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1.
Pain ; 160(5): 1070-1081, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30855519

RESUMO

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Limiar da Dor/fisiologia , Dor/etiologia , Síndrome WAGR/complicações , Síndrome WAGR/genética , Adolescente , Adulto , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Criança , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Perfilação da Expressão Gênica , Humanos , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Lasers/efeitos adversos , Masculino , Mutação/genética , Dor/genética , Medição da Dor , Estimulação Física/efeitos adversos , Ratos , Ratos Transgênicos , Medula Espinal/metabolismo , Medula Espinal/patologia , Adulto Jovem
2.
Pain ; 160(5): 1019-1028, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30624343

RESUMO

Inhibitory pain modulation has been reported to be deficient in adults across different types of chronic pain, including migraine. To determine whether a similar phenomenon occurs in youth, we performed a quantitative sensory testing investigation in adolescents with migraine (N = 19). These patients were compared to healthy adolescents with (Fam-His; N = 20) or without (Healthy; N = 29) a family history of migraine (eg, first-degree relative with migraine). Subjects were first familiarized with the stimuli and visual analogue rating scales using graded noxious stimuli (0°C, 43-49°C range). These data were used to explore potential pain sensitivity differences between the groups. Pain inhibition was assessed by conditioned pain modulation (CPM), which used both suprathreshold heat pain (heat CPM) and pressure pain thresholds (pressure CPM) as the test stimuli before and during cold-water immersion (8°C). In response to the graded heat stimuli, Fam-His participants reported higher pain intensity ratings compared with patients with migraine, who in turn reported higher pain intensity ratings than the healthy controls (F = 3.6, [df = 2, 459], P = 0.027). For heat and pressure CPM, there was no significant group difference in the magnitude of CPM responses. Thus, adolescents with migraine and healthy adolescents have similar inhibitory pain modulation capability, despite having marked differences in pain sensitivity. Although Fam-His participants are asymptomatic, they demonstrate alterations in pain processing, which may serve as markers for prediction of migraine development.


Assuntos
Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/psicologia , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Dor/fisiopatologia , Adolescente , Criança , Correlação de Dados , Avaliação da Deficiência , Feminino , Humanos , Masculino , Dor/etiologia , Dor/psicologia , Medição da Dor , Pais/psicologia , Estimulação Física/efeitos adversos , Estatísticas não Paramétricas , Inquéritos e Questionários
3.
Pain ; 160(5): 1037-1049, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30649100

RESUMO

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with many known structural and functional changes in the central nervous system. A well-recognized, but poorly understood, complication of MS is chronic pain. Little is known regarding the influence of sex on the development and maintenance of MS-related pain. This is important to consider, as MS is a predominantly female disease. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we demonstrate sex differences in measures of spinal cord inflammation and plasticity that accompany tactile hypersensitivity. Although we observed substantial inflammatory activity in both sexes, only male EAE mice exhibit robust staining of axonal injury markers and increased dendritic arborisation in morphology of deep dorsal horn neurons. We propose that tactile hypersensitivity in female EAE mice may be more immune-driven, whereas pain in male mice with EAE may rely more heavily on neurodegenerative and plasticity-related mechanisms. Morphological and inflammatory differences in the spinal cord associated with pain early in EAE progression supports the idea of differentially regulated pain pathways between the sexes. Results from this study may indicate future sex-specific targets that are worth investigating for their functional role in pain circuitry.


Assuntos
Sistema Nervoso Central/fisiopatologia , Encefalomielite Autoimune Experimental/complicações , Plasticidade Neuronal/fisiologia , Dor/etiologia , Dor/patologia , Animais , Axônios/patologia , Axônios/ultraestrutura , Proteínas de Ligação ao Cálcio/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/ultraestrutura , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Ciclo Estral/fisiologia , Feminino , Adjuvante de Freund/toxicidade , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Atividade Motora/fisiologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Limiar da Dor/fisiologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Toxina Pertussis/toxicidade , Estimulação Física/efeitos adversos , Fatores Sexuais
4.
Pain ; 160(4): 784-792, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30681982

RESUMO

The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyperalgesia rather than hypoalgesia during or immediately after receiving a conditioning stimulus. We observed that mice undergoing tonic inflammatory pain in the abdominal cavity (the conditioning stimulus) display hyperalgesia, not hypoalgesia, to noxious thermal stimulation (the test stimulus) applied to the hindpaw. In a series of parametric studies, we show that this hyperalgesia can be reliably observed using multiple conditioning stimuli (acetic acid and orofacial formalin), test stimuli (hindpaw and forepaw-withdrawal, tail-withdrawal, hot-plate, and von Frey tests) and genotypes (CD-1, DBA/2, and C57BL/6 mice and Sprague-Dawley rats). Although the magnitude of the hyperalgesia is dependent on the intensity of the conditioning stimulus, we find that the direction of effect is dependent on the effective test stimulus intensity, with lower-intensity stimuli leading to hyperalgesia and higher-intensity stimuli leading to hypoalgesia.


Assuntos
Dor Facial/complicações , Hiperalgesia/etiologia , Hipestesia/etiologia , Dor/complicações , Dor/etiologia , Ácido Acético/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Medição da Dor , Traumatismos dos Nervos Periféricos/complicações , Estimulação Física/efeitos adversos , Psicofísica , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
5.
Pain ; 160(4): 833-843, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30531308

RESUMO

Changes in central pain processing have been shown in patients with chronic low-back pain (cLBP). We used quantitative sensory testing methods to identify differences in pain sensitization between patients with cLBP (N = 167) and healthy controls (N = 33). Results indicated that, compared with healthy pain-free controls, cLBP patients showed increased sensitivity and greater painful aftersensations for mechanical pressure and pin-prick stimuli and lower tactile spatial acuity in the 2-point discrimination task (ps < 0.05). Then, we examined the role of pain catastrophizing as a mediator of the group differences in pain sensitization. We found that catastrophizing partially accounted for group differences in pressure required to produce moderate pain. Finally, we examined the relationship between pain sensitization, catastrophizing, and clinical pain among patients with cLBP. We found that catastrophizing and deep-tissue pressure pain were associated with greater pain intensity in the past month, week, and at the visit as well as low-back pain bothersomeness. Furthermore, deep-tissue pressure pain mediated the associations between catastrophizing and both pain in the past month and low-back pain severity. Taken together, these results indicate that not only do patients with cLBP demonstrate increased pain sensitization and decreased sensitivity to innocuous stimuli, but these changes are also linked with increased catastrophizing. Furthermore, both catastrophizing and sensitization are associated with increased clinical pain among cLBP patients.


Assuntos
Catastrofização/complicações , Dor Crônica/complicações , Dor Lombar/complicações , Dor Lombar/psicologia , Limiar da Dor/fisiologia , Adolescente , Adulto , Dor Crônica/psicologia , Feminino , Humanos , Hiperalgesia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estimulação Física/efeitos adversos , Autorrelato , Adulto Jovem
6.
Pain ; 160(4): 793-804, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30531372

RESUMO

Primary afferent neurons transduce distension of the bladder wall into action potentials that are relayed into the spinal cord and brain, where autonomic reflexes necessary for maintaining continence are coordinated with pathways involved in sensation. However, the relationship between spinal circuits involved with physiological and nociceptive signalling from the bladder has only been partially characterised. We used ex vivo bladder afferent recordings to characterise mechanosensitive afferent responses to graded distension (0-60 mm Hg) and retrograde tracing from the bladder wall to identify central axon projections within the dorsal horn of the lumbosacral (LS) spinal cord. Labelling of dorsal horn neurons with phosphorylated-MAP-kinase (pERK), combined with labelling for neurochemical markers (calbindin, calretinin, gamma aminobutyric acid, and parvalbumin) after in vivo bladder distension (20-60 mm Hg), was used to identify spinal cord circuits processing bladder afferent input. Ex vivo bladder distension evoked an increase in primary afferent output, and the recruitment of both low- and high-threshold mechanosensitive afferents. Retrograde tracing revealed bladder afferent projections that localised with pERK-immunoreactive dorsal horn neurons within the superficial laminae (superficial dorsal horn), dorsal gray commissure, and lateral collateral tracts of the LS spinal cord. Populations of pERK-immunoreactive neurons colabelled with calbindin, calretinin, or gamma aminobutyric acid, but not parvalbumin. Noxious bladder distension increased the percentage of pERK-immunoreactive neurons colabelled with calretinin. We identified LS spinal circuits supporting autonomic and nociceptive reflexes responsible for maintaining continence and bladder sensations. Our findings show for the first time that low- and high-threshold bladder afferents relay into similar dorsal horn circuits, with nociceptive signalling recruiting a larger number of neurons.


Assuntos
Vias Aferentes/fisiologia , Mecanorreceptores/fisiologia , Neurônios Aferentes/fisiologia , Medula Espinal/citologia , Bexiga Urinária/inervação , Animais , Calbindina 2/metabolismo , Toxina da Cólera/metabolismo , Feminino , Gânglios Espinais/citologia , Região Lombossacral , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Física/efeitos adversos , Estatísticas não Paramétricas , Ácido gama-Aminobutírico/metabolismo
7.
Pain ; 160(4): 882-894, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30585985

RESUMO

This prospective cohort study aimed to characterize the sensory profile during acute herpes zoster (AHZ) and to explore sensory signs as well as physical and psychosocial health as predictors for postherpetic neuralgia (PHN). Results of quantitative sensory testing of 74 patients with AHZ at the affected site and at the distant contralateral control site were compared to a healthy control group. Pain characteristics (Neuropathic Pain and Symptom Inventory and SES), physical functioning, and psychosocial health aspects (Pain Disability Index, SF-36, and STAI) were assessed by questionnaires. Patients with PHN (n = 13) at 6-month follow-up were compared to those without PHN (n = 45). Sensory signs at the affected site were thermal and vibratory hypesthesia, dynamic mechanical allodynia (DMA), pressure hyperalgesia, and high wind-up (18%-29%), as well as paradoxical heat sensations and pinprick hypalgesia (13.5%). The unaffected control site exhibited thermal and vibratory hypesthesia, DMA, and pressure hyperalgesia. Dynamic mechanical allodynia and pinprick hypalgesia were mutually exclusive. Postherpetic neuralgia was associated with DMA (38.5% vs 6.7%; P = 0.010) and vibratory hypesthesia (38.5% vs 11.1%; P = 0.036) at the control site, with mechanical gain and/or loss combined with normal thermal detection (affected site: 69.2% vs 31.1%; P = 0.023; control site: 53.8% vs 15.5%; P = 0.009). Pain Disability Index (P = 0.036) and SES affective pain perception scores (P = 0.031) were over 50% higher, and 6 of 8 SF-36 subscores were over 50% lower (P < 0.045) in PHN. Sensory profiles in AHZ indicate deafferentation and central but not peripheral sensitization. Sensory signs at distant body sites, strong affective pain perception, as well as reduced quality of life and physical functioning in the acute phase may reflect risk factors for the transition to PHN.


Assuntos
Herpes Zoster/fisiopatologia , Hiperalgesia/fisiopatologia , Neuralgia Pós-Herpética/fisiopatologia , Limiar da Dor/fisiologia , Terapia por Acupuntura , Adulto , Idoso , Antivirais/uso terapêutico , Estudos de Coortes , Estudos Cross-Over , Feminino , Herpes Zoster/psicologia , Herpes Zoster/terapia , Humanos , Hiperalgesia/terapia , Masculino , Pessoa de Meia-Idade , Neuralgia Pós-Herpética/psicologia , Neuralgia Pós-Herpética/terapia , Medição da Dor , Estimulação Física/efeitos adversos , Qualidade de Vida , Inquéritos e Questionários
8.
Pain ; 160(2): 493-500, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30422872

RESUMO

Changes in facial expression are an essential form of social communication and in nonverbal infants are often used to alert care providers to pain-related distress. However, studies of early human brain development suggest that premature infants aged less than 34 weeks' gestation do not display discriminative brain activity patterns to equally salient noxious and innocuous events. Here we examine the development of facial expression in 105 infants, aged between 28 and 42 weeks' gestation. We show that the presence of facial expression change after noxious and innocuous stimulation is age-dependent and that discriminative facial expressions emerge from approximately 33 weeks' gestation. In a subset of 49 infants, we also recorded EEG brain activity and demonstrated that the temporal emergence of facial discrimination mirrors the developmental profile of the brain's ability to generate discriminative responses. Furthermore, within individual infants, the ability to display discriminative facial expressions is significantly related to brain response maturity. These data demonstrate that the emergence of behavioural discrimination in early human life corresponds to our brain's ability to discriminate noxious and innocuous events and raises fundamental questions as to how best to interpret infant behaviours when measuring and treating pain in premature infants.


Assuntos
Mapeamento Encefálico , Encéfalo/crescimento & desenvolvimento , Expressão Facial , Comportamento do Lactente/fisiologia , Comportamento do Lactente/psicologia , Eletroencefalografia , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Estimulação Física/efeitos adversos , Tempo de Reação , Estudos Retrospectivos
9.
Pain ; 159(12): 2547-2564, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30439720

RESUMO

Changes in brain function in chronic pain have been studied using paradigms that deliver acute pain-eliciting stimuli or assess the brain at rest. Although motor disability accompanies many chronic pain conditions, few studies have directly assessed brain activity during motor function in individuals with chronic pain. Using chronic jaw pain as a model, we assessed brain activity during a precisely controlled grip force task and during a precisely controlled pain-eliciting stimulus on the forearm. We used multivariate analyses to identify regions across the brain whose activity together best separated the groups. We report 2 novel findings. First, although the parameters of grip force production were similar between the groups, the functional activity in regions including the prefrontal cortex, insula, and thalamus best separated the groups. Second, although stimulus intensity and pain perception were similar between the groups, functional activity in brain regions including the dorsal lateral prefrontal cortex, rostral ventral premotor cortex, and inferior parietal lobule best separated the groups. Our observations suggest that chronic jaw pain is associated with changes in how the brain processes motor and pain-related information even when the effector producing the force or experiencing the pain-eliciting stimulus is distant from the jaw. We also demonstrate that motor tasks and multivariate analyses offer alternative approaches for studying brain function in chronic jaw pain.


Assuntos
Encéfalo/diagnóstico por imagem , Dor Crônica/diagnóstico por imagem , Dor Crônica/patologia , Dor Crônica/fisiopatologia , Arcada Osseodentária/patologia , Atividade Motora/fisiologia , Adolescente , Adulto , Idoso , Mapeamento Encefálico , Feminino , Antebraço/inervação , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Oxigênio/sangue , Estimulação Física/efeitos adversos , Inquéritos e Questionários , Escala Visual Analógica , Adulto Jovem
10.
Somatosens Mot Res ; 35(3-4): 192-198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30461318

RESUMO

BACKGROUND: Many researchers have tried to investigate pain by studying brain responses. One method used to investigate pain-related brain responses is continuous electroencephalography (EEG). The objective of the current study is to add on to our understanding of EEG responses during pain, by differentiation between EEG patterns indicative of (i) the noxious stimulus intensity and (ii) the subjective pain sensation. METHODS: EEG was recorded during the administration of tonic experimental pain, consisting of six minutes of contact heat applied to the leg via a thermode. Two stimuli above pain threshold, one at pain threshold and two non-painful stimuli were administered. Thirty-six healthy participants provided a subjective pain rating during thermal stimulation. Relative EEG power was calculated for the frequency bands alpha1, alpha2, beta1, beta2, delta, and theta. RESULTS: Whereas EEG activity could not be predicted by stimulus intensity (except in one frequency band), subjective pain sensation could significantly predict differences in EEG activity in several frequency bands. An increase in the subjective pain sensation was associated with a decrease in alpha2, beta1, beta2 as well as in theta activity across the midline electrodes. CONCLUSION: The subjective experience of pain seems to capture unique variance in EEG activity above and beyond what is captured by noxious stimulus intensity.


Assuntos
Potenciais Somatossensoriais Evocados/fisiologia , Hiperalgesia/fisiopatologia , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Dor/fisiopatologia , Adulto , Feminino , Temperatura Alta/efeitos adversos , Humanos , Masculino , Medição da Dor , Estimulação Física/efeitos adversos , Análise de Regressão , Adulto Jovem
11.
Brain Inj ; 32(13-14): 1866-1878, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30346868

RESUMO

Blast-induced traumatic brain injury (blast-TBI) is associated with vestibulomotor dysfunction, persistent post-traumatic headaches and post-traumatic stress disorder, requiring extensive treatments and reducing quality-of-life. Treatment and prevention of these devastating outcomes require an understanding of their underlying pathophysiology through studies that take advantage of animal models. Here, we report that cranium-directed blast-TBI in rats results in signs of pain that last at least 8 weeks after injury. These occur without significantly elevated behavioural markers of anxiety-like conditions and are not associated with glial up-regulation in sensory thalamic nuclei. These injuries also produce transient vestibulomotor abnormalities that resolve within 3 weeks of injury. Thus, blast-TBI in rats recapitulates aspects of the human condition.


Assuntos
Lesões Encefálicas/complicações , Dor Facial/etiologia , Reflexo Vestíbulo-Ocular/fisiologia , Transtornos das Sensações/etiologia , Análise de Variância , Animais , Traumatismos por Explosões/complicações , Lesões Encefálicas/etiologia , Adaptação à Escuridão/fisiologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Hiperalgesia/diagnóstico , Hiperalgesia/etiologia , Masculino , Aprendizagem em Labirinto , Neuroglia/metabolismo , Neuroglia/patologia , Medição da Dor , Limiar da Dor/fisiologia , Estimulação Física/efeitos adversos , Equilíbrio Postural , Ratos , Ratos Long-Evans , Teste de Desempenho do Rota-Rod , Tálamo/patologia , Fatores de Tempo
12.
J Neuroinflammation ; 15(1): 245, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30165876

RESUMO

BACKGROUND: The mechanism underlying migraine chronification remains unclear. Central sensitization may account for this progression. The microglia P2X4 receptor (P2X4R) plays a pivotal role in the central sensitization of inflammatory and neuropathic pain, but there is no information about P2X4R in migraine. Therefore, the aim of this study was to identify the precise role of microglia P2X4R in chronic migraine (CM). METHODS: We used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal and acute mechanical hypersensitivity were evaluated using the von Frey filament test. Then, we detected Iba1 immunoreactivity (Iba1-IR) and P2X4R expression in the trigeminal nucleus caudalis (TNC). To understand the effect of microglia and P2X4R on central sensitization of CM, we examined whether minocycline, an inhibitor of microglia activation, and 5-BDBD, a P2X4R antagonist, altered NTG-induced mechanical hyperalgesia. In addition, we also evaluated the effect of 5-BDBD on c-Fos and calcitonin gene-related peptide (CGRP) expression within the TNC. RESULTS: Chronic intermittent administration of NTG resulted in acute and chronic basal mechanical hyperalgesia, accompanied with microglia activation and upregulation of P2X4R expression. Minocycline significantly decreased basal pain hypersensitivity but did not alter acute NTG-induced hyperalgesia. Minocycline also reduced microglia activation. 5-BDBD completely blocked the basal and acute hyperalgesia induced by NTG. This effect was associated with a significant inhibition of the NTG-induced increase in c-Fos protein and CGRP release in the TNC. CONCLUSIONS: Our results indicate that blocking microglia activation may have an effect on the prevention of migraine chronification. Moreover, we speculate that the P2X4R may be implicated in the microglia-neuronal signal in the TNC, which contributes to the central sensitization of CM.


Assuntos
Microglia/metabolismo , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/patologia , Nitroglicerina , Receptores Purinérgicos P2X4/metabolismo , Animais , Benzodiazepinonas/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Transtornos de Enxaqueca/complicações , Minociclina/farmacologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Estimulação Física/efeitos adversos , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/genética , Núcleo Espinal do Trigêmeo/efeitos dos fármacos , Núcleo Espinal do Trigêmeo/metabolismo , Núcleo Espinal do Trigêmeo/patologia
13.
Mol Pain ; 14: 1744806918796763, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178698

RESUMO

Chronic orofacial pain is a significant health problem requiring identification of regulating processes. Involvement of epigenetic modifications that is reported for hindlimb neuropathic pain experimental models, however, is less well studied in cranial nerve pain models. Three independent observations reported here are the (1) epigenetic profile in mouse trigeminal ganglia (TG) after trigeminal inflammatory compression (TIC) nerve injury mouse model determined by gene expression microarray, (2) H3K9 acetylation pattern in TG by immunohistochemistry, and (3) efficacy of histone deacetylase (HDAC) inhibitors to attenuate development of hypersensitivity. After TIC injury, ipsilateral whisker pad mechanical sensitization develops by day 3 and persists well beyond day 21 in contrast to sham surgery. Global acetylation of H3K9 decreases at day 21 in ipsilateral TG . Thirty-four genes are significantly ( p < 0.05) overexpressed in the ipsilateral TG by at least two-fold at either 3 or 21 days post-trigeminal inflammatory compression injury. The three genes most overexpressed three days post-trigeminal inflammatory compression nerve injury are nerve regeneration-associated gene ATF3, up 6.8-fold, and two of its regeneration-associated gene effector genes, Sprr1a and Gal, up 174- and 25-fold, respectively. Although transcription levels of 25 of 32 genes significantly overexpressed three days post-trigeminal inflammatory compression return to constitutive levels by day 21, these three regeneration-associated genes remain significantly overexpressed at the later time point. On day 21, when tissues are healed, other differentially expressed genes include 39 of the top 50 upregulated and downregulated genes. Remarkably, preemptive manipulation of gene expression with two HDAC inhibitors (HDACi's), suberanilohydroxamic acid (SAHA) and MS-275, reduces the magnitude and duration of whisker pad mechanical hypersensitivity and prevents the development of a persistent pain state. These findings suggest that trigeminal nerve injury leads to epigenetic modifications favoring overexpression of genes involved in nerve regeneration and that maintaining transcriptional homeostasis with epigenetic modifying drugs could help prevent the development of persistent pain.


Assuntos
Dor Facial/complicações , Regulação da Expressão Gênica/fisiologia , Inibidores de Histona Desacetilases/uso terapêutico , Hiperalgesia/etiologia , Hiperalgesia/prevenção & controle , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Benzamidas/uso terapêutico , Proteínas Ricas em Prolina do Estrato Córneo/genética , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Modelos Animais de Doenças , Dor Facial/etiologia , Dor Facial/patologia , Lateralidade Funcional , Gânglios Espinais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nylons , Limiar da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Traumatismos do Nervo Trigêmeo/complicações , Vibrissas/inervação
14.
Mol Pain ; 14: 1744806918804441, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30209982

RESUMO

Background The amygdala plays a key role in fear learning and extinction and has emerged as an important node of emotional-affective aspects of pain and pain modulation. Impaired fear extinction learning, which involves prefrontal cortical control of amygdala processing, has been linked to neuropsychiatric disorders. Here, we tested the hypothesis that fear extinction learning ability can predict the magnitude of neuropathic pain. Results We correlated fear extinction learning in naive adult male rats with sensory and affective behavioral outcome measures (mechanical thresholds, vocalizations, and anxiety- and depression-like behaviors) before and after the induction of the spinal nerve ligation model of neuropathic pain compared to sham controls. Auditory fear conditioning, extinction learning, and extinction retention tests were conducted after baseline testing. All rats showed increased freezing responses after fear conditioning. During extinction training, the majority (75%) of rats showed a decline in freezing level to 50% in 5 min (fear extinction+), whereas 25% of the rats maintained a high freezing level (>50%, fear extinction-). Fear extinction- rats showed decreased open-arm preference in the elevated plus maze, reflecting anxiety-like behavior, but there were no significant differences in sensory thresholds, vocalizations, or depression-like behavior (forced swim test) between fear extinction+ and fear extinction- types. In the neuropathic pain model (four weeks after spinal nerve ligation), fear extinction- rats showed a greater increase in vocalizations and anxiety-like behavior than fear extinction+ rats. Fear extinction- rats, but not fear extinction+ rats, also developed depression-like behavior. Extracellular single unit recordings of amygdala (central nucleus) neurons in behaviorally tested rats (anesthetized with isoflurane) found greater increases in background activity, bursting, and evoked activity in fear extinction- rats than fear extinction+ rats in the spinal nerve ligation model compared to sham controls. Conclusion The data may suggest that fear extinction learning ability predicts the magnitude of neuropathic pain-related affective rather than sensory behaviors, which correlates with differences in amygdala activity changes.


Assuntos
Extinção Psicológica/fisiologia , Medo/psicologia , /patologia , Neuralgia/complicações , Estimulação Acústica , Potenciais de Ação/fisiologia , Tonsila do Cerebelo/patologia , Análise de Variância , Animais , Condicionamento Clássico/fisiologia , Modelos Animais de Doenças , Masculino , Transtornos do Humor/etiologia , Neuralgia/psicologia , Neurônios/fisiologia , Medição da Dor , Limiar da Dor/fisiologia , Estimulação Física/efeitos adversos , Ratos , Ratos Sprague-Dawley
15.
Neurology ; 91(9): e793-e799, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30068630

RESUMO

OBJECTIVE: To evaluate an observational-behavioral pain tool among individuals with acute poststroke aphasia. METHODS: We performed a randomized, double-blind, controlled study of experimental pain assessment among 36 adult patients with acute poststroke aphasia. Patients were administered 3 levels of mechanical pain, including placebo. The behavioral responses were video recorded and then evaluated by 3 neurology nurses using the Pain Assessment Checklist for Seniors With Limited Ability to Communicate (PACSLAC-II). Pain-specific facial action units were quantified with FaceReader version 6.1. RESULTS: Median PACSLAC-II ratings for 0-, 2-, and 4.5-lb weight stimuli were 2 (0, 3), 1 (0, 3), and 2 (1, 5), respectively. Overall, differences were not detected (p = 0.06). Pairwise comparisons with the Wilcoxon method demonstrated significance in differentiating PACSLAC-II ratings of patients experiencing the 4.5-lb stimulus vs either the 2-lb weight (p = 0.03) or placebo (p = 0.05). Overall interrater reliability by the Cronbach α was strong at 0.87, 0.94, and 0.96 for weights of 0, 2, and 4.5 lb, respectively. Pain-specific facial activation and negative valence were observed similarly in placebo and experimental pain groups. CONCLUSIONS: Among our cohort with acute poststroke aphasia, the PACSLAC-II was not able to overall differentiate patients experiencing experimental mechanical pain, although differences in those experiencing the strongest pain stimulus were significant. The detection of pain-specific facial activation and negative valence in the placebo group indicates that pain and distress are unmet needs among stroke patients who are unable to verbally communicate.


Assuntos
Afasia/complicações , Medição da Dor/métodos , Dor/diagnóstico , Dor/etiologia , Idoso , Afasia/etiologia , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Física/efeitos adversos , Estimulação Física/métodos , Psicofísica , Autorrelato , Acidente Vascular Cerebral/complicações
16.
Neurology ; 91(10): e931-e938, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30068635

RESUMO

OBJECTIVE: To characterize the pain-related somatosensory and psychological presentation of very early acute patients with a mild traumatic brain injury (mTBI). METHODS: Patients with an mTBI participated in a prospective observational study undergoing clinical, psychophysic, and psychological assessment within 72 hours after the accident. Healthy controls underwent similar protocol. RESULTS: One hundred acute patients with an mTBI (age 36 ± 12.5 [SD] years, range 19-67 years, 42 women) and 80 healthy controls (age 43 ± 14.3 years, range 24-74 years, 40 women) participated. Patients with an mTBI demonstrated a pronociceptive psychophysic response in most tests such as less efficient pressure-pain threshold-conditioned pain modulation (0.19 ±0.19±.09 vs. 0.91±.10 kg, p < 0.001) and lower temperature needed to elicit a Pain50 response (44.72 ± 0.26°C vs 46.41 ± 0.30°C, p < 0.001). Their psychophysic findings correlated with clinical pain measures, e.g., Pain50 temperature and mean head (r = -0.21, p = 0.045) and neck (r = -0.26, p = 0.011) pain. The pain-catastrophizing magnification subscale was the only psychological variable to show a difference from the controls, while no significant correlations were found between any psychological measures and the clinical or psychophysic pain measures. CONCLUSIONS: There appears to be a dichotomy between somatosensory and psychological findings in the very early acute post-mTBI stage; while the first is altered and is associated with the clinical picture, the second is unchanged. In the context of the ongoing debate on the pathophysiologic nature of the post-mTBI syndrome, our findings support its "physical" basis, free of mental influence, at least in the short time window after the injury.


Assuntos
Concussão Encefálica/complicações , Concussão Encefálica/psicologia , Dor/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/psicologia , Medição da Dor , Estimulação Física/efeitos adversos , Estudos Prospectivos , Testes Psicológicos , Psicofísica , Estatísticas não Paramétricas , Adulto Jovem
17.
Mol Pain ; 14: 1744806918795930, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30146940

RESUMO

Objective Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model. Methods P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis. Results Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons. Conclusions These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia-neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transportador 3 de Aminoácido Excitatório/metabolismo , Hiperalgesia/etiologia , Receptores Purinérgicos P2X4/metabolismo , Transdução de Sinais/fisiologia , Neuralgia do Trigêmeo/complicações , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/toxicidade , Análise de Variância , Animais , Azepinas/farmacologia , Benzamidas/farmacologia , Modelos Animais de Doenças , Masculino , Estimulação Física/efeitos adversos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X4/genética , Transdução de Sinais/efeitos dos fármacos , Neuralgia do Trigêmeo/induzido quimicamente
18.
Pain ; 159(12): 2620-2629, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30130298

RESUMO

Although nonsteroidal anti-inflammatory drugs are the first line of therapeutics for the treatment of mild to moderate somatic pain, they are not generally considered to be effective for neuropathic pain. In the current study, direct activation of spinal Toll-like 4 receptors (TLR4) by the intrathecal (IT) administration of KDO2 lipid A (KLA), the active component of lipopolysaccharide, elicits a robust tactile allodynia that is unresponsive to cyclooxygenase inhibition, despite elevated expression of cyclooxygenase metabolites in the spinal cord. Intrathecal KLA increases 12-lipoxygenase-mediated hepoxilin production in the lumbar spinal cord, concurrent with expression of the tactile allodynia. The TLR4-induced hepoxilin production was also observed in primary spinal microglia, but not in astrocytes, and was accompanied by increased microglial expression of the 12/15-lipoxygenase enzyme 15-LOX-1. Intrathecal KLA-induced tactile allodynia was completely prevented by spinal pretreatment with the 12/15-lipoxygenase inhibitor CDC or a selective antibody targeting rat 15-LOX-1. Similarly, pretreatment with the selective inhibitors ML127 or ML351 both reduced activity of the rat homolog of 15-LOX-1 heterologously expressed in HEK-293T cells and completely abrogated nonsteroidal anti-inflammatory drug-unresponsive allodynia in vivo after IT KLA. Finally, spinal 12/15-lipoxygenase inhibition by nordihydroguaiaretic acid (NDGA) both prevents phase II formalin flinching and reverses formalin-induced persistent tactile allodynia. Taken together, these findings suggest that spinal TLR4-mediated hyperpathic states are mediated at least in part through activation of microglial 15-LOX-1.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Lipoxigenases/uso terapêutico , Neuroglia/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Cromatografia Líquida , Inibidores Enzimáticos/uso terapêutico , Lipopolissacarídeos/toxicidade , Masculino , Espectrometria de Massas , Estimulação Física/efeitos adversos , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia , Receptor 4 Toll-Like/antagonistas & inibidores , Transfecção
19.
Pain ; 159(12): 2606-2619, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30130302

RESUMO

Neuropathic pain is a chronic condition that is challenging to treat. It often produces considerable physical disability and emotional distress. Patients with neuropathic pain often experience depression and anxiety both of which are known to be temporally correlated with noradrenergic dysfunction in the locus coeruleus (LC) as pain becomes chronic. Antidepressants are the first-line drug therapy for neuropathic pain, and the LC represents a potential target for such therapy. In this study, we evaluated the efficacy of the tricyclic antidepressant desipramine (DMI, a noradrenaline reuptake inhibitor) in preventing or relieving the noradrenergic impairment induced by neuropathic pain. The treatment started before or after the onset of the anxiodepressive phenotype ("early or late treatment") in adult rats subjected to chronic sciatic constriction. Electrophysiological and western blotting assays showed LC dysfunction (increased bursting activity, alpha2-adrenoceptor sensitivity, tyrosine hydroxylase, and noradrenaline transporter expression) in chronic constriction injury at long term. These noradrenergic changes were concomitant to the progression of anxiety and despair-like features. Desipramine induced efficient analgesia, and it counteracted the despair-like behavior in chronic constriction injury-DMI animals, reducing the burst rate and tyrosine hydroxylase expression. Surprisingly, "early" DMI treatment did not modify pain-induced anxiety, and it dampened pain aversion, although these phenomena were abolished when the treatment commenced after noradrenaline impairment had been established. Hence, DMI seems to produce different outcomes depending when the treatment commences, indicating that the balance between the benefits and adverse effects of DMI therapy may shift as neuropathy progresses.


Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Desipramina/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/etiologia , Neuralgia/complicações , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Proteína de Ligação a CREB/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Reação de Fuga/efeitos dos fármacos , Hiperalgesia/complicações , Hiperalgesia/etiologia , Locus Cerúleo/citologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Estimulação Física/efeitos adversos , Ratos , Ratos Sprague-Dawley , Natação , Tubulina (Proteína)/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
20.
Neuron ; 99(5): 1016-1028.e5, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30122379

RESUMO

Emotions evoked by environmental cues are important for animal survival and life quality. However, neural circuits responsible for transforming sensory signals to aversive emotion and behavioral avoidance remain unclear. Here, we found that medial septum (MS) mediates aversion induced by both auditory and somatosensory stimuli. Ablation of glutamatergic or GABAergic MS neurons results in impaired or strengthened aversion, respectively. Optogenetic activation of the two cell types results in place avoidance and preference, respectively. Cell-type-specific screening reveals that glutamatergic MS projections to the lateral habenula (LHb) are responsible for the induction of aversion, which can be antagonized by GABAergic MS projections to LHb. Additionally, the sensory-induced place avoidance is facilitated by enhanced locomotion mediated by glutamatergic MS projections to the preoptic area. Thus, MS can transmit innately aversive signals via a bottom-up multimodal sensory pathway and produce concurrent emotional and motional effects, allowing animals to efficiently avoid unfavorable environments.


Assuntos
Aprendizagem da Esquiva/fisiologia , Sinais (Psicologia) , Emoções/fisiologia , Habenula/fisiologia , Sensação/fisiologia , Septo do Cérebro/fisiologia , Estimulação Acústica/efeitos adversos , Animais , Feminino , Habenula/química , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/química , Vias Neurais/fisiologia , Técnicas de Cultura de Órgãos , Estimulação Física/efeitos adversos , Septo do Cérebro/química
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