RESUMO
There are different physiological processes that influence behavior. One of this processes that produces approach behavior to a stimuli that induces a positive affective (PA) state, commonly known as reward, plays an important role in modulating behavior. There is an extensive literature in which the rewarding effects of drugs have been investigated. Less research has been devoted to the study of naturally occurring behaviors that produce a PA or reward state. Hormones modulate different behaviors, including sex. However, little attention has been devoted to study the possible role of hormones in reward states. One of the methods most frequently used to study reward or PA states is the conditioned place preference (CPP) paradigm. Hopefully this review will encourage researchers to directly address the effects of hormones on reward, research that is much needed.
Assuntos
Hormônios/fisiologia , Recompensa , Comportamento Sexual Animal/fisiologia , Corticosteroides/fisiologia , Animais , Colecistocinina/fisiologia , Condicionamento Clássico/fisiologia , Estradiol/fisiologia , Feminino , Grelina/fisiologia , Hormônio Liberador de Gonadotropina/fisiologia , Humanos , Masculino , Melatonina/fisiologia , Camundongos , Ocitocina/fisiologia , Progesterona/fisiologia , Ratos , Substância P/fisiologia , Testosterona/fisiologiaRESUMO
Dental pulp is a soft mesenchymal tissue densely innervated by afferent (sensory) fibers, sympathetic fibers, and parasympathetic fibers. This complexity in pulp innervation has motivated numerous investigations regarding how these 3 major neuronal systems regulate pulp physiology and pathology. Most of this research is focused on neuropeptides and their role in regulating pulpal blood flow and the development of neurogenic inflammation. These neuropeptides include substance P, calcitonin gene-related peptide, neurokinin A, neuropeptide Y, and vasoactive intestinal polypeptide among others. The purpose of this article is to review recent advances in neuropeptide research on dental pulp, including their role in pulp physiology, their release in response to common dental procedures, and their plasticity in response to extensive pulp and dentin injuries. Special attention will be given to neuropeptide interactions with pulp and immune cells via receptors, including studies regarding receptor identification, characterization, mechanisms of action, and their effects in the development of neurogenic inflammation leading to pulp necrosis. Their role in the growth and expansion of periapical lesions will also be discussed. Because centrally released neuropeptides are involved in the development of dental pain, the pain mechanisms of the pulpodentin complex and the effectiveness of present and future pharmacologic therapies for the control of dental pain will be reviewed, including receptor antagonists currently under research. Finally, potential clinical therapies will be proposed, particularly aimed to manipulate neuropeptide expression or blocking their receptors, to modulate a variety of biologic mechanisms, which preliminary results have shown optimistic results.
Assuntos
Polpa Dentária/inervação , Polpa Dentária/metabolismo , Inflamação Neurogênica , Neuropeptídeos/fisiologia , Odontalgia/fisiopatologia , Perda do Osso Alveolar/fisiopatologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Polpa Dentária/irrigação sanguínea , Humanos , Neurocinina A/biossíntese , Neurocinina A/fisiologia , Neurônios Aferentes/fisiologia , Neuropeptídeo Y/biossíntese , Neuropeptídeo Y/fisiologia , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/biossíntese , Pulpite/fisiopatologia , Substância P/biossíntese , Substância P/fisiologia , Odontalgia/tratamento farmacológico , Peptídeo Intestinal Vasoativo/biossíntese , Peptídeo Intestinal Vasoativo/fisiologiaRESUMO
BACKGROUND AND OBJECTIVE: Substance P may play a role in the pathogenesis of periodontal disease; however, its mechanisms of modulation are not clear. This study evaluated the effect of two concentrations of Substance P on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cultured human gingival fibroblasts. MATERIAL AND METHODS: Fibroblasts were stimulated for 48 h with 10(-4) or 10(-9) m Substance P; untreated fibroblasts served as controls. The expression of MMP-1, -2, -3, -7 and -11 and of TIMP-1 and -2 was evaluated using real-time polymerase chain reaction and western blotting. RESULTS: There was a significant, concentration-dependent stimulatory effect of Substance P on MMP-1, -2, -3 and -7 and TIMP-2 gene expression (p < 0.05), and a probable effect on MMP-11 (p = 0.06). At the higher concentration (10(-4) m Substance P), MMP-1, -2, -3, -7 and -11 and TIMP-2 showed the greatest up-regulation; at the lower concentration (10(-9) m Substance P), MMP-1, -3 and -7 and TIMP-2 exhibited diminished up-regulation, with MMP-2 and -11 showing down-regulation (p < 0.05). Expression of TIMP-1 was not affected by Substance P (p > 0.05). Western blotting confirmed that Substance P up-regulated MMP-1, -2, -3 and -11 and TIMP-2. MMP-1, -3 and -11 and TIMP-2 showed greater up-regulation at the higher Substance P concentration and diminished up-regulation at the lower concentration. MMP-2 was up-regulated to a similar degree at both Substance P concentrations. CONCLUSION: In gingival fibroblast cells, Substance P at the higher concentration (10(-4) m) induced greater up-regulation of MMP-1, -3 and -11 and TIMP-2 expression, but at the lower concentration (10(-9) m) induced diminished up-regulation, which may represent a mechanism for modulating periodontal breakdown.
Assuntos
Gengiva/enzimologia , Metaloproteinases da Matriz/biossíntese , Substância P/fisiologia , Inibidores Teciduais de Metaloproteinases/biossíntese , Western Blotting , Células Cultivadas , Relação Dose-Resposta a Droga , Ativação Enzimática , Fibroblastos/enzimologia , Expressão Gênica , Gengiva/citologia , Humanos , Reação em Cadeia da Polimerase , Estatísticas não Paramétricas , Substância P/administração & dosagem , Substância P/farmacologia , Regulação para CimaRESUMO
This study aimed to investigate the relationship between substance P (SP) and diazepam (DZP) in the modulation of anxiety and memory in rats as evaluated in the elevated T-maze (ETM). For this purpose, in the first experiment, rats were intraperitoneally (i.p.) pretreated with saline or DZP (1mg/kg) and 25min later they were intracerebroventricularly (i.c.v.) injected with PBS or SP (10 pmol). In the second experiment, rats were i.p. pretreated with saline or DZP (1mg/kg) and 25 min later were i.c.v. injected with FK888 (100 pmol, a NK1 antagonist). After 1 min, animals were i.c.v. injected with vehicle (PBS+ethanol 10%) or SP (10 pmol). Our results show that DZP significantly decreased the latency to leave the enclosed arm of the ETM in the test and re-test session, indicating an anxiolytic and an amnesic effect, respectively. Although the central administration of SP did not significantly alter 'per se' the latency to leave the enclosed arm of the ETM in the test and re-test sessions, there was a trend to increase this parameter in the test session (indicating an anxiogenic-like effect). Furthermore, SP was able to reverse, via NK1 receptors, the effect produced by DZP during the test session. Moreover, none of the treatments interfered in the one-way escape behavior recorded in the test or re-test session in the ETM. In conclusion, our results strengthen and extend previous experimental data showing an interaction between the tachykinergic and benzodiazepine-GABA systems in the modulation of anxiety.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/psicologia , Diazepam/farmacologia , Substância P/fisiologia , Animais , Ansiedade/tratamento farmacológico , Aprendizagem da Esquiva/efeitos dos fármacos , Dipeptídeos/farmacologia , Medo/efeitos dos fármacos , Medo/psicologia , Indóis/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Memória/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Ratos , Ratos Wistar , Substância P/antagonistas & inibidoresRESUMO
Substance P (SP) is involved in the pathophysiology of several psychiatric disorders and is considered a central stress neurotransmitter. Endogenous SP does not inhibit the initial extent of the HPA axis response to restraint stress, but reduces the duration of the stress suggesting that SP plays an important role in the transition between acute and chronic stress. Stress hormones can alter metabolic functions in white adipose tissue and liver. The HPA axis is the endocrine pathway that promotes lipolysis elevating free fatty acid levels (FFA) in blood, besides indirectly causing hyperglycemia. In the present study, changes in the blood levels of stress markers in the anxiogenic-like effects of SP, as evaluated on the elevated plus-maze (EPM), were studied in adult male rats. Serum corticosterone was used as the traditional stress marker, while the plasma FFA and glucose were used as alternative anxiety/stress markers. Our findings show: (a) elevated corticosterone levels, confirming the aversive situation induced by SP (behaviorally assessed in the EPM) and indicating SP as a "chemical" stressor; (b) elevated levels of FFA and glucose, indicators of stress-induced mobilization of energy substrates, confirming the stressor effect of SP; (c) FFA levels can be used as an accurate, sensitive and reliable index of acute stress situations, including in the anxiogenic-like effect of SP, with the FFA response being as good as corticosterone as a stress marker in this case; (d) NK1 receptors involvement in the underlying mechanisms of the behavioral and metabolic effects of SP. Finally, our study indicates that some of these physiological variables are positively related to the stressor intensity.
Assuntos
Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Receptores da Neurocinina-1/metabolismo , Estresse Fisiológico/metabolismo , Substância P/fisiologia , Análise de Variância , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Biomarcadores/sangue , Corticosterona/sangue , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Estresse Fisiológico/induzido quimicamente , Substância P/administração & dosagemRESUMO
PURPOSE: The role of substance P, inducible nitric oxide synthase, and cyclooxygenase-1 and 2 on the pathogenesis of cyclophosphamide induced cystitis was investigated in rats. MATERIALS AND METHODS: Sprague-Dawley male rats received 1 of certain treatments, including 1) 0.9 weight per volume saline (0.10 ml/100 gm intraperitoneally), 2) cyclophosphamide (75 mg/kg intraperitoneally), 3) cyclophosphamide plus the NK(1) receptor antagonist Win-51.708 (20 mg/kg intraperitoneally), 4) cyclophosphamide plus the inducible nitric oxide synthase inhibitor S-methylthiourea (20 mg/kg intraperitoneally), 5) cyclophosphamide plus the highly selective cyclooxygenase-2 inhibitor rofecoxib (15 mg/kg intraperitoneally), 6) cyclophosphamide plus the selective cyclooxygenase-2 inhibitor meloxicam (15 mg/kg intraperitoneally), 7) cyclophosphamide plus the nonselective cyclooxygenase inhibitor ketoprofen (20 mg/kg intraperitoneally) or 8) cyclophosphamide plus methylthiourea plus meloxicam. Parameters were evaluated 6 hours after cyclophosphamide administration, including plasma protein extravasation, histological changes, myeloperoxidase and inducible nitric oxide synthase activities in the bladder, plasmatic nitric oxide metabolites and urinary nitric oxide metabolites, and prostaglandin E(2) levels. RESULTS: Cyclophosphamide produced inflammatory and cytotoxic changes in the bladder, accompanied by increased nitric oxide metabolites, urinary prostaglandins, myeloperoxidase and inducible nitric oxide synthase activity. Pretreatment with Win-51.708 and with methylthiourea prevented all of these effects except myeloperoxidase activity, which was only prevented by Win-51.708. All inducible cyclooxygenases were able to prevent prostaglandin synthesis and increases in myeloperoxidase activity. Combined inhibition of inducible nitric oxide synthase and cyclooxygenase-2/cyclooxygenase-1 (methylthiourea plus meloxicam) did not provide any additional protection against bladder damage, increased inducible nitric oxide synthase activity or prostaglandin E(2) synthesis. Additionally, this combination was unable to prevent increased myeloperoxidase activity. CONCLUSIONS: The results of this study suggest that there is crosstalk between nitric oxide and the cyclooxygenase enzyme with cyclooxygenase-1/cyclooxygenase-2 isoforms having an important role in this relationship. Augmented myeloperoxidase activity seems to be associated with NK(1) receptor activation and low levels of nitric oxide with cyclooxygenase-1 having an important role.
Assuntos
Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/fisiologia , Ciclofosfamida/administração & dosagem , Cistite/induzido quimicamente , Cistite/enzimologia , Óxido Nítrico Sintase/fisiologia , Receptores da Neurocinina-1/fisiologia , Substância P/fisiologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Substância P/antagonistas & inibidoresRESUMO
UNLABELLED: Substance P (SP) and neurokinins have been implicated in modulating pain and mood but little is known about their effect on sleep-wake behavior. The purpose of the present study was to examine the possible involvement of SP in sleep-wake mechanisms without activation of painful responses. Electrophysiological recordings of the sleep-wake cycle were conducted in C57BL/6J male mice that had intracerebral ventricular cannula inserted for drug administration. Initially, in order to determine the highest dose of SP that would not induce nociceptive response, 10 animals per group received administration of either SP doses or artificial cerebrospinal fluid (CSF-sham group) through the cannula and were assessed by the hot plate test. The sleep-wake cycle of two other groups of mice was recorded for 24 h before (baseline) and after receiving CSF (n=10) or SP-1 mM (n=11), dose that had been determined in the previous hot plate test. SP interfered with sleep, when compared to baseline and to sham group, by reducing sleep efficiency, increasing latency of sleep and the number of awakening bouts. To examine the reversal of SP effects, eight mice were administered with an NK1 receptor antagonist before SP administration. Prior administration of the NK1 antagonist prevented the disturbances in sleep. CONCLUSIONS: The results suggest that SP produces disturbances in sleep, likely mediated by the NK1 receptor.
Assuntos
Fases do Sono/fisiologia , Transtornos do Sono-Vigília/induzido quimicamente , Substância P/fisiologia , Vigília/fisiologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Fases do Sono/efeitos dos fármacos , Estatísticas não Paramétricas , Substância P/administração & dosagemRESUMO
The origin of the endothelial damage leading to the ischemia-reperfusion injury after lung transplantation has not been elucidated. We postulated that neurotransmitters released during the preservation of the donor lung might explain this vascular derangement. Thus, in isolated rabbit lungs preserved over 24 hours, we evaluated the release of acetylcholine (ACh) and substance P (SP), the activity of their major degrading enzymes, acetylcholinesterase (AChE) and neutral endopeptidase (NEP), and changes in the capillary permeability. Both neurotransmitters showed the highest release rate in the first 15 minutes, followed by a sharp exponential decrement at 1, 6, 12 and 24 hours. AChE and NEP activities showed no variation at these time intervals. Basal capillary permeability significantly increased (P<0.01) after 24 hours preservation with saline. This increased permeability was avoided (P<0.01) by the SP fragment 4-11 (an SP receptors antagonist), but not by atropine. These results suggest for the first time a pathogenic role of SP in the ischemia-reperfusion injury, and thus the potential usefulness of SP antagonists as additives in the lung preservation solutions should be explored.
Assuntos
Pulmão , Traumatismo por Reperfusão/fisiopatologia , Substância P/fisiologia , Animais , Atropina/farmacologia , Técnicas In Vitro , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Pulmão/fisiopatologia , Masculino , Modelos Animais , Preservação de Órgãos/métodos , CoelhosRESUMO
Adjuvant-induced arthritis (AA) is thought to be a model for experimental chronic stress that has as main features decreased adrenocorticotropin hormone (ACTH) plasma levels and a rise in median eminence content of arginine vasopressin (AVP) due to the activity of substance P. In experimental allergic encephalomyelitis (EAE), another chronic stress model, the role of substance P action is not clear. In this paper we tried to clarify the role of substance P in Lewis rats, which are susceptible to this disease. EAE was induced using myelin basic protein plus complete Freund's adjuvant injected into the hind limbs. One day later injections of an antagonist to substance P (RP 67580), saline, and substance P were administered daily for 12-14 days through a stainless steel cannula into the lateral ventricle of the brain, and then the rats were killed. The rats were divided into groups of controls, sham, diseased controls (no intracerebroventricular injections) and EAE (injected intracerebroventricularly). Plasma was used for the quantification of ACTH and corticosterone but not AVP which was assayed in hypothalamic median eminence extracts. In noninjected diseased rats the plasma levels of ACTH and corticosterone were significantly higher than in noninjected control rats, whereas the AVP concentrations in the median eminence were unchanged. The substance P antagonist did not affect the levels of these hormones in plasma or the median eminence. Substance P decreased the plasma levels of ACTH and corticosterone but did not increase the median eminence content of vasopressin. Administration of the antagonist 30 min before an equivalent dose of substance P increased the plasma levels of the two hormones, but did not change the content of AVP. Based on the lack of response to the antagonist RP 67580 we suggest that the substance P has different roles in EAE and AA at least in the later stages of EAE (after 11 days of immunization).
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Substância P/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Arginina Vasopressina/sangue , Peso Corporal , Doença Crônica , Corticosterona/sangue , Encefalomielite Autoimune Experimental/patologia , Indóis , Isoindóis , Masculino , Mesencéfalo/patologia , Neuroimunomodulação/fisiologia , Antagonistas dos Receptores de Neurocinina-1 , Ratos , Ratos Endogâmicos Lew , Estresse Fisiológico/imunologia , Substância P/antagonistas & inibidores , Substância P/farmacologiaRESUMO
Immunoreactive substance P was investigated in turtle lumbar spinal cord after sciatic nerve transection. In control animals immunoreactive fibers were densest in synaptic field Ia, where the longest axons invaded synaptic field III. Positive neuronal bodies were identified in the lateral column of the dorsal horn and substance P immunoreactive varicosities were observed in the ventral horn, in close relationship with presumed motoneurons. Other varicosities appeared in the lateral and anterior funiculi. After axotomy, substance P immunoreactive fibers were reduced slightly on the side of the lesion, which was located in long fibers that invaded synaptic field III and in the varicosities of the lateral and anterior funiculus. The changes were observed at 7 days after axonal injury and persisted at 15, 30, 60 and 90 days after the lesion. These findings show that turtles should be considered as a model to study the role of substance P in peripheral axonal injury, since the distribution and temporal changes of substance P were similar to those found in mammals.