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1.
Proc Natl Acad Sci U S A ; 119(33): e2118501119, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35943985

RESUMO

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.


Assuntos
Galanina , Gânglios Espinais , Rede Nervosa , Neurotensina , Nociceptores , Dor , Prurido , Animais , Galanina/metabolismo , Gânglios Espinais/ultraestrutura , Herpesvirus Humano 1 , Camundongos , Camundongos Transgênicos , Rede Nervosa/ultraestrutura , Neurotensina/metabolismo , Nociceptores/metabolismo , Dor/fisiopatologia , Prurido/fisiopatologia , Núcleo Solitário/ultraestrutura
2.
Proc Natl Acad Sci U S A ; 119(30): e2114094119, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35858441

RESUMO

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Hiperalgesia , Dor , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Modelos Animais de Doenças , Giro do Cíngulo/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Comportamento Impulsivo , Camundongos , Optogenética , Oxidopamina/farmacologia , Dor/induzido quimicamente , Dor/fisiopatologia , Simpatolíticos/farmacologia
3.
Science ; 377(6601): 80-86, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35617374

RESUMO

Activation of microglia in the spinal cord dorsal horn after peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that after peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.


Assuntos
Hiperalgesia , Microglia , Dor , Traumatismos dos Nervos Periféricos , Corno Dorsal da Medula Espinal , Animais , Matriz Extracelular/patologia , Hiperalgesia/etiologia , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Microglia/patologia , Dor/patologia , Dor/fisiopatologia , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/patologia , Ratos , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/patologia , Corno Dorsal da Medula Espinal/fisiopatologia
4.
Brain ; 145(7): 2586-2601, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35598161

RESUMO

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved. We now expose a cellular circuit that inhibits nocioception and itch in mice. Through a combination of molecular, tracing and behavioural approaches, we found that rostral ventromedial medulla neurons containing the kappa-opioid receptor inhibit itch and nocioception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that rostral ventromedial medulla kappa-opioid receptor neurons inhibit nocioception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal grey that modulates nociception within the rostral ventromedial medulla. These discoveries highlight a distinct population of rostral ventromedial medulla neurons capable of broadly and robustly inhibiting itch and nocioception.


Assuntos
Bulbo , Neurônios , Dor , Prurido , Receptores Opioides kappa , Animais , Bulbo/citologia , Camundongos , Neurônios/fisiologia , Dor/fisiopatologia , Prurido/fisiopatologia , Receptores Opioides kappa/metabolismo
5.
Proc Natl Acad Sci U S A ; 119(21): e2118847119, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35594393

RESUMO

G protein­coupled receptors (GPCRs) are involved in regulation of manifold physiological processes through coupling to heterotrimeric G proteins upon ligand stimulation. Classical therapeutically active drugs simultaneously initiate several downstream signaling pathways, whereas biased ligands, which stabilize subsets of receptor conformations, elicit more selective signaling. This concept of functional selectivity of a ligand has emerged as an interesting property for the development of new therapeutic molecules. Biased ligands are expected to have superior efficacy and/or reduced side effects by regulating biological functions of GPCRs in a more precise way. In the last decade, 5-HT7 receptor (5-HT7R) has become a promising target for the treatment of neuropsychiatric disorders, sleep and circadian rhythm disorders, and pathological pain. In this study, we showed that Serodolin is unique among a number of agonists and antagonists tested: it behaves as an antagonist/inverse agonist on Gs signaling while inducing ERK activation through a ß-arrestin­dependent signaling mechanism that requires c-SRC activation. Moreover, we showed that Serodolin clearly decreases hyperalgesia and pain sensation in response to inflammatory, thermal, and mechanical stimulation. This antinociceptive effect could not be observed in 5-HT7R knockout (KO) mice and was fully blocked by administration of SB269-970, a specific 5-HT7R antagonist, demonstrating the specificity of action of Serodolin. Physiological effects of 5-HT7R stimulation have been classically shown to result from Gs-dependent adenylyl cyclase activation. In this study, using a ß-arrestin­biased agonist, we provided insight into the molecular mechanism triggered by 5-HT7R and revealed its therapeutic potential in the modulation of pain response.


Assuntos
Arrestina , Dor , Serotonina , Arrestina/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Ligantes , Dor/tratamento farmacológico , Dor/fisiopatologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , beta-Arrestina 1/metabolismo , beta-Arrestinas/metabolismo
7.
Arthroscopy ; 38(3): 783-785, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35248229

RESUMO

There is a well-established relationship between mental distress, mental health disorders, and the perception of pain and physical dysfunction. While determining the root cause is often challenging, increasing levels of mental distress are associated with increasingly disruptive manifestation of physical symptoms and vice versa. In femoroacetabular impingement syndrome, patients with preoperative mental distress exhibit more impactful levels of symptoms. Patients do show symptomatic improvement with appropriate surgical management, even in the presence of mental distress. Patients and surgeons should recognize both the physical and mental contributions to pain perception when developing a treatment plan for musculoskeletal pathologies and incorporate this as part of the postoperative rehabilitation process.


Assuntos
Artroscopia , Impacto Femoroacetabular , Impacto Femoroacetabular/fisiopatologia , Impacto Femoroacetabular/cirurgia , Articulação do Quadril/fisiopatologia , Articulação do Quadril/cirurgia , Humanos , Dor/fisiopatologia , Percepção
8.
Neuron ; 110(4): 559-561, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35176237

RESUMO

Transfer between cells is an unexpected addition to the mitochondrial life cycle. In this issue of Neuron, Van der Vlist et al. now provide evidence that M2-macrophages infiltrating sensory ganglia resolve pain by transferring particles containing mitochondria to neurons-thus boosting nociceptors back to normal function.


Assuntos
Gânglios Espinais , Nociceptores , Gânglios Espinais/citologia , Humanos , Mitocôndrias , Neurônios , Nociceptores/metabolismo , Dor/fisiopatologia
9.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35181604

RESUMO

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes' expression-as proxy for cellular activity-after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others-like the dentate gyrus-dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this "strategy" changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Dor/fisiopatologia , Animais , Eletrochoque/métodos , Pé/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Análise de Célula Única , Análise Espaço-Temporal , Estresse Fisiológico/fisiologia
10.
J Integr Neurosci ; 21(1): 34, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164470

RESUMO

This research explored how the manipulation of interoceptive attentiveness (IA) can influence the frontal (dorsolateral prefrontal cortex (DLPFC) and somatosensory cortices) activity associated with the emotional regulation and sensory response of observing pain in others. 20 individuals were asked to observe face versus hand, painful/non-painful stimuli in an individual versus social condition while brain hemodynamic response (oxygenated (O2Hb) and deoxygenated hemoglobin (HHb) components) was measured via functional Near-Infrared Spectroscopy (fNIRS). Images represented either a single person (individual condition) or two persons in social interaction (social condition) both for the pain and body part set of stimuli. The participants were split into experimental (EXP) and control (CNT) groups, with the EXP explicitly required to concentrate on its interoceptive correlates while observing the stimuli. Quantitative statistical analyses were applied to both oxy- and deoxy-Hb data. Firstly, significantly higher brain responsiveness was detected for pain in comparison to no-pain stimuli in the individual condition. Secondly, a left/right hemispheric lateralization was found for the individual and social condition, respectively, in both groups. Besides, both groups showed higher DLPFC activation for face stimuli presented in the individual condition compared to hand stimuli in the social condition. However, face stimuli activation prevailed for the EXP group, suggesting the IA phenomenon has certain features, namely it manifests itself in the individual condition and for pain stimuli. We can conclude that IA promoted the recruitment of internal adaptive regulatory strategies by engaging both DLPFC and somatosensory regions towards emotionally relevant stimuli.


Assuntos
/fisiologia , Empatia/fisiologia , Face , Lateralidade Funcional/fisiologia , Mãos , Interocepção/fisiologia , Dor/fisiopatologia , Percepção Social , Córtex Somatossensorial/fisiologia , Adulto , Mapeamento Encefálico , Feminino , Humanos , Masculino , Dor/diagnóstico por imagem , Córtex Somatossensorial/diagnóstico por imagem , Espectroscopia de Luz Próxima ao Infravermelho , Adulto Jovem
11.
Sci Rep ; 12(1): 1414, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35082352

RESUMO

Flat foot pain is a common complaint that requires therapeutic intervention. Currently, myofascial release techniques are often used in the therapy of musculoskeletal disorders. A group of 60 people suffering from flat feet with associated pain. Patients were assigned to four groups (15 people each): MF-myofascial release, E-the exercise program, MFE-myofascial release and the exercise program, C-no intervention. The rehabilitation program lasted 4 weeks. The NRS scale was used to examine pain intensity and FreeMed ground reaction force platform was used to examine selected static and dynamic foot indicators. Statistically significant pain reduction was obtained in all research. A static test of foot load distribution produced statistically significant changes only for selected indicators. In the dynamic test, statistically significant changes were observed for selected indicators, only in the groups subjected to therapeutic intervention. Most such changes were observed in the MF group. In the dynamic test which assessed the support phase of the foot, statistically significant changes were observed only for selected subphases. Most such changes were observed in the MFE group. Both exercise and exercise combined with myofascial release techniques, and especially myofascial release techniques alone, significantly reduce pain in a flat foot. This study shows a limited influence of both exercises and myofascial release techniques on selected static and dynamic indicators of a flat foot.


Assuntos
Terapia por Exercício/métodos , Pé Chato/terapia , Terapia de Liberação Miofascial/métodos , Medição da Dor/psicologia , Dor/prevenção & controle , Adulto , Exercício Físico/fisiologia , Pé Chato/diagnóstico , Pé Chato/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor/diagnóstico , Dor/fisiopatologia , Dor/psicologia , Resultado do Tratamento
12.
Cell Mol Life Sci ; 79(1): 35, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34989866

RESUMO

Multiple representatives of eulipotyphlan mammals such as shrews have oral venom systems. Venom facilitates shrews to hunt and/or hoard preys. However, little is known about their venom composition, and especially the mechanism to hoard prey in comatose states for meeting their extremely high metabolic rates. A toxin (BQTX) was identified from venomous submaxillary glands of the shrew Blarinella quadraticauda. BQTX is specifically distributed and highly concentrated (~ 1% total protein) in the organs. BQTX shares structural and functional similarities to toxins from snakes, wasps and snails, suggesting an evolutional relevancy of venoms from mammalians and non-mammalians. By potentiating thrombin and factor-XIIa and inhibiting plasmin, BQTX induces acute hypertension, blood coagulation and hypokinesia. It also shows strong analgesic function by inhibiting elastase. Notably, the toxin keeps high plasma stability with a 16-h half-life in-vivo, which likely extends intoxication to paralyze or immobilize prey hoarded fresh for later consumption and maximize foraging profit.


Assuntos
Analgesia/métodos , Hipocinesia/fisiopatologia , Musaranhos/metabolismo , Toxinas Biológicas/metabolismo , Peçonhas/metabolismo , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Pressão Sanguínea/efeitos dos fármacos , Feminino , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Humanos , Macaca mulatta , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dor/induzido quimicamente , Dor/fisiopatologia , Dor/prevenção & controle , Homologia de Sequência de Aminoácidos , Musaranhos/genética , Trombina/antagonistas & inibidores , Trombina/metabolismo , Toxinas Biológicas/administração & dosagem , Toxinas Biológicas/genética , Peçonhas/genética
13.
Behav Pharmacol ; 33(1): 23-31, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35007233

RESUMO

The monoiodoacetate-induced rat model of osteoarthritis knee pain is widely used. However, there are between-study differences in the pain behavioural endpoints assessed and in the dose of intraarticular monoiodoacetate administered. This study evaluated the robustness of gait analysis as a pain behavioural endpoint in the chronic phase of this model, in comparison with mechanical hyperalgesia in the injected (ipsilateral) joint and development of mechanical allodynia in the ipsilateral hind paws. Groups of Sprague-Dawley rats received a single intraarticular injection of monoiodoacetate at 0.5, 1, 2 or 3 mg or vehicle (saline) into the left (ipsilateral) knee joint. An additional group of rats were not injected (naïve group). The pain behavioural methods used were gait analysis, measurement of pressure algometry thresholds in the ipsilateral knee joints, and assessment of mechanical allodynia in the ipsilateral hind paws using von Frey filaments. These pain behavioural endpoints were assessed premonoiodoacetate injection and for up to 42-days postmonoiodoacetate injection in a blinded manner. Body weights were also assessed as a measure of general health. Good general health was maintained as all rats gained weight at a similar rate for the 42-day study period. In the chronic phase of the model (days 9-42), intraarticular monoiodoacetate at 3 mg evoked robust alterations in multiple gait parameters as well as persistent mechanical allodynia in the ipsilateral hind paws. For the chronic phase of the monoiodoacetate-induced rat model of osteoarthritis knee pain, gait analysis, such as mechanical allodynia in the ipsilateral hind paws, is a robust pain behavioural measure.


Assuntos
Artralgia , Sintomas Comportamentais , Análise da Marcha/métodos , Hiperalgesia , Osteoartrite , Dor , Animais , Artralgia/induzido quimicamente , Artralgia/psicologia , Técnicas de Observação do Comportamento/métodos , Comportamento Animal , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Hiperalgesia/diagnóstico , Hiperalgesia/fisiopatologia , Hiperalgesia/psicologia , Ácido Iodoacético/administração & dosagem , Osteoartrite/fisiopatologia , Osteoartrite/psicologia , Dor/fisiopatologia , Dor/psicologia , Ratos , Ratos Sprague-Dawley
14.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983852

RESUMO

The perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual's expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas which generate evoked potentials and oscillatory responses at different latencies and frequencies. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. Here, we therefore applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain.


Assuntos
Encéfalo/fisiopatologia , Dor/fisiopatologia , Transdução de Sinais , Teorema de Bayes , Eletroencefalografia , Humanos , Medição da Dor
15.
PLoS One ; 17(1): e0262422, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35025935

RESUMO

OBJECTIVES: The overall purpose of this research programme is to develop and test the feasibility of a complex intervention for knee pain delivered by a nurse, and comprising both non-pharmacological and pharmacological interventions. In this first phase, we examined the acceptability of the non-pharmacological component of the intervention; issues faced in delivery, and resolved possible challenges to delivery. METHODS: Eighteen adults with chronic knee pain were recruited from the community. The intervention comprised holistic assessment, education, exercise, weight-loss advice (where appropriate) and advice on adjunctive treatments such as hot/cold treatments, footwear modification and walking aids. After nurse training, the intervention was delivered in four sessions spread over five weeks. Participants had one to one semi-structured interview at the end of the intervention. The nurse was interviewed after the last visit of the last participant. These were audio recorded and transcribed verbatim. Themes were identified by one author through framework analysis of the transcripts, and cross-checked by another. RESULTS: Most participants found the advice from the nurse easy to follow and were satisfied with the package, though some felt that too much information was provided too soon. The intervention changed their perception of managing knee pain, learning that it can be improved with self-management. However, participants thought that the most challenging part of the intervention was fitting the exercise regime into their daily routine. The nurse found discussion of goal setting to be challenging. CONCLUSION: The nurse-led package of care is acceptable within a research setting. The results are promising and will be applied in a feasibility randomised-controlled trial.


Assuntos
Traumatismos do Joelho/terapia , Manejo da Dor/métodos , Adulto , Exercício Físico/fisiologia , Terapia por Exercício/métodos , Estudos de Viabilidade , Feminino , Humanos , Joelho/fisiopatologia , Traumatismos do Joelho/tratamento farmacológico , Articulação do Joelho , Masculino , Papel do Profissional de Enfermagem/psicologia , Enfermeiras e Enfermeiros , Dor/fisiopatologia , Reino Unido
16.
PLoS One ; 17(1): e0263356, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35089966

RESUMO

OBJECTIVES: Chronic pain is a significant societal problem and pain complaints are one of the main causes of work absenteeism and emergency room visits. Physical activity has been associated with reduced risk of suffering from musculoskeletal pain complaints, but the exact relationship in an older adult sample is not known. METHODS: Participants self-reported their physical activity level and whether they were often troubled by bone, joint, or muscle pain. Logistic regression analyses revealed the nature of the relationship between musculoskeletal pain and physical activity cross-sectionally and longitudinally over the course of 10 years. Data were taken from the English Longitudinal Study of Ageing, comprising of 5802 individuals residing in England aged 50 or older. RESULTS: Only high levels of physical activity were associated with a reduced risk of suffering from musculoskeletal pain compared to a sedentary lifestyle longitudinally. In addition, having low wealth, being female, and being overweight or obese were found to be risk factors for suffering from musculoskeletal pain. CONCLUSIONS: The development of interventions aimed at alleviating and preventing musculoskeletal pain complaints might benefit from incorporating physical activity programs, weight loss, and aspects addressing wealth inequality to maximise their efficacy.


Assuntos
Exercício Físico/fisiologia , Dor/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/fisiopatologia
17.
Br J Anaesth ; 128(1): 159-173, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34844727

RESUMO

BACKGROUND: Cannabinoid type-1 receptors (CB1Rs) are expressed in primary sensory neurones, but their role in pain modulation remains unclear. METHODS: We produced Pirt-CB1R conditional knockout (cKO) mice to delete CB1Rs in primary sensory neurones selectively, and used behavioural, pharmacological, and electrophysiological approaches to examine the influence of peripheral CB1R signalling on nociceptive and inflammatory pain. RESULTS: Conditional knockout of Pirt-CB1R did not alter mechanical or heat nociceptive thresholds, complete Freund adjuvant-induced inflammation, or heat hyperalgesia in vivo. The intrinsic membrane properties of small-diameter dorsal root ganglion neurones were also comparable between cKO and wild-type mice. Systemic administration of CB-13, a peripherally restricted CB1/CB2R dual agonist (5 mg kg-1), inhibited nociceptive pain and complete Freund adjuvant-induced inflammatory pain. These effects of CB-13 were diminished in Pirt-CB1R cKO mice. In small-diameter neurones from wild-type mice, CB-13 concentration-dependently inhibited high-voltage activated calcium current (HVA-ICa) and induced a rightward shift of the channel open probability curve. The effects of CB-13 were significantly attenuated by AM6545 (a CB1R antagonist) and Pirt-CB1R cKO. CONCLUSION: CB1R signalling in primary sensory neurones did not inhibit nociceptive or inflammatory pain, or the intrinsic excitability of nociceptive neurones. However, peripheral CB1Rs are important for the analgesic effects of systemically administered CB-13. In addition, HVA-ICa inhibition appears to be a key ionic mechanism for CB-13-induced pain inhibition. Thus, peripherally restricted CB1R agonists could have utility for pain treatment.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Naftalenos/farmacologia , Dor/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfolinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/fisiopatologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo
18.
Dev Med Child Neurol ; 64(3): 364-371, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34553772

RESUMO

AIM: To explore the lived experiences of pain in children and young people with cerebral palsy (CP). METHOD: Participants were recruited from the Sydney Children's Hospitals Network and the New South Wales/Australian Capital Territory CP Registers. Inclusion criteria were as follows: CP; aged 9 to 17 years; current/past experience of pain; fluent in English; no greater than mild intellectual disability. Purposive sampling ensured representation across age, motor subtypes, and Gross Motor Function Classification System (GMFCS) levels. Semi-structured face-to-face interviews were conducted. Data were analysed following an interpretative phenomenological approach. RESULTS: Ten participants (three male) were included (mean age 14y 5mo, SD 2y), GMFCS levels I (n=4), II (n=3), III (n=2), and IV (n=1). Analysis led to three superordinate themes: (1) Everybody's experience of pain is different; (2) When the pain is winning; (3) 'I know how to deal with it'. Pain contributors and locations varied between children. Pain intruded on school, physical activity, and psychosocial functioning. Children described personalized strategies used to deal with pain. INTERPRETATION: In this study, children self-reported highly individualized pain experiences which interfered with their daily life and psychosocial well-being. There is a need for improvement in pain assessment and a personalized approach to pain management.


Assuntos
Atividades Cotidianas , Paralisia Cerebral/complicações , Dor/fisiopatologia , Dor/psicologia , Funcionamento Psicossocial , Sistema de Registros , Adolescente , Criança , Feminino , Humanos , Masculino , New South Wales , Dor/etiologia , Manejo da Dor , Medição da Dor , Pesquisa Qualitativa
19.
Dev Med Child Neurol ; 64(3): 357-363, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34448501

RESUMO

AIM: To investigate the pain characteristics, pain interference with activities of daily living, and use of analgesics in adolescents with cerebral palsy (CP) and compare the results with previous findings. METHOD: Sixty-seven adolescents (median age 14y 4mo, range 12y 2mo-17y, 28 females, 39 males) classified in Gross Motor Function Classification System (GMFCS) levels III to V, who participated in a CP surveillance programme, were assessed on pain measures twice, 5 years apart. Primary caregivers marked recurrent pain sites and graded pain interference with activities of daily living and sleep. Information on pain severity was obtained through two questions from the Child Health Questionnaire (CHQ) and were transformed into a pain score scaled from 0 to 100, where 100 represented no pain. The use of short-acting analgesics was recorded. RESULTS: Over 5 years, the prevalence of recurrent pain, number of pain sites, pain intensity, and pain frequency all increased significantly. The most frequent pain sites were the hip/thigh in GMFCS level V and knee in GMFCS level III. The median CHQ pain score decreased from 60 to 40 (p<0.001). Pain interference with activities of daily living increased (p=0.011) but not for sleep. Twenty-eight of 54 participants with moderate or severe pain (CHQ pain score ≤60) received no short-acting analgesics. INTERPRETATION: In adolescents with CP, pain increased over 5 years despite follow-up in a surveillance programme. For enhanced management of pain, we propose that an algorithm on pain should be included in surveillance programmes.


Assuntos
Atividades Cotidianas , Paralisia Cerebral/complicações , Paralisia Cerebral/fisiopatologia , Dor/etiologia , Dor/fisiopatologia , Adolescente , Analgésicos/uso terapêutico , Paralisia Cerebral/epidemiologia , Criança , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Dor/tratamento farmacológico , Dor/epidemiologia , Medição da Dor , Prevalência , Índice de Gravidade de Doença
20.
J Neurosci ; 42(3): 513-527, 2022 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-34880118

RESUMO

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception in male and female mice. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS triggered LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12-16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting α2δ-1 with gabapentin, or α2δ-1 knockout abolished TBS-induced LTP in lamina II neurons. Also, disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide prevented TBS-induced LTP in VGluT2-expressing neurons. Furthermore, TBS of the sciatic nerve induced long-lasting allodynia and hyperalgesia in wild-type, but not α2δ-1 knockout, mice. TBS significantly increased the α2δ-1-NMDAR interaction and synaptic trafficking in the spinal cord. In addition, treatment with NMDAR antagonists, gabapentin, or α2δ-1Tat peptide reversed TBS-induced pain hypersensitivity. Therefore, TBS-induced primary afferent input causes a neuropathic pain-like phenotype and LTP predominantly in excitatory dorsal horn neurons via α2δ-1-dependent NMDAR activation. α2δ-1-bound NMDARs may be targeted for reducing chronic pain development at the onset of tissue/nerve injury.SIGNIFICANCE STATEMENT Spinal dorsal horn synaptic plasticity is a hallmark of chronic pain. Although sensory nerves display rhythmic bursting discharges at theta frequencies during painful conditions, the significance of this naturally occurring firing activity in the induction of spinal synaptic plasticity is largely unknown. In this study, we found that theta-burst stimulation (TBS) of sensory nerves induced LTP mainly in excitatory dorsal horn neurons and that the prevalence of TBS-induced LTP was potentiated by nerve injury. This TBS-driven synaptic plasticity required α2δ-1 and its interaction with NMDARs. Furthermore, TBS of sensory nerves induced persistent pain, which was maintained by α2δ-1-bound NMDARs. Thus, TBS-induced LTP at primary afferent-dorsal horn neuron synapses is an appropriate cellular model for studying mechanisms of chronic pain.


Assuntos
Potenciação de Longa Duração/fisiologia , Dor/fisiopatologia , Células do Corno Posterior/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/fisiopatologia , Ritmo Teta/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Dor/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Medula Espinal/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
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