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1.
Life Sci ; 237: 116926, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31614148

RESUMO

Sex-related differences in pain and opioids has been the focus of many researches. It is demonstrated that women experience greater clinical pain, lower pain threshold and tolerance, more sensitivity and distress to experimentally induced pain compared to men. Sex differences in response to opioid treatment revealed inconsistent results. However, the etiology of these disparities is not fully elucidated. It is, therefore, conceivable now that this literature merits to be revisited comprehensively. Possible multifaceted factors seem to be associated. These include neuroanatomical, hormonal, neuroimmunological, psychological, social and cultural aspects and comorbidities. This review aims at providing an overview of the substantial literature documenting the sex differences in pain and analgesic response to opioids from animal and human studies within the context of the modulatory effects of the aforementioned factors. A detailed and critical discussion of the cellular and molecular signaling pathways underlying the modulatory actions of gonadal hormones in the sexual dimorphism in pain processing and opioid analgesia is extensively presented. It is indicated that sexual dimorphic activation of certain brain regions contributes to differential pain sensitivity between females and males. Plausible crosstalk between sex hormones and neuroimmunological signaling pertinent to toll-like and purinergic receptors is uncovered as causal cues underlying sexually dimorphic pain and opioid analgesia. Conceivably, a thorough understanding of these factors may aid in sex-related advancement in pain therapeutic management.


Assuntos
Analgésicos Opioides/administração & dosagem , Hormônios Gonadais/metabolismo , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Animais , Feminino , Humanos , Masculino , Nociceptividade/fisiologia , Dor/metabolismo , Caracteres Sexuais
2.
PLoS Comput Biol ; 15(7): e1007106, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31295266

RESUMO

Experimental studies show that human pain sensitivity varies across the 24-hour day, with the lowest sensitivity usually occurring during the afternoon. Patients suffering from neuropathic pain, or nerve damage, experience an inversion in the daily modulation of pain sensitivity, with the highest sensitivity usually occurring during the early afternoon. Processing of painful stimulation occurs in the dorsal horn (DH), an area of the spinal cord that receives input from peripheral tissues via several types of primary afferent nerve fibers. The DH circuit is composed of different populations of neurons, including excitatory and inhibitory interneurons, and projection neurons, which constitute the majority of the output from the DH to the brain. In this work, we develop a mathematical model of the dorsal horn neural circuit to investigate mechanisms for the daily modulation of pain sensitivity. The model describes average firing rates of excitatory and inhibitory interneuron populations and projection neurons, whose activity is directly correlated with experienced pain. Response in afferent fibers to peripheral stimulation is simulated by a Poisson process generating nerve fiber spike trains at variable firing rates. Model parameters for fiber response to stimulation and the excitability properties of neuronal populations are constrained by experimental results found in the literature, leading to qualitative agreement between modeled responses to pain and experimental observations. We validate our model by reproducing the wind-up of pain response to repeated stimulation. We apply the model to investigate daily modulatory effects on pain inhibition, in which response to painful stimuli is reduced by subsequent non-painful stimuli. Finally, we use the model to propose a mechanism for the observed inversion of the daily rhythmicity of pain sensation under neuropathic pain conditions. Underlying mechanisms for the shift in rhythmicity have not been identified experimentally, but our model results predict that experimentally-observed dysregulation of inhibition within the DH neural circuit may be responsible. The model provides an accessible, biophysical framework that will be valuable for experimental and clinical investigations of diverse physiological processes modulating pain processing in humans.


Assuntos
Ritmo Circadiano/fisiologia , Modelos Neurológicos , Dor/fisiopatologia , Corno Dorsal da Medula Espinal/fisiopatologia , Biologia Computacional , Gânglios Espinais/fisiopatologia , Humanos , Interneurônios/fisiologia , Rede Nervosa/fisiologia , Neuralgia/fisiopatologia , Nociceptividade/fisiologia , Dor Nociceptiva/fisiopatologia , Percepção da Dor/fisiologia
3.
Nat Neurosci ; 22(9): 1477-1492, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358991

RESUMO

Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors. OXT population activity reflects the sensorimotor transformation of the noxious stimulus, with some neurons encoding sensory information and others correlating more strongly with large-angle swims. Notably, OXT neuron activation is sufficient to generate this defensive behavior via the recruitment of brainstem premotor targets, whereas ablation of OXT neurons or loss of the peptide attenuates behavioral responses to TRPA1 activation. These data highlight a crucial role for OXT neurons in the generation of appropriate defensive responses to noxious input.


Assuntos
Tronco Encefálico/fisiologia , Vias Neurais/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia , Animais , Tronco Encefálico/citologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Vias Neurais/citologia , Nociceptores/citologia , Ocitocina , Peixe-Zebra
4.
Invest Ophthalmol Vis Sci ; 60(7): 2532-2542, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31195410

RESUMO

Purpose: The purpose of this study was to study the status and association among tear-soluble factors, corneal dendritic cell density, vitamin D, and signs and symptoms in dry eye disease (DED). Methods: A total of 33 control subjects and 47 evaporative dry eye patients were included in the study. DED diagnosis and classification was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). DED workup, including tear film break-up time (TBUT), Schirmer's test I (STI), corneal and conjunctival staining, ocular surface disease index (OSDI) scoring, and in vivo confocal microscopy (to assess corneal dendritic cell density [cDCD] and subbasal nerve plexus [SBNP] features) was performed in the study subjects. Tear fluid using Schirmer's strip and serum were collected from the subjects. Multiplex ELISA or single analyte ELISA was performed to measure 34 tear-soluble factors levels including vitamin D. Results: Significantly higher OSDI discomfort score, lower TBUT, and lower STI were observed in DED patients. cDCD was significantly higher in DED patients. No significant difference was observed in SBNP features. Tear fluid IL-1ß, IL-17A, MMP9, MMP10, MMP9/TIMP ratio, and VEGF-B were significantly higher in DED patients. Significantly lower tear fluid IL-2, IP-10, NPY, VEGF-A, and vitamin D was observed in DED patients. These dysregulated tear factors showed significant associations with DED signs and symptoms. Conclusions: Altered tear fluid soluble factors with potential to modulate nociception exhibited a distinct association with ocular surface discomfort status, TBUT, STI, and cDCD. This implies a functional relationship between the various tear-soluble factors and dry eye pathogenesis, indicating new molecular targets for designing targeted therapies.


Assuntos
Córnea/patologia , Células Dendríticas/patologia , Síndromes do Olho Seco/metabolismo , Proteínas do Olho/metabolismo , Nociceptividade/fisiologia , Vitamina D/sangue , Adulto , Contagem de Células , Estudos Transversais , Síndromes do Olho Seco/diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Microscopia Confocal , Lágrimas/metabolismo
5.
Ann Anat ; 225: 28-32, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195095

RESUMO

Anterior cruciate ligament (ACL) tears is a devastating injury and one of the most common knee injuries experienced by athletes in the United States. Although patients reach maximal subjective improvement by one-year following ACL reconstruction, many patients often experience moderate to severe post-operative pain. Opioids, intra-articular injections, and regional anesthesia have been previously implemented to mediate post-operative pain. However, chronic opioid usage has become an epidemic in the United States. Alternative analgesic modalities, such as nerve blocks, have been implemented in clinical practice to provide adequate pain relief and minimize opioid usage. Periarticular injections targeted towards local neurological structures performed concomitantly with nerve blocks provides superior pain relief and satisfaction than isolated nerve blocks. Therefore, it is imperative for physicians to understand local neurological anatomy around the knee joint in order to provide adequate analgesia while minimizing opioid consumption. This purpose of this investigation is to summarize (1) neurogenic origins of pain generators and mediators in sites affected by ACL reconstruction and autograft harvest sites and (2) analgesia utilized in ACL reconstruction.


Assuntos
Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/anatomia & histologia , Articulação do Joelho/irrigação sanguínea , Articulação do Joelho/inervação , Dor Pós-Operatória/etiologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestesia Local , Anestésicos Locais/administração & dosagem , Ligamento Cruzado Anterior/inervação , Ligamento Cruzado Anterior/cirurgia , Autoenxertos , Canais Iônicos/metabolismo , Mecanorreceptores/fisiologia , Bloqueio Nervoso , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia
6.
Neural Plast ; 2019: 2057308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223307

RESUMO

Our previous studies have confirmed that electroacupuncture (EA) can effectively intervene in pain memory, but the neural mechanism involved remains unclear. In this study, we observed the effects of EA in regulating pain memory-related behaviors and synchronous neural oscillations in the rostral anterior cingulate cortex (rACC). During nociceptive behavioral testing, pain memory induced a nonpain stimulus that spurred a neural oscillatory reaction similar to that caused by pain stimuli in the rACC. After EA, nonpain stimuli did not induce decreased neural oscillatory activity in the rACC until the presentation of pain stimuli. During aversive behavioral testing, EA, through the downregulation of theta power, inhibited the retrieval of aversive memory and relieved pain memory-induced aversive behaviors. These changes of oscillatory activity may be the hallmarks of EA therapy for pain memory.


Assuntos
Comportamento Animal/fisiologia , Ondas Encefálicas/fisiologia , Eletroacupuntura , Giro do Cíngulo/fisiopatologia , Memória/fisiologia , Dor/fisiopatologia , Animais , Masculino , Nociceptividade/fisiologia , Limiar da Dor , Ratos , Ratos Sprague-Dawley
7.
J Headache Pain ; 20(1): 46, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053057

RESUMO

BACKGROUND: Despite the growing body of advanced studies investigating the neuronal correlates of pain processing in patients with migraine without aura (MwoA), only few similar studies have been conducted in patients with migraine with aura (MwA). Therefore, we aimed to explore the functional brain response to trigeminal noxious heat stimulation in patients with MwA. METHODS: Seventeen patients with MwA and 15 age- and sex-matched healthy controls (HC) underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during trigeminal noxious heat stimulation. To examine the specificity of any observed differences between patients with MwA and HC, the functional response of neural pathways to trigeminal noxious heat stimulation in patients with MwA was compared with 18 patients with MwoA. Secondary analyses investigated the correlations between BOLD signal changes and clinical parameters of migraine severity. RESULTS: We observed a robust cortical and subcortical pattern of BOLD response to trigeminal noxious heat stimulation across all participants. Patients with MwA showed a significantly increased activity in higher cortical areas known to be part of a distributed network involved in advanced visual processing, including lingual gyrus, inferior parietal lobule, inferior frontal gyrus and medial frontal gyrus. Moreover, a significantly greater cerebellar activation was observed in patients with MwA when compared with both patients with MwA and HC. Interestingly, no correlations were found between migraine severity parameters and magnitude of BOLD response in patients with MwA. CONCLUSION: Our findings, characterized by abnormal visual pathway response to trigeminal noxious heat stimulation, support the role of a functional integration between visual and trigeminal pain networks in the pathophysiological mechanisms underlying migraine with aura. Moreover, they expand the concept of "neurolimbic-pain network" as a model of MwoA including both limbic dysfunction and cortical dys-excitability. Indeed, we suggest a model of "neurolimbic-visual-pain network" in MwA patients, characterized by dysfunctional correlations between pain-modulating circuits not only with the cortical limbic areas but with advanced visual areas as well. Furthermore, the abnormal cerebellar response to trigeminal noxious heat stimulation may suggest a dysfunctional cerebellar inhibitory control on thalamic sensory gating, impinging on the advanced visual processing cortical areas in patients with MwA.


Assuntos
Cerebelo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Enxaqueca com Aura/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Núcleos do Trigêmeo/diagnóstico por imagem , Córtex Visual/diagnóstico por imagem , Adulto , Cerebelo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/fisiopatologia , Rede Nervosa/fisiopatologia , Vias Neurais/fisiopatologia , Nociceptividade/fisiologia , Dor/diagnóstico por imagem , Dor/fisiopatologia , Medição da Dor/métodos , Estudos Prospectivos , Distribuição Aleatória , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologia , Núcleos do Trigêmeo/fisiopatologia , Córtex Visual/fisiopatologia , Vias Visuais/diagnóstico por imagem , Vias Visuais/fisiopatologia , Adulto Jovem
8.
J Clin Neurosci ; 65: 17-22, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31080004

RESUMO

Pain sensitivity is a recognized feature of fibromyalgia syndrome (FMS) but the contribution of spinal nociceptive circuitry to this phenomenon is unknown. Therefore, the objectives were to study the changes in spinal nociception i.e. nociceptive flexion reflex (NFR) in patients with FMS and to investigate correlation if any, between NFR threshold, pain duration and tender points in FMS. One hundred and three patients with FMS and 74 healthy volunteers participated in the study. To record NFR, sural nerve was stimulated in the retro malleolar region and the reflex response was recorded from the short head of biceps femoris muscle. NFR was elicited at significantly lower [21.0(18.0-25.0)V] thresholds in FMS group when compared to healthy subjects [30.0(24.75-35.0)V; p = 0.001] indicating hyperalgesic response to electrocutaneous stimulation in FMS patients. The latency and other parameters of NFR were comparable in both the groups. No significant correlation was found among NFR threshold and pain duration or tender points. On the basis of results of present study, it may be concluded that the functional deficit of the spinal nociceptive system can contribute to hyperalgesia in FMS. This is first study that correlates a marker of central hyper-excitability (NFR threshold) with clinical symptoms (pain duration and tender points) of FMS.


Assuntos
Fibromialgia/fisiopatologia , Hiperalgesia/fisiopatologia , Nociceptividade/fisiologia , Limiar da Dor/fisiologia , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/fisiopatologia , Reflexo/fisiologia
9.
Curr Opin Anaesthesiol ; 32(3): 427-437, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30985340

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to describe the anesthesiologist's perioperative challenges when caring for the patient with substance use disorder and, in particular, opioid use disorder. RECENT FINDINGS: With the introduction of the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, psychiatric literature recently changed the criteria for defining substance use disorder. In patients with known opioid use disorder, who are undergoing elective surgery and also on maintenance therapy, use of multimodal analgesia is essential to treat postoperative pain. SUMMARY: Patients with substance use disorders and, in particular, those addicted to opioids, present a challenge to the anesthesiologist. Whether the diagnosis of substance use disorder is known or unknown and whether on maintenance therapy, in withdrawal, or remission, patients with this condition represent a special surgical population whose perioperative care can influence their postoperative and disease course for many years.


Assuntos
Analgésicos/administração & dosagem , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/complicações , Dor Pós-Operatória/terapia , Assistência Perioperatória/métodos , Relação Dose-Resposta a Droga , Humanos , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Manejo da Dor/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/fisiopatologia , Período Pós-Operatório
10.
Neuroscience ; 408: 259-271, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30999033

RESUMO

Human studies have repeatedly shown that conditioning pain modulation (CPM) exerts an overall descending inhibitory effect over spinal nociceptive activity. Previous studies have reported a reduction of the nociceptive withdrawal reflex (NWR) under CPM. Still, how descending control influences the muscle activation patterns involved in this protective behavior remains unknown. This study aimed to characterize the effects of CPM on the withdrawal pattern assessed by a muscle synergy analysis of several muscles involved in the lower limb NWR. To trigger descending inhibition, CPM paradigm was applied using the cold-pressor test (CPT) as conditioning stimulus. Sixteen healthy volunteers participated. The NWR was evoked by electrical stimulation on the arch of the foot before, during and after the CPT. Electromyographic (EMG) activity of two proximal (rectus femoris and biceps femoris) and two distal (tibialis anterior and soleus) muscles was recorded. A muscle synergy analysis was performed on the decomposition of the EMG signals, based on a non-negative matrix factorization algorithm. Results showed that two synergies (Module I and II) were sufficient to describe the NWR pattern. Under CPM, Module I activation amplitude was significantly reduced in a narrow time-window interval (118-156 ms) mainly affecting distal muscles, whereas Module II activation amplitude was significantly reduced in a wider time-window interval (150-250 ms), predominantly affecting proximal muscles. These findings suggest that proximal muscles are largely under supraspinal control. The descending inhibitory drive exerted onto the spinal cord may adjust the withdrawal pattern by differential recruitment of the muscles involved in the protective behavior.


Assuntos
Músculo Esquelético/fisiopatologia , Nociceptividade/fisiologia , Limiar da Dor/fisiologia , Dor/fisiopatologia , Reflexo/fisiologia , Adulto , Estimulação Elétrica , Eletromiografia , Feminino , Humanos , Masculino , Medição da Dor , Adulto Jovem
11.
Brain Behav ; 9(5): e01285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30980517

RESUMO

INTRODUCTION: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10-15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. METHODS: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12-19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11-17). RESULTS: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. CONCLUSIONS: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.


Assuntos
Nociceptividade/fisiologia , Sistema Nervoso Periférico , Síndrome de Rett , Células Receptoras Sensoriais , Pele , Adolescente , Biópsia/métodos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Criança , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Microscopia Confocal/métodos , Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/fisiopatologia , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Pele/inervação , Pele/patologia , Adulto Jovem
12.
Neural Plast ; 2019: 2098083, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984253

RESUMO

Although referred pain or hypersensitivity has been repeatedly reported in irritable bowel syndrome (IBS) patients and experimental colitis rodents, little is known about the neural mechanisms. Spinal long-term potentiation (LTP) of nociceptive synaptic transmission plays a critical role in the development of somatic hyperalgesia in chronic pain conditions. Herein, we sought to determine whether spinal LTP contributes to the referral hyperalgesia in colitis rats and particularly whether electroacupuncture (EA) is effective to alleviate somatic hyperalgesia via suppressing spinal LTP. Rats in the colitis group (induced by colonic infusion of 2,4,6-trinitrobenzenesulfonic acid, TNBS), instead of the control and vehicle groups, displayed evident focal inflammatory destruction of the distal colon accompanied not only with the sensitized visceromotor response (VMR) to noxious colorectal distension (CRD) but also with referral hindpaw hyperalgesia indicated by reduced mechanical and thermal withdrawal latencies. EA at Zusanli (ST36) and Shangjuxu (ST37) attenuated the severity of colonic inflammation, as well as the visceral hypersensitivity and referral hindpaw hyperalgesia in colitis rats. Intriguingly, the threshold of C-fiber-evoked field potentials (CFEFP) was significantly reduced and the spinal LTP was exaggerated in the colitis group, both of which were restored by EA treatment. Taken together, visceral hypersensitivity and referral hindpaw hyperalgesia coexist in TNBS-induced colitis rats, which might be attributed to the enhanced LTP of nociceptive synaptic transmission in the spinal dorsal horn. EA at ST36 and ST37 could relieve visceral hypersensitivity and, in particular, attenuate referral hindpaw hyperalgesia by suppressing the enhanced spinal LTP.


Assuntos
Colite/fisiopatologia , Eletroacupuntura , Hiperalgesia/fisiopatologia , Potenciação de Longa Duração , Nociceptividade/fisiologia , Medula Espinal/fisiopatologia , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Modelos Animais de Doenças , Membro Posterior/fisiopatologia , Hiperalgesia/complicações , Masculino , Limiar da Dor , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico/administração & dosagem
13.
Br J Anaesth ; 123(2): e322-e327, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30915996

RESUMO

BACKGROUND: Potential methods for objective assessment of postoperative pain include the Analgesia Nociception Index™ (ANI), a real-time index of the parasympathetic tone, the pupillary light reflex (PLR), and the variation coefficient of pupillary diameter (VCPD), a measure of pupillary diameter (PD) fluctuations. Until now, the literature is divided as to their respective accuracy magnitudes for assessing a patient's pain. The VCPD has been demonstrated to strongly correlate with pain in an obstetrical population. However, the pain induced by obstetrical labour is different, given its intermittent nature, than the pain observed during the postoperative period. The aim of the current study was to compare the respective values of these variables at VAS scores ≥4. METHODS: After approval by the Ethics Committee, 345 patients aged on average 50 (SD 17) yr (range: 18-91 yr) of age were included. The protocols of general anaesthesia and postoperative analgesia were left to the anaesthetist's discretion. Some 40 min after tracheal intubation, VAS, ANI, PD, PLR, and VCPD values were recorded. RESULTS: VCPD correlates more strongly (r=0.78) with pain as assessed with the VAS than ANI (r=-0.15). PD and PLR are not statistically correlated with VAS. The ability of VCPD to assess the pain of patients (VAS≥4) is strong [area under the curve (AUC): 0.92, confidence interval (CI): 0.89-0.95], and better than for ANI (AUC: 0.39, CI: 0.33-0.45). CONCLUSIONS: Our study suggests that VCPD could be a useful tool for monitoring pain in conscious patients during the postoperative period. CLINICAL TRIAL REGISTRATION: NCT03267979.


Assuntos
Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Nociceptividade/fisiologia , Medição da Dor/métodos , Dor Pós-Operatória/diagnóstico , Reflexo Pupilar/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgesia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Exp Brain Res ; 237(6): 1551-1561, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30927042

RESUMO

Complexity in movement planning, arising from diverse temporal and spatial sources, places a computational burden on the central nervous system. However, the efficacy with which humans can perform natural, highly trained movements suggests that they have evolved effective behavioral strategies that simplify the computational burden. The specific aim of our research was to use three-dimensional high-speed video to determine whether the tail nociceptive withdrawal response (NWR) to noxious heat stimuli delivered at locations that varied both circumferentially and rostral-caudally on the tail depended on the location of the stimulus in spinalized rats. In particular, we sought to determine whether the movement strategy was categorical (limited number of directions) or continuous (any variation in stimulus location results in a variation in response direction). In spinalized rats, localized, noxious heat stimuli were delivered at eight locations circumferentially around the tail and at five rostral-caudal levels. Our results demonstrate that at all rostral-caudal levels, response movement direction was bimodal regardless of circumferential stimulus location-either ~ 64° left or right of ventral. However, in spite of tight clustering, movement direction varied significantly but weakly according to circumferential location, in that responses to stimuli were more lateral for lateral stimulus locations. In contrast, changes in stimulus level strongly affected movement direction, in that a localized bend response closely matched the level of the stimulus. Together, our results demonstrate, based on movement analysis in spinalized rats, that the NWR employs a hybrid categorical-continuous strategy that may minimize the harmful consequences of noxious stimuli.


Assuntos
Comportamento Animal/fisiologia , Movimento/fisiologia , Nociceptividade/fisiologia , Cauda/fisiologia , Animais , Masculino , Estimulação Física , Ratos , Ratos Sprague-Dawley , Medula Espinal/cirurgia , Temperatura Ambiente
15.
Neuron ; 101(6): 1029-1041, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897355

RESUMO

Since noxious stimulation usually leads to the perception of pain, pain has traditionally been considered sensory nociception. But its variability and sensitivity to a broad array of cognitive and motivational factors have meant it is commonly viewed as inherently imprecise and intangibly subjective. However, the core function of pain is motivational-to direct both short- and long-term behavior away from harm. Here, we illustrate that a reinforcement learning model of pain offers a mechanistic understanding of how the brain supports this, illustrating the underlying computational architecture of the pain system. Importantly, it explains why pain is tuned by multiple factors and necessarily supported by a distributed network of brain regions, recasting pain as a precise and objectifiable control signal.


Assuntos
Encéfalo/fisiologia , Aprendizagem/fisiologia , Motivação , Nociceptividade/fisiologia , Percepção da Dor/fisiologia , Dor , Aprendizagem da Esquiva , Cognição , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Humanos
16.
BMC Anesthesiol ; 19(1): 29, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832563

RESUMO

BACKGROUND: This preclinical study in humans was designed to selectively induce delayed nociceptive pain responses to individually titrated laser stimulation, enabling separate bedside intensity scoring of both immediate and delayed pain. METHODS: Forty-four (fourteen female) healthy volunteers were subjected to repeated nociceptive dermal stimulation in the plantar arc, based on ultra-short carbon dioxide laser with individually titrated energy levels associated with mild pain. RESULTS: Data was analysed in 42 (12 female) subjects, and 29 of them (11 females) consistently reported immediate and delayed pain responses at second-long intervals to each nociceptive stimulus. All single pain responses were delayed and associated with lower levels (p = 0.003) of laser energy density (median 61; IQR 54-71 mJ/mm2), compared with double pain responses (88; 64-110 mJ/mm2). Pain intensity levels associated with either kind of response were readily assessable at bedside. CONCLUSIONS: This study is the first one to show in humans that individually titrated ultra-short pulses of laser stimulation, enabling separate pain intensity scoring of immediate and delayed responses at bedside, can be used to selectively induce and evaluate delayed nociceptive pain, most likely reflecting C-fibre-mediated transmission. These findings might facilitate future research on perception and management of C-fibre-mediated pain in humans.


Assuntos
Lasers de Gás , Nociceptividade/fisiologia , Medição da Dor/métodos , Dor/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Fibras Nervosas Amielínicas/metabolismo , Estudos Prospectivos , Fatores de Tempo , Adulto Jovem
17.
Nat Commun ; 10(1): 983, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816113

RESUMO

In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.


Assuntos
Aprendizagem da Esquiva/fisiologia , Ritmo Gama/fisiologia , Nociceptividade/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Feminino , Humanos , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Vias Neurais/fisiologia , Optogenética , Córtex Pré-Frontal/fisiologia , Neurônios Serotoninérgicos/fisiologia
18.
Cell Mol Life Sci ; 76(10): 1889-1899, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788514

RESUMO

Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.


Assuntos
Neuralgia/fisiopatologia , Dor Nociceptiva/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Pré-Sinápticos/fisiologia , Medula Espinal/fisiopatologia , Animais , Camundongos , Neuralgia/metabolismo , Nociceptividade/fisiologia , Dor Nociceptiva/metabolismo , Nociceptores/metabolismo , Nociceptores/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Pré-Sinápticos/metabolismo
19.
Neuropharmacology ; 149: 113-123, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30768945

RESUMO

BACKGROUND: Recent discovery of mechanosensitive Piezo receptors in trigeminal ganglia suggested the novel molecular candidate for generation of migraine pain. However, the contribution of Piezo channels in migraine pathology was not tested yet. Therefore, in this study, we explored a potential involvement of Piezo channels in peripheral trigeminal nociception implicated in generation of migraine pain. METHODS: We used immunohistochemistry, calcium imaging, calcitonin gene related peptide (CGRP) release assay and electrophysiology in mouse and rat isolated trigeminal neurons and rat hemiskulls to study action of various stimulants of Piezo receptors on migraine-related peripheral nociception. RESULTS: We found that essential (35%) fraction of isolated rat trigeminal neurons responded to chemical Piezo1 agonist Yoda1 and about a half of Yoda1 positive neurons responded to hypo-osmotic solution (HOS) and a quarter to mechanical stimulation by focused ultrasound (US). In ex vivo hemiskull preparation, Yoda1 and HOS largely activated persistent nociceptive firing in meningeal branches of trigeminal nerve. By using our novel cluster analysis of pain spikes, we demonstrated that 42% of fibers responded to Piezo1 agonist and 20% of trigeminal fibers were activated by Yoda1 and by capsaicin, suggesting expression of Piezo receptors in TRPV1 positive peptidergic nociceptive nerve fibers. Consistent with this, Yoda1 promoted the release of the key migraine mediator CGRP from hemiskull preparation. CONCLUSION: Taken together, our data suggest the involvement of mechanosensitive Piezo receptors, in particular, Piezo1 subtype in peripheral trigeminal nociception, which provides a new view on mechanotransduction in migraine pathology and suggests novel molecular targets for anti-migraine medicine.


Assuntos
Canais Iônicos/agonistas , Meninges/fisiologia , Transtornos de Enxaqueca/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Animais , Cálcio , Canais Iônicos/metabolismo , Mecanorreceptores/fisiologia , Mecanotransdução Celular , Meninges/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Aferentes/metabolismo , Nociceptores/fisiologia , Dor , Cultura Primária de Células , Ratos , Ratos Wistar , Células Receptoras Sensoriais , Nervo Trigêmeo/fisiologia
20.
Mol Pain ; 15: 1744806918823477, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799695

RESUMO

Aggressive breast cancer subtypes utilize system xc-, a membrane antiporter, to import cystine for glutathione synthesis and maintenance of redox homeostasis, in turn releasing glutamate as a metabolic pro-nociceptive by-product. Metastatic breast cancers establish themselves at distal sites including bone, where changes in extracellular glutamate levels contribute to cancer-induced bone pain. We previously established that stearically blocking system xc- activity with sulfasalazine delays the onset of nociceptive behaviours and that xCT, the functional antiporter subunit, is positively regulated by signal transducer and activator of transcription 3 (STAT3). In the current investigation, a murine xenograft cancer-induced bone pain model was applied to examine whether pharmacological inhibition of phosphorylated STAT3 (pSTAT3) induces changes in nociception. A high glutamate-releasing, xCT/pSTAT3 over-expressing human breast cancer cell line was selected for injection into the distal epiphysis of the right femur of female nude mice. A 14-day regimen of intraperitoneal injections with either vehicle or the novel STAT3 inhibitor DR-1-55 commenced three weeks after initial intrafemoral bone injection. Nociceptive behaviours were temporally monitored by automated von Frey, dynamic weight bearing and open-field testing for the duration of the study, beginning at the baseline. Prior to sacrifice and at ethical end point, tumour-induced osteolytic lesions were radiographically assessed. Treatment with DR-1-55 significantly delayed the onset and severity of spontaneous and induced nociceptive behaviours, also decreasing human SLC7A11 ( xCT) mRNA levels in tumour-bearing limbs without altering osteolysis. In addition, two pro-inflammatory cytokines released by this cell line, interleukin 6 and interleukin 1ß, were also down-regulated at the mRNA level in response to DR-1-55 treatment in vivo, with lower human interleukin 6 levels detected in the host circulation. This study demonstrates that targeting pSTAT3 may be a viable therapeutic means to manage cancer-induced bone pain, alone or in combination with stearic system xc- blockers.


Assuntos
Osso e Ossos/patologia , Dor do Câncer/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Nociceptividade/fisiologia , Fator de Transcrição STAT3/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/complicações , Dor do Câncer/etiologia , Dor do Câncer/terapia , Carcinoma/complicações , Linhagem Celular Tumoral/patologia , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Nus , Nociceptividade/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Suporte de Carga/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
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