RESUMO
GPR55 is a receptor expressed in several central nervous system areas, including the periaqueductal gray (PAG). Current knowledge of GPR55 physiology in PAG only covers pain integration, but it is involved in other actions such as anxiety, panic, motivated behaviors, and alcohol intake. In the present study, juvenile male Wistar rats were unexposed (alcohol-naïve group; A-naïve) or exposed to alcohol for 5 weeks (alcohol-pre-exposed group; A-pre-exposed). Posteriorly, animals received intra dorsal-PAG (D-PAG) injections of vehicle (10% DMSO), LPI (1 nmol/0.5 µl) and ML-193 (1 nmol/0.5 µl, a selective GPR55 antagonist). Finally, defensive burying behavior (DBB) paradigm and alcohol preference were evaluated. Compared to the A-naïve group, the A-pre-exposed vehicle group had higher (p < 0.05): (i) time of immobility; (ii) latency to and duration of burying; and (iii) alcohol consumption. In both groups (i.e., A-naïve and A-pre-exposed) treatment with LPI: (i) decreased duration of burying (p < 0.05); (ii) suppressed time of immobility; and (iii) increased alcohol intake (p < 0.05). On the other hand, treatment with ML-193: (i) decreased duration of immobility in A-pre-exposed (but not in A-naïve rats); (ii) promoted an aggressive response against the shock-probe in A-pre-exposed rats (p < 0.05); and (iii) increased alcohol intake (p < 0.05). Our results suggest that blockade of GPR55 in D-PAG is associated with anxiety-like behaviors, defensive aggressive behaviors, and higher alcohol intake, whereas LPI in D-PAG produced anxiolytic-like effects (probably GPR55-mediated), but not prevention of alcohol intake.
Assuntos
Agressão/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/fisiopatologia , Ansiedade/induzido quimicamente , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Agressão/fisiologia , Animais , Ansiedade/fisiopatologia , Comportamento Animal , Lisofosfolipídeos/administração & dosagem , Masculino , Modelos Animais , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/fisiopatologia , Ratos , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Nociception alterations are frequent non-motor symptoms of the prodromal phase of Parkinson's disease (PD). The period for the onset of symptoms and the pathophysiological mechanisms underlying these alterations remain unclear. We investigated the course of nociception alterations in a progressive model of parkinsonism induced by reserpine (RES) in rats. Male Wistar rats (6-7 months) received 5 or 10 subcutaneous injections of RES (0.1 mg/kg) or vehicle daily for 20 days. Motor evaluation and nociceptive assessment were performed throughout the treatment. At the end of the treatment rats were euthanized, the brains removed and processed for immunohistochemical analysis (TH and c-Fos). The RES-treated rats exhibited an increased nociceptive response to mechanical and chemical stimulation in the electronic von Frey and formalin tests, respectively. Moreover, these alterations preceded the motor impairment observed in the catalepsy test. In addition, the RES treatment reduced the TH-immunoreactivity in the ventral tegmental area (VTA) and increased the c-Fos expression in the ventral-lateral periaqueductal gray (vlPAG), rostral ventral medulla (RVM) and dorsal raphe nucleus (DRN) after noxious stimuli induced by formalin. Taken together, our results reinforce that nociceptive changes are one of the early signs of PD and monoamine depletion in basal ganglia can be involved in the abnormal processing of nociceptive information in PD.
Assuntos
Núcleo Dorsal da Rafe/metabolismo , Atividade Motora/fisiologia , Nociceptividade/fisiologia , Doença de Parkinson Secundária/fisiopatologia , Substância Cinzenta Periaquedutal/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/fisiopatologia , Masculino , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Substância Cinzenta Periaquedutal/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Reserpina , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/fisiopatologiaRESUMO
Tonic immobility (TI) is an innate defensive response exhibited by prey when physical contact with a predator is prolonged and inescapable. This defensive response is able to activate analgesia mechanisms; this activation has adaptive value because, during an attack by a predator, the manifestation of recuperative behaviors can affect the appropriate behavioral defense strategy. Some studies have suggested that similar structures of the central nervous system can regulate the response of both TI and nociception. Thus, this study evaluated the effect of chemical lesion through the administration of ibotenic acid in restricted brain areas of the periaqueductal gray matter (PAG) in guinea pig on the TI response and nociception evaluated in the hot plate test before and after emission of TI. The data showed that an irreversible chemical lesion in the ventrolateral PAG reduced of the TI response as well as defensive antinociception. However, a lesion in the dorsal PAG blocked the defensive antinociception induced by TI but did not alter TI duration. In summary, one could hypothesize that the neural substrates responsible for defensive behavior and antinociception represent similar systems that are distinct in modulation. Thus, the ventrolateral PAG has been associated with the modulation of TI and the defensive antinociception induced by TI. In contrast, the integrity of the dorsal PAG should be necessary for defensive antinociception to occur but not to elicit TI behavior in guinea pigs.
Assuntos
Analgesia , Ácido Ibotênico/farmacologia , Resposta de Imobilidade Tônica/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , Animais , Cobaias , Ácido Ibotênico/administração & dosagem , Masculino , Microinjeções , Medição da Dor , Substância Cinzenta Periaquedutal/efeitos dos fármacosRESUMO
Painful conditions and sleep disturbances are major public health problems worldwide and one directly affects the other. Sleep loss increases pain prevalence and severity; while pain disturbs sleep. However, the underlying mechanisms are largely unknown. Here we asked whether chronic sleep restriction for 6â¯h daily progressively increases pain sensitivity and if this increase is reversed after two days of free sleep. Also, whether the pronociceptive effect of chronic sleep restriction depends on the periaqueductal grey and on the nucleus accumbens, two key regions involved in the modulation of pain and sleep-wake cycle. We showed that sleep restriction induces a pronociceptive effect characterized by a significant decrease in the mechanical paw withdrawal threshold in rats. Such effect increases progressively from day 3 to day 12 remaining stable thereafter until day 26. Two consecutive days of free sleep were not enough to reverse the effect, not even to attenuate it. This pronociceptive effect depends on the periaqueductal grey and on the nucleus accumbens, since it was prevented by their excitotoxic lesion. Complementarily, chronic sleep restriction significantly increased c-Fos protein expression within the periaqueductal grey and the nucleus accumbens and this correlates with the intensity of the pronociceptive effect, suggesting that the greater the neural activity in this regions, the greater the effect. These findings may contribute not only to understand why painful conditions are more prevalent and severe among people who sleep poorly, but also to develop therapeutic strategies to prevent this, increasing the effectiveness of pain management in this population.
Assuntos
Núcleo Accumbens/fisiopatologia , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , Privação do Sono/fisiopatologia , Animais , Masculino , N-Metilaspartato/toxicidade , Dor Nociceptiva/patologia , Dor Nociceptiva/fisiopatologia , Núcleo Accumbens/patologia , Substância Cinzenta Periaquedutal/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Privação do Sono/patologia , Fatores de Tempo , TatoRESUMO
The present study examined whether early life maternal separation (MS), a model of childhood separation anxiety, predisposes to panic at adulthood. For this purpose, male pups were submitted to 3-h daily maternal separations along postnatal (PN) days of either the 'stress hyporesponsive period' (SHRP) from PN4 to PN14 (MS11) or throughout lactation from PN2 to PN21 (MS20). Pups were further reunited to conscious (CM) or anesthetized (AM) mothers to assess the effect of mother-pup interaction upon reunion. Controls were subjected to brief handling (15â¯s) once a day throughout lactation (BH20). As adults (PN60), rats were tested for the thresholds to evoke panic-like behaviors upon electrical stimulation of dorsal periaqueductal gray matter and exposed to an elevated plus-maze, an open-field, a forced swim and a sucrose preference test. A factor analysis was also performed to gain insight into the meaning of behavioral tests. MS11-CM rather than MS20-CM rats showed enhanced panic responses and reductions in both swimming and sucrose preference. Panic facilitations were less intense in mother-neglected rats. Although MS did not affect anxiety, MS11-AM showed robust reductions of defecation in an open-field. Factor analysis singled out anxiety, hedonia, exploration, coping and gut activity. Although sucrose preference and coping loaded on separate factors, appetite (adult weight) correlated with active coping in both forced swim and open-field (central area exploration). Concluding, whereas 3h-daily maternal separations during SHRP increased rat's susceptibility to experimental panic attacks, separations throughout lactation had no effects on panic and enhanced active coping.
Assuntos
Período Crítico Psicológico , Privação Materna , Pânico/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , Estresse Psicológico/fisiopatologia , Adaptação Psicológica , Animais , Animais Recém-Nascidos , Ansiedade/fisiopatologia , Apetite , Suscetibilidade a Doenças , Estimulação Elétrica , Comportamento Exploratório , Comportamento Alimentar , Lactação , Masculino , Atividade Motora , Ratos Wistar , Resiliência PsicológicaRESUMO
It is known that diabetic (DBT) animals present dysregulation on the serotonergic system in several brain areas associated with anxiety-like responses. The aim of this study was to investigate the involvement of 5-HT1A receptors on dorsal periaqueductal gray (dPAG) in the behavioral response related to panic disorder in type-1 DBT animals. For this, the escape response by electric stimulation (ES) of dPAG in DBT and normoglycemic (NGL) animals was assessed. Both NGL and DBT animals were exposed to an open-field test (OFT) 28 days after DBT confirmation. The current threshold to induce escape behavior in DBT animals was reduced compared with NGL animals. No impairment in locomotor activity was observed when DBT animals were compared with NGL animals. An intra-dPAG injection of the 5-HT1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the [INCREMENT] threshold in both DBT and NGL, suggesting a panicolytic-like effect. DBT animals presented a more pronounced panicolytic-like response compared with NGL as a higher [INCREMENT] threshold was observed after 8-OH-DPAT treatment, which could be a consequence of the increased expression of the 5-HT1A receptor in the dPAG from DBT animals. Our results are in line with the proposal that a deficiency in serotonergic modulation of the dPAG is involved in triggering the panic attack and the 5-HT1A receptors might be essential for the panicolytic-like response.
Assuntos
Pânico/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Animais , Ansiedade/metabolismo , Diabetes Mellitus Experimental/psicologia , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.
Assuntos
Nociceptividade , Substância Cinzenta Periaquedutal/fisiopatologia , Estimulação Transcraniana por Corrente Contínua , Animais , Eletrodos , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Masculino , Substância Cinzenta Periaquedutal/patologia , Células do Corno Posterior/patologia , Ratos , Ratos WistarRESUMO
Interactions between the prelimbic cortex and the basolateral amygdala underlie fear memory processing, mostly through acquiring and consolidating the learning of a conditioned fear. More recently, studies highlighted the role of the dorsal periaqueductal gray (DPAG) in the modulation of learning fear responses. In addition, extensive data in the literature have signaled the importance of serotonin (5-HT) on fear and anxiety. In the present study, the role of 5-HT neurotransmission of the prelimbic cortex, basolateral amygdala or the DPAG on the unconditioned and conditioned fear responses in rats previously selected as low- (LA) or high-anxious (HA) were assessed through local infusions of 5-HT itself (10nmol/0.2µl) or the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT - 0.3µg/0.2µl). Behavioral analysis was conducted using the fear-potentiated startle (FPS) procedure. Dependent variables recorded were the latency and amplitude of the unconditioned startle response and FPS. Our findings suggest that, on the prelimbic cortex, 5-HT modulates the expression of conditioned fear response in HA rats and this modulation is dependent on 5-HT1A receptors. This is not true, however, for the basolateral amygdala or the DPAG. In these regions LA but not HA rats were susceptible to the anxiolytic-like effect of 5-HT1A receptor activation. It is thought that the expression of conditioned fear in HA subjects may be dependent on other 5-HT receptors, as the 5-HT1B subtype, and/or changes in other systems such as the GABA and glutamate neurotransmitters. These results increase our understanding of the rostrocaudal influence of 5-HT on the unconditioned and conditioned fear responses in LA and HA subjects and, to some extent, are in disagreement with the theoretical current that emphasizes the role of 5-HT on anxiety, mainly at the subcortical and midbrain levels.
Assuntos
Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ansiedade/tratamento farmacológico , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Encéfalo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Individualidade , Masculino , Testes Neuropsicológicos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiopatologia , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
AIM: Although periaqueductal grey matter activation is known to elicit respiratory and cardiovascular responses, the role of this midbrain area in the compensatory responses to hypoxia is still unknown. To test the participation of the periaqueductal grey matter in cardiorespiratory and thermal responses to hypoxia in adult male Wistar rats, we performed a chemical lesion of the dorsolateral/dorsomedial or the ventrolateral/lateral periaqueductal grey matter using ibotenic acid. METHODS: Pulmonary ventilation, mean arterial pressure, heart rate and body temperature were measured in unanaesthetized rats during normoxic and hypoxic exposure (5, 15, 30 min, 7% O2). RESULTS: An ibotenic acid lesion of the dorsolateral/dorsomedial periaqueductal grey matter caused a higher increase in pulmonary ventilation (67.1%, 1730±282.5 mL kg(-1) min(-1)) compared to the Sham group (991.4±194 mL kg(-1) min(-1)) after 15 min in hypoxia, whereas for the ventrolateral/Lateral periaqueductal grey matter lesion, no differences were observed between groups. Mean arterial pressure, heart rate and body temperature were not affected by a dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter lesion. CONCLUSION: Middle to caudal portions of the dorsolateral/dorsomedial periaqueductal grey matter neurones modulate the hypoxic ventilatory response, exerting an inhibitory modulation during low O2 situations. In addition, the middle to caudal portions of the dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter do not appear to exert a tonic role on cardiovascular or thermal parameters during normoxic and hypoxic conditions.
Assuntos
Hipóxia/fisiopatologia , Pulmão/inervação , Substância Cinzenta Periaquedutal/fisiopatologia , Ventilação Pulmonar , Animais , Pressão Arterial , Regulação da Temperatura Corporal , Dióxido de Carbono/sangue , Estado de Consciência , Modelos Animais de Doenças , Frequência Cardíaca , Hipóxia/sangue , Ácido Ibotênico/toxicidade , Masculino , Oxigênio/sangue , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/patologia , Ventilação Pulmonar/efeitos dos fármacos , Ratos Wistar , Reflexo , Fatores de TempoRESUMO
Plenty of evidence suggests that childhood separation anxiety (CSA) predisposes the subject to adult-onset panic disorder (PD). As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG). Accordingly, here we examined whether the neonatal social isolation (NSI), a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST) respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2) until weaning (PN21) allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, nâ=â26) whilst siblings (sham-isolated rats, SHAM, nâ=â27) and dam were moved to another box in a separate room. Non-handled controls (CTRL, nâ=â18) remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60) and subjected to sessions of intracranial stimulation (PN65), EPM (PN66) and FST (PN67-PN68). Groups were compared by Fisher's exact test (stimulation sites), likelihood ratio chi-square tests (stimulus-response threshold curves) and Bonferroni's post hoc t-tests (EPM and FST), for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate the DPAG not only in panic attacks but also in separation-anxious children's predispositions to the late development of PD.