RESUMO
The ventrolateral periaqueductal gray (vlPAG) serves as a central hub for descending pain modulation. It receives upstream projections from the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), and projects downstream to the locus coeruleus (LC) and the rostroventral medulla (RVM). While much research has focused on upstream circuits and the LC-RVM connection, less is known about the PAG-LC circuit and its involvement in neuropathic pain. Here we examined the intrinsic electrophysiological properties of vlPAG-LC projecting neurons in Sham and spared nerve injury (SNI) operated mice. Injection of the retrotracer Cholera Toxin Subunit B (CTB-488) into the LC allowed the identification of LC-projecting neurons in the vlPAG. Electrophysiological recordings from CTB-488 positive cells revealed that both GABAergic and glutamatergic cells that project to the LC exhibited reduced intrinsic excitability after peripheral nerve injury. By contrast, CTB-488 negative cells did not exhibit alterations in firing properties after SNI surgery. An SNI-induced reduction of LC projecting cells was confirmed with c-fos labeling. Hence, SNI induces plasticity changes in the vlPAG that are consistent with a reduction in the descending modulation of pain signals.
Assuntos
Locus Cerúleo , Camundongos Endogâmicos C57BL , Neurônios , Substância Cinzenta Periaquedutal , Animais , Substância Cinzenta Periaquedutal/fisiopatologia , Substância Cinzenta Periaquedutal/fisiologia , Locus Cerúleo/fisiopatologia , Locus Cerúleo/patologia , Locus Cerúleo/fisiologia , Neurônios/fisiologia , Masculino , Camundongos , Potenciais de Ação/fisiologia , Vias Neurais/fisiopatologia , Neuralgia/fisiopatologia , Neuralgia/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Traumatismos dos Nervos Periféricos/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
The stress-induced cardiovascular response is based on the defensive reaction in mammals. It has been shown that the sympathetic vasomotor pathway of acute psychological stress is indirectly mediated via neurons in the rostroventral medulla (RVM) from the hypothalamic stress center. In this study, direct projections to the RVM and distribution of neuroexcitatory marker c-Fos-expressed neurons were investigated during social defeat stress (SDS) in conscious rats. The experimental rat that was injected with a neural tracer, FluoroGold (FG) into the unilateral RVM, was exposed to the SDS. Double-positive neurons of both c-Fos and FG were locally distributed in the lateral/ventrolateral periaqueductal gray matter (l/vl PAG) in the midbrain. These results suggest that the neurons in the l/vl PAG contribute to the defensive reaction evoked by acute psychological stress, such as the SDS. During the SDS period, arterial pressure (AP) and heart rate (HR) showed sustained increases in the rat. Therefore, we performed chemical stimulation by excitatory amino acid microinjection within the l/vl PAG and measured cardiovascular response and sympathetic nerve activity in some anesthetized rats. The chemical stimulation of neurons in the l/vl PAG caused significant increases in arterial pressure and renal sympathetic nerve activity. Taken together, our results suggest that neurons in the l/vl PAG are a possible candidate for the cardiovascular descending pathway that modulates sympathetic vascular resistance evoked by acute psychological stress, like the SDS.NEW & NOTEWORTHY The sympathetic vasomotor pathway of an acute psychological stress-induced cardiovascular response is mediated via neurons in the RVM indirectly from the hypothalamus. In this study, we showed the relaying area of the efferent sympathetic vasomotor pathway from the hypothalamus to the RVM. The results suggested that the pressor response during psychological stress is mediated via neurons in the lateral/ventrolateral PAG to the RVM.
Assuntos
Bulbo , Substância Cinzenta Periaquedutal , Derrota Social , Estresse Psicológico , Sistema Vasomotor , Animais , Estresse Psicológico/fisiopatologia , Masculino , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/fisiopatologia , Bulbo/fisiopatologia , Bulbo/metabolismo , Sistema Vasomotor/fisiopatologia , Ratos , Frequência Cardíaca , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Sistema Nervoso Simpático/fisiopatologia , Ratos Sprague-Dawley , Pressão Arterial , Comportamento AnimalRESUMO
Growing evidence suggests that aging is associated with impaired endogenous pain modulation, and that this likely underlies the increased transition from acute to chronic pain in older individuals. Resting-state functional connectivity (rsFC) offers a valuable tool to examine the neural mechanisms behind these age-related changes in pain modulation. RsFC studies generally observe decreased within-network connectivity due to aging, but its relevance for pain modulation remains unknown. We compared rsFC within a set of brain regions involved in pain modulation between young and older adults and explored the relationship with the efficacy of distraction from pain. This revealed several age-related increases and decreases in connectivity strength. Importantly, we found a significant association between lower pain relief and decreased strength of three connections in older adults, namely between the periaqueductal gray and right insula, between the anterior cingulate cortex (ACC) and right insula, and between the ACC and left amygdala. These findings suggest that the functional integrity of the pain control system is critical for effective pain modulation, and that its function is compromised by aging.
Assuntos
Envelhecimento , Giro do Cíngulo , Imageamento por Ressonância Magnética , Dor , Humanos , Envelhecimento/fisiologia , Masculino , Idoso , Feminino , Adulto , Adulto Jovem , Dor/fisiopatologia , Pessoa de Meia-Idade , Giro do Cíngulo/fisiopatologia , Giro do Cíngulo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Tonsila do Cerebelo/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Substância Cinzenta Periaquedutal/fisiopatologia , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Córtex Insular/diagnóstico por imagem , Córtex Insular/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/diagnóstico por imagemRESUMO
Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.
Assuntos
Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Transmissão Sináptica , Triptofano/sangue , Ansiedade , Estudos de Casos e Controles , Depressão , Emoções , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos de Enxaqueca/psicologia , Percepção da Dor , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Triptofano/fisiologiaRESUMO
The descending pain modulatory system in humans is commonly investigated using conditioned pain modulation (CPM). Whilst variability in CPM efficiency, i.e., inhibition and facilitation, is normal in healthy subjects, exploring the inter-relationship between brain structure, resting-state functional connectivity (rsFC) and CPM readouts will provide greater insight into the underlying CPM efficiency seen in healthy individuals. Thus, this study combined CPM testing, voxel-based morphometry (VBM) and rsFC to identify the neural correlates of CPM in a cohort of healthy subjects (n =40), displaying pain inhibition (n = 29), facilitation (n = 10) and no CPM effect (n = 1). Clusters identified in the VBM analysis were implemented in the rsFC analysis alongside key constituents of the endogenous pain modulatory system. Greater pain inhibition was related to higher volume of left frontal cortices and stronger rsFC between the motor cortex and periaqueductal grey. Conversely, weaker pain inhibition was related to higher volume of the right frontal cortex - coupled with stronger rsFC to the primary somatosensory cortex, and rsFC between the amygdala and posterior insula. Overall, healthy subjects showed higher volume and stronger rsFC of brain regions involved with descending modulation, while the lateral and medial pain systems were related to greater pain inhibition and facilitation during CPM, respectively. These findings reveal structural alignments and functional interactions between supraspinal areas involved in CPM efficiency. Ultimately understanding these underlying variations and how they may become affected in chronic pain conditions, will advance a more targeted subgrouping in pain patients for future cross-sectional studies investigating endogenous pain modulation.
Assuntos
Inibição Psicológica , Vias Neurais/fisiopatologia , Dor/fisiopatologia , Adolescente , Adulto , Idoso , Tonsila do Cerebelo/fisiopatologia , Encéfalo/fisiopatologia , Mapeamento Encefálico , Estudos Transversais , Feminino , Lobo Frontal/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Substância Cinzenta Periaquedutal/fisiopatologia , Descanso , Suíça , Adulto JovemRESUMO
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
The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.
Assuntos
Substância Cinzenta/fisiologia , Rede Nervosa/fisiologia , Neuropeptídeos/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Núcleos da Rafe/fisiologia , Animais , Substância Cinzenta/fisiopatologia , Humanos , Rede Nervosa/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Núcleos da Rafe/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologiaRESUMO
BACKGROUND: The restraint water immersion stress (RWIS) model includes both psychological and physical stimulation, which may lead to gastrointestinal disorders and cause gastric mucosal damage. The ventrolateral periaqueductal gray (VLPAG) contributes to gastrointestinal function, but whether it is involved in RWIS-induced gastric mucosal damage has not yet been reported. METHODS: The expression of glial fibrillary acidic protein, neuronal c-Fos, and phosphorylated extracellular signal regulated kinase 1/2 in the VLPAG after RWIS was assessed using western blotting and immunocytochemical staining methods. Lateral ventricle injection of astrocytic toxin L-a-aminoadipate and treatment with extracellular signal-regulated kinase (ERK)1/2 signaling pathway inhibitor PD98059 were further used to study protein expression and distribution in the VLPAG after RWIS. RESULTS: The expression of c-Fos, glial fibrillary acidic protein, and phosphorylated extracellular signal regulated kinase 1/2 in the VLPAG significantly increased following RWIS and peaked at 1 hour after RWIS. Lateral ventricle injection of the astrocytic toxin L-a-aminoadipate significantly alleviated gastric mucosal injury and decreased the activation of neurons and astrocytes. Treatment with the ERK1/2 signaling pathway inhibitor PD98059 obviously suppressed gastric mucosal damage as well as the RWIS-induced activation of neurons and astrocytes in the VLPAG. CONCLUSIONS: These results suggested that activation of VLPAG neurons and astrocytes induced by RWIS through the ERK1/2 signaling pathway may play a critical role in RWIS-induced gastric mucosa damage.
Assuntos
Astrócitos/fisiologia , Mucosa Gástrica/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Gastropatias , Estresse Psicológico , Animais , Astrócitos/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos Wistar , Restrição Física , Gastropatias/etiologia , Gastropatias/metabolismo , Gastropatias/fisiopatologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Chronic pain is considered an economic burden on society as it often results in disability, job loss, and early retirement. Opioids are the most common analgesics prescribed for the management of moderate to severe pain. However, chronic exposure to these drugs can result in opioid tolerance and opioid-induced hyperalgesia. On pain modulation strategies, exploiting the multitarget drugs with the ability of the superadditive or synergistic interactions attracts more attention. In the present report, we have reviewed the analgesic effects of different dopamine receptors, particularly D1 and D2 receptors, in different regions of the central nervous system, including the spinal cord, striatum, nucleus accumbens (NAc), and periaqueductal gray (PAG). According to the evidence, these regions are not only involved in pain modulation but also express a high density of DA receptors. The findings can be categorized as follows: (1) D2-like receptors may exert a higher analgesic potency, but D1-like receptors act in different manners across several mechanisms in the mentioned regions; (2) in the spinal cord and striatum, antinociception of DA is mainly mediated by D2-like receptors, while in the NAc and PAG, both D1- and D2-like receptors are involved as analgesic targets; and (3) D2-like receptor agonists can act as adjuvants of µ-opioid receptor agonists to potentiate analgesic effects and provide a better approach to pain relief.
Assuntos
Dor/tratamento farmacológico , Dor/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Receptores de Dopamina D2/agonistas , Analgésicos/farmacologia , Animais , Tolerância a Medicamentos/fisiologia , Humanos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Medição da Dor/métodos , Substância Cinzenta Periaquedutal/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/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
The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.
Assuntos
Neuralgia/fisiopatologia , Córtex Olfatório/fisiopatologia , Animais , Humanos , Masculino , Neurônios/citologia , Limiar da Dor , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/fisiopatologia , Ratos , Ratos Wistar , Corno Dorsal da Medula Espinal/fisiopatologiaRESUMO
AIMS: The periaqueductal gray (PAG) is a brain stem area involved in processing signals related to urine storage and voiding. The PAG is proposed to be responsible for projecting afferent information from the bladder to cortical and subcortical brain areas and acts as a relay station projecting efferent information from cortical and subcortical areas to the pons and spinal cord. Here, we use 7-Tesla functional magnetic resonance imaging to parcellate the PAG into functionally distinct clusters during a bladder filling protocol. METHODS: We assess the similarity between parcellation results in empty and full bladder states and show how these parcellations can be used to create dynamic response profiles of connectivity changes between clusters as a function of bladder sensations. RESULTS: For each of our six healthy female participants, we found that the agreement between at least one of the clusters in both states resulting from the parcellation procedure was higher than could be expected based on chance (p ≤ .05), and observed that these clusters are significantly organized in a symmetrical lateralized fashion (p ≤ .05). Correlations between clusters change significantly as a function of experienced sensations during bladder filling (p ≤ .05). CONCLUSIONS: This opens new possibilities to investigate the effects of treatments of lower urinary tract symptoms on signal processing in the PAG, as well as the investigation of disease-specific bladder filling related dynamic signal processing in this small brain structure.
Assuntos
Imageamento por Ressonância Magnética/métodos , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Bexiga Urinária/diagnóstico por imagem , Feminino , Humanos , Substância Cinzenta Periaquedutal/fisiopatologiaRESUMO
Cocaine-dependent (CD) individuals demonstrate significant anxiety and dysphoria during withdrawal, a negative emotional state that may perpetuate drug seeking and consumption. An extensive body of work has focused on characterizing reward circuit dysfunction, but relatively little is known about the pain circuit during cocaine withdrawal. In an earlier study, we highlighted how cue-elicited functional connectivity between the periaqueductal gray (PAG), a subcortical hub of the pain circuit, and ventromedial prefrontal cortex supports tonic craving in recently abstinent CD. The functional organization of the brain can be characterized by intrinsic connectivities, and it is highly likely that the resting state functional connectivity (rsFC) of the PAG may also be altered in association with cocaine use variables. Here, we examined this issue in 52 CD and 52 healthy control (HC) participants. Imaging data were processed with published routines, and the findings were evaluated with a corrected threshold. In a covariance analysis, CD as compared with HC showed higher PAG rsFC with the hypothalamus, dorsomedial prefrontal, and inferior parietal cortices. Further, these connectivities were correlated negatively with tonic cocaine craving and recent cocaine use, respectively. Higher hypothalamic and frontoparietal rsFC with the PAG may reflect a compensatory process to regulate craving and compulsive drug use. The findings provide additional evidence in humans implicating the PAG circuit and may help research of the role of negative reinforcement in sustaining habitual drug use in cocaine addiction.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Hipotálamo/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Adulto , Encéfalo/fisiopatologia , Mapeamento Encefálico , Fissura , Sinais (Psicologia) , Comportamento de Procura de Droga , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Parietal/fisiopatologia , Recompensa , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
We report an 86-year-old woman who suffered sudden onset of diplopia while cooking. The patient presented with binocular diplopia, bilateral adduction weakness, convergence disorder and bilateral abduction nystagmus. Although brain MRI on admission detected no abnormality, a repeat MRI examination on the following day demonstrated a focal hyperintense lesion in the tegmentum of the midbrain on diffusion-weighted images. At 36 hours after admission, lower abdominal distension became apparent, and about 1 liter of urine was drained via a urethral catheter. Bladder filling sensation was not present, and we considered that the midbrain lesion had been responsible for the oculomotor disorder and urinary retention. As cerebral infarction was the most likely pathology of this lesion, an antiplatelet agent was administered. At two months after onset, the eye movement disorder was resolved and there was no diplopia. Bladder voiding also resumed at normal intervals. We considered that the bilateral medial longitudinal fasciculi and subgroups of the oculomotor nucleus, which contain motor neurons supplying the medial rectus muscle, had been responsible for the oculomotor disorder. The urinary retention was thought to have been caused by a lesion in the periaqueductal gray, which is one structure controlling micturition. This was a rare case of urinary retention due to a small midbrain infarction.
Assuntos
Infarto Cerebral/complicações , Mesencéfalo/diagnóstico por imagem , Transtornos da Motilidade Ocular/etiologia , Retenção Urinária/etiologia , Idoso de 80 Anos ou mais , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Diplopia/etiologia , Feminino , Humanos , Mesencéfalo/fisiopatologia , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Substância Cinzenta Periaquedutal/fisiopatologia , MicçãoRESUMO
Early adolescent adversity increases adult risk for anxiety disorders. The ventrolateral periaqueductal gray (vlPAG) and neighboring dorsal raphe (DR) are integral to threat prediction, and are responsive to acute stressors. Here, we tested the hypothesis that early adolescent adversity reshapes vlPAG/DR threat-related cue activity and threat probability signaling. Female, Long Evans rats experienced a battery of adverse adolescent experiences (n = 12), while controls did not (n = 8). Single-unit activity was recorded 50 + days following the final adverse experience, when the adult rats received fear discrimination consisting of danger, uncertainty and safety cues. Despite achieving fear discrimination that was equivalent to controls, vlPAG/DR threat responding was altered in adverse-experienced rats. Early adolescent adversity resulted in a greater proportion of cue-responsive neurons. Cue-excited neurons showed greater increases in firing and cue-inhibited neurons showed greater decreases. Even more, early adversity reduced flexible, threat probability signaling by cue-excited neurons and promoted more rigid, fear output signaling by cue-inhibited neurons. The results reveal long-lasting changes in vlPAG/DR threat responding resulting from early adolescent adversity.
Assuntos
Sinais (Psicologia) , Discriminação Psicológica/fisiologia , Núcleo Dorsal da Rafe/fisiopatologia , Medo , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , Estresse Psicológico/fisiopatologia , Envelhecimento , Animais , Feminino , Ratos , Ratos Long-Evans , NataçãoRESUMO
Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.
Assuntos
Dor Crônica/fisiopatologia , Hiperalgesia/fisiopatologia , Neuralgia/fisiopatologia , Substância Cinzenta Periaquedutal/patologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Dor Crônica/etiologia , Dor Crônica/patologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Proteínas de Arcabouço Homer/genética , Proteínas de Arcabouço Homer/metabolismo , Humanos , Hiperalgesia/etiologia , Hiperalgesia/patologia , Masculino , Neuralgia/etiologia , Neuralgia/patologia , Percepção da Dor/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , RatosRESUMO
When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.
Assuntos
Antecipação Psicológica , Transtornos de Ansiedade/psicologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/fisiopatologia , Mapeamento Encefálico , Estimulação Elétrica , Medo , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Resposta Galvânica da Pele , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Substância Cinzenta Periaquedutal/fisiopatologia , Estimulação Luminosa , Estudos Prospectivos , Núcleos Septais/diagnóstico por imagem , Núcleos Septais/fisiopatologia , Incerteza , Adulto JovemRESUMO
BACKGROUND: Withdrawal from chronic cocaine use leads to anxiety and dysphoria that may perpetuate habitual drug use. The pain circuit is widely implicated in the processing and manifestations of negative emotions. Numerous studies have focused on characterizing reward circuit dysfunction but relatively little is known about the pain circuit response during cocaine withdrawal. METHODS: Here we examined the activity and connectivity of the periaqueductal gray (PAG), a hub of the pain circuit, during cocaine cue exposure in 52 recently abstinent cocaine dependent participants (CD, 42 men). Imaging data were processed with published routines, and the results were evaluated at a corrected threshold. RESULTS: CD showed higher activation of the PAG and connectivity of the PAG with the ventromedial prefrontal cortex (vmPFC) during cocaine as compared to neutral cue exposure. PAG-vmPFC connectivity was positively and negatively correlated with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire, in male and female CD, respectively, and the sex difference was confirmed by a slope test. Granger causality analyses showed that the PAG Granger caused vmPFC time series in men and the reverse was true in women, substantiating sex differences in the directional interactions of the PAG and vmPFC. CONCLUSION: The findings provide the first evidence in humans implicating the PAG circuit in cocaine withdrawal and cocaine craving and advance our understanding of the role of the pain circuit and negative reinforcement in sustaining habitual drug use in cocaine addiction.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína , Substância Cinzenta Periaquedutal/fisiopatologia , Adulto , Ansiedade , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Fissura , Sinais (Psicologia) , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Córtex Pré-Frontal/fisiopatologia , Recompensa , Síndrome de Abstinência a Substâncias/fisiopatologia , Adulto JovemRESUMO
Postherpetic Neuralgia (PHN), develops after the resolution of the herpes zoster mucocutaneous eruption, is a debilitating chronic pain. However, there is a lack of knowledge regarding the underlying mechanisms associated with ascending and descending pain modulations in PHN patients. Here, we combined psychophysics with structural and functional magnetic resonance imaging (MRI) techniques to investigate the brain alternations in PHN patients. Psychophysical tests showed that compared with healthy controls, PHN patients had increased state and trait anxiety and depression. Structural MRI data indicated that PHN patients had significantly smaller gray matter volumes of the thalamus and amygdala than healthy controls, and the thalamus volume was negatively correlated with pain intensity (assessed using the Short-form of the McGill pain questionnaire) in PHN patients. When the thalamus and periaqueductal gray matter (PAG) were used as the seeds, resting-state functional MRI data revealed abnormal patterns of functional connectivity within ascending and descending pain pathways in PHN patients, e.g., increased functional connectivity between the thalamus and somatosensory cortices and decreased functional connectivity between the PAG and frontal cortices. In addition, subjective ratings of both Present Pain Index (PPI) and Beck-Depression Inventory (BDI) were negatively correlated with the strength of functional connectivity between the PAG and primary somatosensory cortex (SI), and importantly, the effect of BDI on PPI was mediated by the PAG-SI functional connectivity. Overall, our results provided evidence suggesting deficits in ascending and descending pain modulation pathways, which were highly associated with the intensity of chronic pain and its emotional comorbidities in PHN patients. Therefore, our study deepened our understanding of the pathogenesis of PHN, which would be helpful in determining the optimized treatment for the patients.
Assuntos
Tonsila do Cerebelo , Córtex Cerebral , Conectoma , Substância Cinzenta , Imageamento por Ressonância Magnética , Rede Nervosa , Neuralgia Pós-Herpética/fisiopatologia , Substância Cinzenta Periaquedutal , Tálamo , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Ansiedade/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Depressão/fisiopatologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Neuralgia Pós-Herpética/diagnóstico por imagem , Neuralgia Pós-Herpética/patologia , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Substância Cinzenta Periaquedutal/patologia , Substância Cinzenta Periaquedutal/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/patologia , Tálamo/fisiopatologiaRESUMO
Cellular and synaptic mechanisms underlying how chronic pain induces maladaptive alterations to local circuits in the medial prefrontal cortex (mPFC), while emerging, remain unresolved. Consistent evidence shows that chronic pain attenuates activity in the prelimbic (PL) cortex, a mPFC subregion. This reduced activity is thought to be driven by increased inhibitory tone within PL circuits. Enhanced input from the basolateral amygdala (BLA) to inhibitory neurons in PL cortex is one well-received mechanism for this circuit change. In mice, we used retrograde labeling, brain slice recordings, and optogenetics to selectively stimulate and record ascending BLA inputs onto PL neurons that send projections to the periaqueductal gray (PAG), which is a midbrain structure that plays a significant role in endogenous analgesia. Activating BLA projections evoked both excitatory and inhibitory currents in cortico-PAG (CP) neurons, as we have shown previously. We measured changes to the ratio of BLA-evoked excitatory to inhibitory currents in the spared nerve injury (SNI) model of neuropathic pain. Our analysis reveals a reduced excitation-inhibition (E/I) ratio of BLA inputs to PL-CP neurons 7 days after SNI. The E/I ratio of BLA inputs to CP neurons in neighboring infralimbic (IL) cortex was unchanged in SNI animals. Collectively, this study reveals that the overall E/I balance of BLA inputs to PL neurons projecting to the PAG is reduced in a robust neuropathic pain model. Overall, our findings provide new mechanistic insight into how nerve injury produces dysfunction in PL circuits connected to structures involved in pain modulation.