia , Colecistocinina/fisiologia , Tolerância a Medicamentos/fisiologia , Morfina/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Antiulcerosos/farmacologia , Colecistocinina/metabolismo , Masculino , Microinjeções/métodos , Morfina/administração & dosagem , Medição da Dor , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/fisiologia , Proglumida/farmacologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Fatores de TempoRESUMO
Blockade of cholecystokinin (CCK) receptors potentiates the morphine-induced disruption of maternal behavior. The present study was undertaken to determine whether treatment with lorglumide, a CCK1 antagonist during late pregnancy and early lactation can influence the maternal behavior during lactation. A possible influence of this treatment on general activity was also assessed. Twenty-seven female Wistar rats were pretreated with lorglumide (1.0mg/kg/day; sc) or saline for seven days, starting on the 17th d of pregnancy. After the withdrawal of this treatment, animals were acutely challenged with saline on day 5 and with morphine sulfate (3.0mg/kg; sc) on days 6,10, and 17 of lactation. Groups were pretreated with saline and challenged with saline (group SS) and morphine (group SM), pretreated with lorglumide and challenged with saline (group LS) and morphine (group LM). Animals were also tested for general activity on days 25 and 33 postpartum after an acute challenge with saline and morphine, respectively. Maternal behavior testing began 30 min after the acute injections at which time pups were placed throughout each mother's cage. Latencies for pup retrieval, grouping, crouching and for full maternal behavior responses were scored. Lorglumide pretreatment inhibited maternal behavior of LS vs SS group and potentiated the morphine-induced disruption of this behavior in all days of test (LM vs SM group). No significant differences were found in general activity on days 25 and 33 postpartum. These data suggest that blockade of CCK1 receptors during puerperal period has long-term implications for maternal behavior.
Assuntos
Encéfalo/efeitos dos fármacos , Colecistocinina/metabolismo , Antagonistas de Hormônios/farmacologia , Lactação/efeitos dos fármacos , Comportamento Materno/efeitos dos fármacos , Morfina/farmacologia , Proglumida/análogos & derivados , Proglumida/farmacologia , Receptores da Colecistocinina/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Encéfalo/metabolismo , Interações Medicamentosas/fisiologia , Feminino , Lactação/fisiologia , Masculino , Comportamento Materno/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Gravidez , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores da Colecistocinina/metabolismoRESUMO
Serotonin [5-hydroxytryptamine (5-HT)] and CCK injected into the lateral parabrachial nucleus (LPBN) inhibit NaCl and water intake. In this study, we investigated interactions between 5-HT and CCK into the LPBN to control water and NaCl intake. Male Holtzman rats with cannulas implanted bilaterally in the LPBN were treated with furosemide + captopril to induce water and NaCl intake. Bilateral LPBN injections of high doses of the 5-HT antagonist methysergide (4 microg) or the CCK antagonist proglumide (50 microg), alone or combined, produced similar increases in water and 1.8% NaCl intake. Low doses of methysergide (0.5 microg) + proglumide (20 microg) produced greater increases in NaCl intake than when they were injected alone. The 5-HT(2a/2c) agonist 2,5-dimetoxy-4-iodoamphetamine hydrobromide (DOI; 5 microg) into the LPBN reduced water and NaCl intake. After proglumide (50 microg) + DOI treatment, the intake was not different from vehicle treatment. CCK-8 (1 microg) alone produced no effect. CCK-8 combined with methysergide (4 microg) reduced the effect of methysergide on NaCl intake. The data suggest that functional interactions between 5-HT and CCK in the LPBN may be important for exerting inhibitory control of NaCl intake.
Assuntos
Apetite/fisiologia , Núcleos Intralaminares do Tálamo/fisiologia , Serotonina/farmacologia , Sincalida/análogos & derivados , Sincalida/farmacologia , Sódio na Dieta , Anfetaminas/farmacologia , Animais , Apetite/efeitos dos fármacos , Interações Medicamentosas , Homeostase , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Masculino , Metisergida/administração & dosagem , Metisergida/farmacologia , Microinjeções , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proglumida/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia , Sincalida/administração & dosagemRESUMO
Cholecystokinin (CCK) can have effects opposite those of opioids. The present study was undertaken to determine whether peripheral injections of antagonists of the CCK1 receptor (lorglumide) and the CCK2 receptor (L-365,260) can influence the effects of morphine on maternal behavior during lactation. A total of 110 female Wistar rats were tested on days 5 and 6 postpartum. Groups were randomly assigned to morphine vehicle (MV-SC) + saline (S-IP), MV + lorglumide (LOR: 1.0 or 10.0 mg/kg), MV + L-365,260 (10 mg/kg), morphine chlorhydrate (MC: 7.0 mg/kg) + S, MC + LOR (1.0 or 10.0 mg/kg), and MC + L-365,260 (1.0 or 10 mg/kg). Maternal behavior testing was started 30 min after the injections, at which time pups were placed in the home cage of their mother. Latencies for retrieval, grouping, and crouching responses were scored. The results show that both lorglumide and L-365,260 potentiated the MC-induced inhibition of maternal behavior. In addition L-365,260 treatment alone inhibited maternal behavior. Blockade of both the CCK1 and CCK2 receptors potentiated the morphine-induced disruption of maternal behavior, while CCK2 antagonism alone also inhibited this behavior. The results suggest that CCK antagonism of opioid-induced disruption of maternal behavior occurs due to the action of CCK on both CCK1 and CCK2 receptor subtypes.
Assuntos
Comportamento Materno/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Receptores da Colecistocinina/antagonistas & inibidores , Animais , Benzodiazepinonas/farmacologia , Feminino , Antagonistas de Hormônios/farmacologia , Lactação/fisiologia , Compostos de Fenilureia/farmacologia , Proglumida/análogos & derivados , Proglumida/farmacologia , Ratos , Ratos Wistar , Receptor de Colecistocinina A , Receptor de Colecistocinina BRESUMO
Eight Panthera onca (Po), 13 Felis concolor (Fc), Felis yagouaroundi (Fy) 7 Felis tigrina (Ft) and 5 Felis pardalis (Fp) specimens from SÒo Paulo State zoos were used. All animals were restrained with darts containing 10 mg/kg ketamine and 1 mg/kg xylazine. Venous blood samples were collected as soon as possible (within 15-20 min) and serum was frozen until the time for cortisol quantification. Cortisol was determined using a solid phase radioimmunoassay with and intra-assay coefficient of 8.51 percent. Data were analyzed statistically by the Kruskal-Wallis test, followed by Dunn´s multiple comparisons test, and the one-sample t-test, with the level of significance set at P<0.05. Data are reported as means + SEM. Cortisol levels differed among the captive felines: Po = 166 + 33a, Fc = 670 + 118b, Fy = 480 + 83b, Ft = 237 + 42ab, Fp = 97 + 12a nmol/l (values followed by different superscript letters were significantly different (P<0.001). Since most of the veterinary procedures on these species involve chemical restraint, these results show the necessity of preventive measures in order to minimize the effect of restraint stress on more susceptible species.
Assuntos
Animais , Carnívoros/fisiologia , Homeostase/efeitos dos fármacos , Hidrocortisona/sangue , Estresse Fisiológico/induzido quimicamente , Brasil , Ketamina/efeitos adversos , Ketamina/farmacologia , Proglumida/efeitos adversos , Proglumida/farmacologiaRESUMO
Eight Panthera onca (Po), 13 Felis concolor (Fc), 7 Felis yagouaroundi (Fy), 7 Felis tigrina (Ft) and 5 Felis pardalis (Fp) specimens from São Paulo State zoos were used. All animals were restrained with darts containing 10 mg/kg ketamine and 1 mg/kg xylazine. Venous blood samples were collected as soon as possible (within 15-20 min) and serum was frozen until the time for cortisol quantification. Cortisol was determined using a solid phase radioimmunoassay with an intra-assay coefficient of 8.51%. Data were analyzed statistically by the Kruskal-Wallis test, followed by Dunn's multiple comparisons test, and the one-sample t-test, with the level of significance set at P < 0.05. Data are reported as means +/- SEM. Cortisol levels differed among the captive felines: Po = 166 +/- 33a, Fc = 670 +/- 118b, Fy = 480 +/- 83b, Ft = 237 +/- 42ab, Fp = 97 +/- 12a nmol/l (values followed by different superscript letters were significantly different (P < 0.001)). Since most of the veterinary procedures on these species involve chemical restraint, these results show the necessity of preventive measures in order to minimize the effect of restraint stress on more susceptible species.