RESUMO
The periaqueductal gray matter (PAG) is an essential structure involved in the elaboration of defensive responses, such as when facing predators and conspecific aggressors. Using a prey vs predator paradigm, we aimed to evaluate the PAG activation pattern evoked by unconditioned and conditioned fear situations. Adult male guinea pigs were confronted either by a Boa constrictor constrictor wild snake or by the aversive experimental context. After the behavioral test, the rodents were euthanized and the brain prepared for immunohistochemistry for Fos protein identification in different PAG columns. Although Fos-protein-labeled neurons were found in different PAG columns after both unconditioned and conditioned fear situations at the caudal level of the PAG, we found greater activation of the lateral column compared to the ventrolateral and dorsomedial columns after predator exposure. Moreover, the lateral column of the PAG showed higher Fos-labeled cells at the caudal level compared to the same area at the rostral level. The present results suggested that there are different activation patterns of PAG columns during unconditioned and conditioned fear in guinea pigs. It is possible to hypothesize that the recruitment of specific PAG columns depended on the nature of the threatening stimulus.
Assuntos
Boidae , Substância Cinzenta Periaquedutal , Animais , Medo/fisiologia , Cobaias , Imuno-Histoquímica , Masculino , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/metabolismoRESUMO
The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test and mechanical allodynia (by von Frey test). The effect of blockade of synapses with cobalt chloride (CoCl2), and the treatment of the PrL cortex with cannabidiol (CBD), the CB1 receptor antagonist AM251 and the 5-HT1A receptor antagonist WAY-100635 were also investigated. Our results showed that CoCl2 decreased the time spent immobile during the FS test but did not alter mechanical allodynia. CBD (at 15, 30 and 60 nmol) in the PrL cortex also decreased the frequency and duration of immobility; however, only the dose of 30 nmol of CBD attenuated mechanical allodynia in rats with chronic NP. AM251 and WAY-100635 in the PrL cortex attenuated the antidepressive and analgesic effect caused by CBD but did not alter the immobility and the mechanical allodynia when administered alone. These data show that the PrL cortex is part of the neural substrate underlying the comorbidity between NP and depression. Also, the previous blockade of CB1 cannabinoid receptors and 5-HT1A serotonergic receptors in the PrL cortex attenuated the antidepressive and analgesics effect of the CBD. They also suggest that CBD could be a potential medicine for the treatment of depressive and pain symptoms in patients with chronic NP/depression comorbidity.
Assuntos
Canabidiol/farmacologia , Depressão/tratamento farmacológico , Neuralgia/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Receptor CB1 de Canabinoide/agonistas , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Animais , Canabidiol/administração & dosagem , Doença Crônica , Cobalto , Depressão/complicações , Sistema Límbico , Microinjeções , Neuralgia/complicações , Piperazinas/uso terapêutico , Piperidinas/farmacologia , Pirazóis/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Wistar , Ciática/tratamento farmacológico , Ciática/patologia , Antagonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Natação/psicologia , Sinapses/efeitos dos fármacosRESUMO
The neurochemical mechanisms underlying neuropathic pain (NP) are related to peripheral and central sensitization caused by the release of inflammatory mediators in the peripheral damaged tissue and ectopic discharges from the injured nerve, leading to a hyperexcitable state of spinal dorsal horn neurons. The aim of this work was to clarify the role played by cyclooxygenase (COX) in the lesioned peripheral nerve in the development and maintenance of NP by evaluating at which moment the non-steroidal anti-inflammatory drug indomethacin, a non-selective COX inhibitor, attenuated mechanical allodynia after placing one loose ligature around the nervus ischiadicus, an adaptation of Bennett and Xie's model in rodents. NP was induced in male Wistar rats by subjecting them to chronic constriction injury (CCI) of the nervus ischiadicus, placing one loose ligature around the peripheral nerve, and a sham surgery (without CCI) was used as control. Indomethacin (2 mg/kg) or vehicle was intraperitoneally and acutely administered in each group of rats and at different time windows (1, 2, 4, 7, 14, 21, and 28 days) after the CCI or sham surgical procedures, followed by von Frey's test for 30 min. The data showed that indomethacin decreased the mechanical allodynia threshold of rats on the first, second, and fourth days after CCI (P<0.05). These findings suggested that inflammatory mechanisms are involved in the induction of NP and that COX-1 and COX-2 are involved in the induction but not in the maintenance of NP.
Assuntos
Indometacina/administração & dosagem , Neuralgia/tratamento farmacológico , Medição da Dor , Nervo Isquiático/lesões , Animais , Constrição , Modelos Animais de Doenças , Masculino , Neuralgia/etiologia , Limiar da Dor , Ratos , Ratos Sprague-Dawley , Ratos WistarAssuntos
Úlcera Duodenal/etiologia , Embolização Terapêutica/efeitos adversos , Neoplasias Hepáticas/radioterapia , Lesões por Radiação/etiologia , Úlcera Gástrica/tratamento farmacológico , Radioisótopos de Ítrio/efeitos adversos , Úlcera Duodenal/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Radioisótopos de Ítrio/uso terapêuticoRESUMO
Inflammation and pain are major clinical burdens contributing to multiple disorders and limiting the quality of life of patients. We previously reported that brain electrical stimulation can attenuate joint inflammation in experimental arthritis. Here, we report that non-aversive electrical stimulation of the locus coeruleus (LC), the paraventricular hypothalamic nucleus (PVN) or the ventrolateral column of the periaqueductal gray matter (vlPAG) decreases thermal pain sensitivity, knee inflammation and synovial neutrophilic infiltration in rats with intra-articular zymosan. We also analyzed the modulation of pain and inflammation during aversive neuronal stimulation, which produces defensive behavioral responses such as freezing immobility to avoid predator detection. Electrical stimulation with higher intensity to induce freezing immobility in rats further reduces pain but not inflammation. However, tonic immobility further reduces pain, knee inflammation and synovial neutrophilic infiltration in guinea pigs. The duration of the tonic immobility increases the control of pain and inflammation. These results reveal survival behavioral and neuromodulatory mechanisms conserved in different species to control pain and inflammation in aversive life-threatening conditions. Our results also suggest that activation of the LC, PVN, or vlPAG by non-invasive methods, such as physical exercise, meditation, psychological interventions or placebo treatments may reduce pain and joint inflammation in arthritis without inducing motor or behavioral alterations.
Assuntos
Encéfalo/fisiologia , Estimulação Elétrica/métodos , Inflamação/fisiopatologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Animais , Reação de Congelamento Cataléptica/fisiologia , Cobaias , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND AND PURPOSE: In this work, a neuroactive peptide from the venom of the neotropical wasp Polybia occidentalis was isolated and its anti-nociceptive effects were characterized in well-established pain induction models. EXPERIMENTAL APPROACH: Wasp venom was analysed by reverse-phase HPLC and fractions screened for anti-nociceptive activity. The structure of the most active fraction was identified by electron-spray mass spectrometry (ESI-MS/MS) and it was further assessed in two tests of anti-nociceptive activity in rats: the hot plate and tail flick tests. KEY RESULTS: The most active fraction contained a peptide whose structure was Arg-Pro-Pro-Gly-Phe-Thr-Pro-Phe-Arg-OH, which corresponds to that of Thr(6)-BK, a bradykinin analogue. This peptide was given by i.c.v. injection to rats. In the tail flick test, Thr(6)-BK induced anti-nociceptive effects, approximately twice as potent as either morphine or bradykinin also given i.c.v. The anti-nociceptive activity of Thr(6)-BK peaked at 30 min after injection and persisted for 2 h, longer than bradykinin. The primary mode of action of Thr(6)-BK involved the activation of B(2) bradykinin receptors, as anti-nociceptive effects of Thr(6)-BK were antagonized by a selective B(2) receptor antagonist. CONCLUSIONS AND IMPLICATIONS: Our data indicate that Thr(6)-BK acts through B(2) bradykinin receptors in the mammalian CNS, evoking antinociceptive behaviour. This activity is remarkably different from that of bradykinin, despite the structural similarities between both peptides. In addition, due to the increased metabolic stability of Thr(6)-BK, relative to that of bradykinin, this peptide could provide a novel tool in the investigation of kinin pathways involved with pain.
Assuntos
Analgésicos/farmacologia , Bradicinina/análogos & derivados , Dor/tratamento farmacológico , Venenos de Vespas/química , Analgésicos/administração & dosagem , Animais , Bradicinina/administração & dosagem , Bradicinina/isolamento & purificação , Bradicinina/farmacologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Sistema Calicreína-Cinina , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Dor/fisiopatologia , Medição da Dor , Ratos , Ratos Wistar , Receptor B2 da Bradicinina/efeitos dos fármacos , Receptor B2 da Bradicinina/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
The periaqueductal gray matter (PAG) is an essential structure involved in the elaboration of defensive responses, such as when facing predators and conspecific aggressors. Using a prey vs predator paradigm, we aimed to evaluate the PAG activation pattern evoked by unconditioned and conditioned fear situations. Adult male guinea pigs were confronted either by a Boa constrictor constrictor wild snake or by the aversive experimental context. After the behavioral test, the rodents were euthanized and the brain prepared for immunohistochemistry for Fos protein identification in different PAG columns. Although Fos-protein-labeled neurons were found in different PAG columns after both unconditioned and conditioned fear situations at the caudal level of the PAG, we found greater activation of the lateral column compared to the ventrolateral and dorsomedial columns after predator exposure. Moreover, the lateral column of the PAG showed higher Fos-labeled cells at the caudal level compared to the same area at the rostral level. The present results suggested that there are different activation patterns of PAG columns during unconditioned and conditioned fear in guinea pigs. It is possible to hypothesize that the recruitment of specific PAG columns depended on the nature of the threatening stimulus.
RESUMO
INTRODUCTION: Breast radial scar (RS) management remains controversial. The need for surgical excision is supported by the concern of an associated high-grade lesion missed in the biopsy. The aim of this study was to assess histologic upgrade rate after a percutaneous biopsy, to determine if vacuum assisted biopsy prevents the need for subsequent RS surgical resection and to evaluate the upgrade risk factors. PATIENTS AND METHODS: This was a uni-institutional retrospective study of consecutive patients with RS histologically diagnosed from January 2010 to December 2015. RESULTS: A total of 113 cases of RS were diagnosed. We verify that there was a histologic upgrade in 22 (19.5%) cases. The upgrade risk factors were the type of biopsy performed, the presence of atypia, the presence of calcifications and the number of fragments obtained in the biopsy (p < 0.05). The biopsy type was vacuum assisted in 25 (22.1%). The upgrade rate in the vacuum assisted biopsy group was 4.0%, whereas in the standard core needle biopsy group was 23,9% (p = 0.041). DISCUSSION AND CONCLUSION: We demonstrated that the risk of upgrade after a RS diagnosis depends on the type of biopsy performed, the presence of atypia, the presence of calcifications and the number of fragments obtained. When a standard core biopsy is performed the risk of upgrade and malignancy is not negligible, and surgery is indicated. When the biopsy is vacuum assisted, the risk of upgrade and malignancy is significantly decreased and so the indication for excisional biopsy seems not to be so imperative.
Assuntos
Biópsia por Agulha/métodos , Doenças Mamárias/patologia , Doenças Mamárias/cirurgia , Mama/patologia , Adolescente , Adulto , Idoso , Doenças Mamárias/diagnóstico por imagem , Neoplasias da Mama/patologia , Calcinose/patologia , Estudos de Casos e Controles , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Vácuo , Adulto JovemRESUMO
The inferior colliculus (IC), a midbrain structure that processes acoustic information of aversive nature, is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Previous evidence relating the IC to motor behavior shows that glutamatergic and GABAergic mechanisms in the IC exert influence on systemic haloperidol-induced catalepsy. There is substantial evidence supporting a role played by the endocannabinoid system as a modulator of the glutamatergic neurotransmission, as well as the dopaminergic activity in the basal nuclei and therefore it may be considered as a potential pharmacological target for the treatment of movement disorders. The present study evaluated if the endocannabinoid system in the IC plays a role in the elaboration of systemic haloperidol-induced catalepsy. Male Wistar rats received intracollicular microinjection of either the endogenous cannabinoid anandamide (AEA) at different concentrations (5, 50 or 100pmol/0.2µl), the CB1 cannabinoid receptor antagonist AM251 at 50, 100 or 200pmol/0.2µl or vehicle, followed by intraperitoneal (IP) administration of either haloperidol at 0.5 or 1mg/kg or physiological saline. Systemic injection of haloperidol at both doses (0.5 or 1mg/kg, IP) produced a cataleptic state, compared to vehicle/physiological saline-treated group, lasting 30 and 50min after systemic administration of the dopaminergic receptors non-selective antagonist. The midbrain microinjection of AEA at 50pmol/0.2µl increased the latency for stepping down from the horizontal bar after systemic administration of haloperidol. Moreover, the intracollicular administration of AEA at 50pmol/0.2µl was able to increase the duration of catalepsy as compared to AEA at 100pmol/0.2-µl-treated group. Intracollicular pretreatment with AM251 at the intermediate concentration (100pmol/0.2µl) was able to decrease the duration of catalepsy after systemic administration of haloperidol. However, neither the intracollicular microinjection of AM251 at the lowest (50pmol/0.2µl) nor at the highest (200pmol/0.2µl) concentration was able to block the systemic haloperidol-induced catalepsy. Furthermore, the intracollicular administration of AM251 at 100pmol/0.2µl was able to decrease the duration of catalepsy as compared to AM251 at 50pmol/0.2µl- and AM251 at 200pmol/0.2-µl-treated group. The latency for stepping down from the horizontal bar - induced by haloperidol administration - was decreased when microinjection of AEA at 50pmol/0.2µl was preceded with blockade of CB1 receptor with AM251 (100pmol/0.2µl). Our results strengthen the involvement of CB1-signaled endocannabinoid mechanisms of the IC in the neuromodulation of catalepsy induced by systemic administration of the dopaminergic receptors non-selective antagonist haloperidol.
Assuntos
Ácidos Araquidônicos/farmacologia , Catalepsia/tratamento farmacológico , Antagonistas de Dopamina/farmacologia , Endocanabinoides/farmacologia , Haloperidol/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Animais , Canabinoides/farmacologia , Catalepsia/induzido quimicamente , Colículos Inferiores/efeitos dos fármacos , Masculino , Ratos Wistar , Receptor CB1 de Canabinoide/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
In the present study, the functional neuroanatomy of nigrotectal-tectonigral pathways as well as the effects of central administration of opioid antagonists on aversive stimuli-induced responses elicited by electrical stimulation of the midbrain tectum were determined. Central microinjections of naloxonazine, a selective mu(1)-opiod receptor antagonist, in the mesencephalic tectum (MT) caused a significant increase in the escape thresholds elicited by local electrical stimulation. Furthermore, either naltrexone or naloxonazine microinjected in the substantia nigra, pars reticulata (SNpr), caused a significant increase in the defensive thresholds elicited by electrical stimulation of the continuum comprised by dorsolateral aspects of the periaqueductal gray matter (dlPAG) and deep layers of the superior colliculus (dlSC), as compared with controls. These findings suggest an opioid modulation of GABAergic inhibitory inputs controlling the defensive behavior elicited by MT stimulation, in cranial aspects. In fact, iontophoretic microinjections of the neurotracer biodextran into the SNpr, a mesencephalic structure rich in GABA-containing neurons, show outputs to neural substrate of the dlSC/dlPAG involved with the generation and organization of fear- and panic-like reactions. Neurochemical lesion of the nigrotectal pathways increased the sensitivity of the MT to electrical (at alertness, freezing and escape thresholds) and chemical (blockade of GABA(A) receptors) stimulation, suggesting a tonic modulatory effect of the nigrotectal GABAergic outputs on the neural networks of the MT involved with the organization of the defensive behavior and panic-like reactions. Labeled neurons of the midbrain tectum send inputs with varicosities to ipsi and contralateral dlSC/dlPAG and ipsilateral substantia nigra, pars reticulata and compacta, in which the anterograde and retrograde tracing from a single injection indicates that the substantia nigra has reciprocal connections with the dlSC/dlPAG featuring close axo-somatic and axo-dendritic appositions in both locations. In addition, ultrastructural approaches show inhibitory axo-axonic synapses in MT and inhibitory axo-somatic/axo-axonic synapses in the SNpr. These findings, in addition to the psychopharmacological evidence for the interaction between opioid and GABAergic mechanisms in the cranial aspects of the MT as well as in the mesencephalic tegmentum, offer a neuroanatomical basis of a pre-synaptic opioid inhibition of GABAergic nigrotectal neurons modulating fear in defensive behavior-related structures of the cranial mesencephalon, in a short link, and through a major neural circuit, also in GABA-containing perikarya and axons of nigrotectal neurons.
Assuntos
Mesencéfalo/citologia , Mesencéfalo/metabolismo , Pânico/fisiologia , Receptores de GABA-A/metabolismo , Receptores Opioides mu/metabolismo , Animais , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Estimulação Elétrica , Antagonistas GABAérgicos/farmacologia , Masculino , Mesencéfalo/efeitos dos fármacos , Microscopia Eletrônica , Naloxona/análogos & derivados , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Vias Neurais , Neurônios/metabolismo , Neurônios/ultraestrutura , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Ratos , Ratos Wistar , Receptores Opioides mu/antagonistas & inibidores , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Teto do Mesencéfalo/citologia , Teto do Mesencéfalo/efeitos dos fármacos , Teto do Mesencéfalo/metabolismoRESUMO
RATIONALE: Sweet-substance-induced analgesia has been widely studied, and the investigation of the neurotransmitters involved in this antinociceptive process is an important way for understanding the involvement of the neural system controlling this kind of antinociception. OBJECTIVE: The aim of this study was to investigate the involvement of opioid and monoaminergic systems in sweet-substance-induced analgesia. METHODS: The present work was carried out in an animal model with the aim of investigating whether acute (24 h) or chronic (14 days) intake of a sweet substance, such as sucrose (250 g/l), is followed by antinociception. Tail withdrawal latencies in the tail-flick test were measured before and immediately after this treatment. Immediately after the recording of baseline values, independent groups of rats were submitted to sucrose or tap-water intake and, after chronic treatment, they were pretreated with intraperitoneal administration of (1) naltrexone at 0.5, 1, 2 or 3 mg/kg; (2) naloxonazine at 5, 10, 20 or 30 mg/kg; (3) methysergide at 0.5, 1, 2 or 3 mg/kg; (4) ketanserin at 0.5, 1, 2 or 3 mg/kg; or (5) physiological saline. RESULTS: Naltrexone and methysergide at two major doses decreased sweet-substance-induced analgesia after chronic intake of a sweet substance. These effects were corroborated by peripheral administration of naloxonazine and ketanserin. CONCLUSIONS: These data give further evidence for: (a) the involvement of endogenous opioids and a mu1-opioid receptor in the sweet-substance-induced antinociception; (b) the involvement of monoamines and 5HT2A serotonergic/alpha1-noradrenergic receptors in the central regulation of the sweet-substance-produced analgesia.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacologia , Analgesia , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores Opioides mu/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Paladar/fisiologia , Animais , Relação Dose-Resposta a Droga , Ketanserina/farmacologia , Masculino , Metisergida/farmacologia , Naloxona/análogos & derivados , Naloxona/farmacologia , Naltrexona/farmacologia , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Sacarose/farmacologiaRESUMO
Several lines of evidence indicate that the dorsal hippocampus (dH) and medial prefrontal cortex (mPFC) regulate contextual fear conditioning. The prelimbic (PrL), infralimbic (IL) and the anterior cingulate cortex (ACC) subregions of the mPFC likely play distinct roles in the expression of fear. Moreover, studies have highlighted the role of serotonin (5-hydroxytryptamine, 5-HT)- and γ-aminobutyric acid (GABA)-mediated mechanisms in the modulation of innate fear in the mPFC. The present study characterized dH-mPFC pathways and investigated the role of serotonergic and GABAergic mechanisms of the PrL, IL and ACC-area 1 (Cg1) in the elaboration of contextual fear conditioning using fear-potentiated startle (FPS) and freezing behavior in Rattus norvegicus. The results of neurotracing with microinjections of biotinylated dextran amine into the dH revealed a neural link of the dH with the PrL and ACC. Intra-PrL injections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and the GABAA receptor-selective agonist muscimol reduced contextual FPS and freezing responses. Intra-Cg1 injections of muscimol but not 8-OH-DPAT decreased FPS and freezing responses. However, neither intra-IL injections of a 5-HT1A agonist nor of a GABAA agonist affected these defensive responses. Labeled neuronal fibers from the dH reached the superficial layers of the PrL cortex and spread to the inner layers of PrL and Cg1 cortices, supporting the pharmacological findings. The present results confirmed the involvement of PrL and Cg1 in the expression of FPS and freezing responses to aversive conditions. In addition, PrL serotoninergic mechanisms play a key role in contextual fear conditioning. This study suggests that PrL, IL and Cg1 distinctively contribute to the modulation of contextual fear conditioning.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Biotina/análogos & derivados , Condicionamento Psicológico/fisiologia , Dextranos , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Lobo Límbico/anatomia & histologia , Lobo Límbico/efeitos dos fármacos , Lobo Límbico/fisiologia , Masculino , Muscimol/farmacologia , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Marcadores do Trato Nervoso , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/fisiologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de GABA-A/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
The substantia nigra pars reticulata (SNpr) is rich in γ-aminobutyric acid (GABA)-ergic neurons and connected to the mesencephalic tectum (MT) structures, such as the superior colliculus and dorsal periaqueductal gray matter. The SNpr presents a high density of cannabinoid receptors (CBRs), suggesting a possible regulatory role that is played by endocannabinoids (eCBs) in the ventral mesencephalon. The present study investigated the involvement of SNpr eCB mechanisms in nigrotectal pathways in the expression of defensive behavior associated with instinctive fear and panic reactions in mice that are confronted with the venomous Viperidae snake Bothrops alternatus. The localization of CB1 receptors (CB1RS) and synaptophysin glycoprotein in the SNpr was also evaluated. Administration of the GABAA receptor antagonist bicuculline in the MT increased defensive responses to the snake that are related to panic, such as freezing and non-oriented escape reactions, sometimes toward the snake itself. Mice that were pretreated with anandamide (5 or 50pmol) in the SNpr, followed by an injection of physiological saline or bicuculline in the MT, exhibited significant decreases in the expression of alertness, freezing, and escape responses. Immunofluorescence showed the presence of fibers that were rich in CB1RS and synaptophysin in the SNpr, indicating that these receptors appear to be located mainly in presynaptic terminals in the striatonigral pathway. These findings suggest that eCB mechanisms in the SNpr facilitate the activity of nigrotectal GABAergic pathways, modulating the activity of striatonigral links during the elaboration and organization of innate fear and panic-like responses in threatening situations.
Assuntos
Endocanabinoides/metabolismo , Medo/fisiologia , Parte Compacta da Substância Negra/fisiologia , Transdução de Sinais/fisiologia , Teto do Mesencéfalo/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Ácidos Araquidônicos/farmacologia , Bicuculina/farmacologia , Venenos de Crotalídeos , Endocanabinoides/farmacologia , Reação de Fuga/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Lateralidade Funcional , Antagonistas de Receptores de GABA-A/farmacologia , Resposta de Imobilidade Tônica/efeitos dos fármacos , Resposta de Imobilidade Tônica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinaptofisina/metabolismo , ViperidaeRESUMO
The neurochemical mechanisms underlying neuropathic pain (NP) are related to peripheral and central sensitization caused by the release of inflammatory mediators in the peripheral damaged tissue and ectopic discharges from the injured nerve, leading to a hyperexcitable state of spinal dorsal horn neurons. The aim of this work was to clarify the role played by cyclooxygenase (COX) in the lesioned peripheral nerve in the development and maintenance of NP by evaluating at which moment the non-steroidal anti-inflammatory drug indomethacin, a non-selective COX inhibitor, attenuated mechanical allodynia after placing one loose ligature around the nervus ischiadicus, an adaptation of Bennett and Xie's model in rodents. NP was induced in male Wistar rats by subjecting them to chronic constriction injury (CCI) of the nervus ischiadicus, placing one loose ligature around the peripheral nerve, and a sham surgery (without CCI) was used as control. Indomethacin (2 mg/kg) or vehicle was intraperitoneally and acutely administered in each group of rats and at different time windows (1, 2, 4, 7, 14, 21, and 28 days) after the CCI or sham surgical procedures, followed by von Frey's test for 30 min. The data showed that indomethacin decreased the mechanical allodynia threshold of rats on the first, second, and fourth days after CCI (P<0.05). These findings suggested that inflammatory mechanisms are involved in the induction of NP and that COX-1 and COX-2 are involved in the induction but not in the maintenance of NP.
Assuntos
Animais , Masculino , Ratos , Nervo Isquiático/lesões , Medição da Dor , Indometacina/administração & dosagem , Neuralgia/tratamento farmacológico , Ratos Wistar , Ratos Sprague-Dawley , Limiar da Dor , Constrição , Modelos Animais de Doenças , Neuralgia/etiologiaRESUMO
Electrical stimulation of the mesencephalic tectum elicits behavioral and autonomic responses similar to those following peripheral noxious stimulation. Benzodiazepine and opioid compounds attenuate escape behavior induced by electrical stimulation of the dorsal periaqueductal gray (PAG) and deep layers of the superior colliculus (SC). The present study determines if microinjections of midazolam and morphine applied to these PAG-SC sites affect both responsiveness to peripheral noxious stimulation and to aversive PAG-SC stimulation. Both aversive brain stimulation or foot-shocks applied at threshold intensities caused running or jumps concomitant with increases in mean arterial blood pressure (MBP) and heart rate (HR). Microinjection of both drugs attenuated the behavioral reaction and increases in MBP and HR induced by mesencephalic tectum stimulation, while attenuating only the increase in heart rate induced by peripheral painful stimulation. These results suggest that the neural substrates of the behavioral and autonomic effects of stimulating the mesencephalic tectum and peripheral nociceptors are different although they may partially overlap.
Assuntos
Sistema Nervoso Central/fisiologia , Midazolam/farmacologia , Morfina/farmacologia , Nervos Periféricos/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Estimulação Elétrica , Eletrodos , Masculino , Microinjeções , Midazolam/administração & dosagem , Morfina/administração & dosagem , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/fisiologia , Nervos Periféricos/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Colículos Superiores/anatomia & histologia , Colículos Superiores/fisiologiaRESUMO
It has been shown that the gradual increase in the intensity of electrical stimulation of the dorsal periaqueductal gray (DPAG), deep layers of the superior colliculus (DLSC) and inferior colliculus of rats induces, in a progressive manner, characteristic aversive responses such as arousal, freezing, and escape behavior. The DPAG-DLSC together with the periventricular gray substance of the diencephalon, amygdala and the inferior colliculus, constitute the neural substrate of aversion in the brain. In general, the behavioral responses induced by midbrain tectum stimulation are accompanied by increases in the mean arterial blood pressure, heart rate, and respiration. Both the behavioral and autonomic consequences of electrical stimulation of the mesencephalic tectum have been shown to be attenuated by minor tranquilizers, probably through enhancement of GABAergic neurotransmission. Besides GABAergic mechanisms several lines of evidence have clearly implicated opioid, serotonergic, and excitatory amino acids-mediated mechanisms in the control of the neural substrates commanding defensive behavior in the brain aversive system.
Assuntos
Agressão/fisiologia , Teto do Mesencéfalo/fisiologia , Animais , Serotonina/fisiologiaRESUMO
Several studies have shown that the anterior pretectal nucleus (APtN) is involved in descending inhibitory pathways that control noxious inputs to the spinal cord and that it may participate in the normal physiological response to noxious stimulation. Among other brain regions known to send inputs to the APtN, the dorsal column nuclei (DCN), pedunculopontine tegmental nucleus (PPTg), deep mesencephalon (DpMe), and dorsal raphe nucleus (DRN) are structures also known to be involved in antinociception. In the present study, the effects of stimulating these structures on the latency of the tail withdrawal reflex from noxious heating of the skin (tail flick test) were examined in rats in which saline or hyperbaric lidocaine (5%) was previously microinjected into the APtN. Brief stimulation of the PPTg, DpMe or DRN, but not the DCN, strongly depressed the tail flick reflex. The antinociceptive effect of stimulating the DRN, but not the PPTg or DpMe was significantly reduced, but not abolished, by the prior administration of the local anaesthetic into the APtN. The antinociception induced by stimulation of the PPTg or DpMe, therefore, is unlikely to depend on connections between these structures and the APtN. Similar inhibition of the effect of stimulating the DRN was obtained from rats previously microinjected with naloxone (2.7 nmol) or methysergide (2 nmol) into the APtN. Strongly labelled cells were identified in the DRN following microinjection of the fluorescent tracer Fast Blue into the APtN. These results indicate that the APtN may participate as a relay station through which the DRN partly modulates spinal nociceptive messages. In addition, they also indicate that endogenous opioid and serotonin can participate as neuromodulators of the DRN-APtN connection.
Assuntos
Mesencéfalo/fisiologia , Nociceptores/fisiologia , Dor/fisiopatologia , Núcleos da Rafe/fisiologia , Vias Aferentes , Amidinas , Anestésicos Locais/farmacologia , Animais , Estimulação Elétrica , Corantes Fluorescentes , Lidocaína/farmacologia , Masculino , Mesencéfalo/citologia , Metisergida/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Medição da Dor , Núcleos da Rafe/citologia , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , CaudaRESUMO
The effects of central administration of opioid antagonists on the aversive responses elicited by electrical (at the freezing and escape thresholds) or chemical stimulation (crossings, rearings, turnings and jumps, induced by microinjections of bicuculline) of the midbrain tectum were determined. Central microinjections of naloxone and naltrexone in the mesencephalic tectum caused a significant increase in the freezing and escape thresholds elicited by electrical midbrain tectum stimulation. Furthermore, both opioid antagonists caused a significant decrease in the mean incidence of aversive behavioral responses induced by microinjections of bicuculline in the deep layers of the superior colliculus (DLSC) and in dorsal aspects of the periaqueductal gray matter (DPAG), as compared with controls. These findings suggest an opioid modulation of the GABAergic inhibitory inputs controlling the aversive behavior elicited by midbrain tectum stimulation. In fact, immunohistochemical evidence suggests that the dorsal mesencephalon is rich in beta-endorphin-containing neurons and fibers with varicosities. Iontophoretical microinjections of the neurotracer biodextran in the substantia nigra, pars reticulata (SNpr), show nigro-tectal pathways connecting SNpr with the same neural substrate of the DPAG rich in neuronal cells immunoreactive for opioid peptides. Labeled neurons of the DLSC and periaqueductal gray matter send inputs with varsicosities to ipsi- and contralateral DPAG and ipsilateral SNpr. These findings, in addition to the psychopharmacological evidence for the interaction between opioid and GABAergic mechanisms, offer a neuroanatomical basis of a possible presynaptic opioid inhibition of GABAergic nigro-tectal neurons modulating the fear in aversive structures of the cranial mesencephalon, in a short link, and maybe through a major neural circuit, also in GABA-containing perikarya of nigro-tectal neurons.
Assuntos
Agressão/fisiologia , Medo/fisiologia , Vias Neurais/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores de GABA/fisiologia , Receptores Opioides/fisiologia , Colículos Superiores/fisiologia , Agressão/efeitos dos fármacos , Animais , Bicuculina/farmacologia , Estimulação Elétrica , Medo/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Imuno-Histoquímica , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/fisiologia , Microinjeções , Naloxona/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de GABA/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Estimulação Química , Colículos Superiores/anatomia & histologia , Colículos Superiores/efeitos dos fármacosRESUMO
RATIONALE: Electrical or chemical stimulation of some structures of the midbrain tectum, such as the dorsal periaqueductal gray matter, deep layers of the superior colliculus and inferior colliculus induce fear and flight behavior. These structures constitute the main neural substrates commanding defensive behavior in brainstem. Many neurotransmitters are implicated in the modulation of aversion at the mesencephalic level. OBJECTIVE: The aim of this work is to investigate the involvement of opioid mechanisms in modulation of defensive behavior in dorsal mesencephalon. METHODS: Male Wistar rats were fixed in a stereotaxic frame and a chemitrode was implanted into the midbrain, targeted to the central nucleus of the inferior colliculus. In the present study, the effects of peripheral and central administration of naloxone, naltrexone or naloxonazine on aversive thresholds (freezing and escape reactions) elicited by electrical stimulation of the midbrain tectum were determined. RESULTS: Peripherally and centrally administered naloxone caused a significant increase in the freezing and flight thresholds elicited by electrical stimulation of the aversive substrates of the inferior colliculus. These effects were confirmed by peripheral and central administration of naltrexone and by microinjections of naloxonazine in inferior colliculus. CONCLUSIONS: These findings suggest that endogenous opioids are involved in the modulation of the aversive behavior elicited by midbrain tectum stimulation. Since microinjections of naloxonazine in the central nucleus of the inferior colliculus caused a significant increase in the aversive thresholds elicited by electrical stimulation of this structure, it is possible that micro1 opioid receptor located in this nucleus may be critically implicated in this neural circuitry.