Females with hip pain walk with altered kinematics at peaks and throughout the gait cycle.

BACKGROUND: Females with acetabular dysplasia and/or labral tears (hip pain) exhibit altered walking kinematics, with studies reporting mixed results in sagittal and frontal planes compared to pain-free controls, often conducting only discrete analyses and warranting further investigation. The objective of this study was to investigate discrete and continuous hip and pelvic kinematics between females with and without hip pain in two walking conditions. METHODS: We collected kinematic walking data from 69 females (35 with hip pain, 34 controls) using motion capture and an instrumented treadmill in two conditions: preferred and fast (125% preferred). We used a general linear model and one-dimensional statistical parametric mapping to conduct discrete and continuous analyses comparing kinematics between groups, with and without adjustment for gait speed. FINDINGS: The hip pain group walked with reduced peak hip extension (Preferred: P = .046, Cohen's d = 0.41; Fast: P = .028, d = 0.48) and greater peak anterior pelvic tilt (Preferred: P = .011, d = 0.57; Fast: P = .012, d = 0.58) compared to controls. From continuous analyses, the hip pain group walked with reduced hip extension during terminal stance (Fast: P = .040), greater anterior pelvic tilt throughout (Preferred: P = .007; Fast: P = .004), and greater contralateral pelvic drop (Preferred: P = .045) during midstance. Adjusting for speed slightly affected p-values, but significance was retained for all prior variables except pelvic drop. INTERPRETATION: Kinematic differences between individuals with and without hip pain may provide insight into potential predisposing factors for hip pathology and/or compensations for pain or pathological processes. This work furthers understanding of altered movement patterns in individuals with hip pain and may inform physical therapy treatments.

D2-like dopamine receptors blockade within the dentate gyrus shows a greater effect on stress-induced analgesia in the tail-flick test compared to D1-like dopamine receptors.

INTRODUCTION: Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain. METHODS: Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals. RESULTS: The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test. DISCUSSION: Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.

Oxytocin neurons in the paraventricular nucleus and fear empathy among male mice.

BACKGROUND: Recent studies have identified empathy deficit as a core impairment and diagnostic criterion for people with autism spectrum disorders; however, the improvement of empathy focuses primarily on behavioural interventions without the target regulation. We sought to compare brain regions associated with empathy-like behaviours of fear and pain, and to explore the role of the oxytocin-oxytocin receptor system in fear empathy. METHODS: We used C57BL mice to establish 2 models of fear empathy and pain empathy. We employed immunofluorescence histochemical techniques to observe the expression of c-Fos throughout the entire brain and subsequently quantified the number of c-Fos-positive cells in different brain regions. Furthermore, we employed chemogenetic technology to selectively manipulate these neurons in Oxt-Cre-/+ mice to identify the role of oxytocin in this process. RESULTS: The regions activated by fear empathy were the anterior cingulate cortex, basolateral amygdala, nucleus accumbens, paraventricular nucleus (PVN), lateral habenula, and ventral and dorsal hippocampus. The regions activated by pain empathy were the anterior cingulate cortex, basolateral amygdala, nucleus accumbens, and lateral habenula. We found that increasing the activity of oxytocin neurons in the PVN region enhanced the response to fear empathy. This enhancement may be mediated through oxytocin receptors. LIMITATIONS: This study included only male animals, which restricts the broader interpretation of the findings. Further investigations on circuit function need to be conducted. CONCLUSION: The brain regions implicated in the regulation of fear and pain empathy exhibit distinctions; the activity of PVN neurons was positively correlated with empathic behaviour in mice. These findings highlight the role of the PVN oxytocin pathway in regulating fear empathy and suggest the importance of oxytocin signalling in mediating empathetic responses.

Pain experience reduces social avoidance to others in pain: a c-Fos-based functional connectivity network study in mice.

Pain experience increases individuals' perception and contagion of others' pain, but whether pain experience affects individuals' affiliative or antagonistic responses to others' pain is largely unknown. Additionally, the neural mechanisms underlying how pain experience modulates individuals' responses to others' pain remain unclear. In this study, we explored the effects of pain experience on individuals' responses to others' pain and the underlying neural mechanisms. By comparing locomotion, social, exploration, stereotyped, and anxiety-like behaviors of mice without any pain experience (naïve observers) and mice with a similar pain experience (experienced observers) when they observed the pain-free demonstrator with intraperitoneal injection of normal saline and the painful demonstrator with intraperitoneal injection of acetic acid, we found that pain experience of the observers led to decreased social avoidance to the painful demonstrator. Through whole-brain c-Fos quantification, we discovered that pain experience altered neuronal activity and enhanced functional connectivity in the mouse brain. The analysis of complex network and graph theory exhibited that functional connectivity networks and activated hub regions were altered by pain experience. Together, these findings reveal that neuronal activity and functional connectivity networks are involved in the modulation of individuals' responses to others' pain by pain experience.

Reduced sympathetic activity is associated with the development of pain and muscle atrophy in a female rat model of fibromyalgia.

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain accompanied by fatigue and muscle atrophy. Although its etiology is not known, studies have shown that FM patients exhibit altered function of the sympathetic nervous system (SNS), which regulates nociception and muscle plasticity. Nevertheless, the precise SNS-mediated mechanisms governing hyperalgesia and skeletal muscle atrophy in FM remain unclear. Thus, we employed two distinct FM-like pain models, involving intramuscular injections of acidic saline (pH 4.0) or carrageenan in prepubertal female rats, and evaluated the catecholamine content, adrenergic signaling and overall muscle proteolysis. Subsequently, we assessed the contribution of the SNS to the development of hyperalgesia and muscle atrophy in acidic saline-injected rats treated with clenbuterol (a selective ß2-adrenergic receptor agonist) and in animals maintained under baseline conditions and subjected to epinephrine depletion through adrenodemedullation (ADM). Seven days after inducing an FM-like model with acidic saline or carrageenan, we observed widespread mechanical hyperalgesia along with loss of strength and/or muscle mass. These changes were associated with reduced catecholamine content, suggesting a common underlying mechanism. Notably, treatment with a ß2-agonist alleviated hyperalgesia and prevented muscle atrophy in acidic saline-induced FM-like pain, while epinephrine depletion induced mechanical hyperalgesia and increased muscle proteolysis in animals under baseline conditions. Together, the results suggest that reduced sympathetic activity is involved in the development of pain and muscle atrophy in the murine model of FM analyzed.

Role of ERK in gender difference of fibromyalgia pain.

This study investigated the ERK pathway of the peripheral nervous system and discovered a gender-specific pattern of ERK activation in the dorsal root ganglion of an acid-induced chronic widespread muscular pain model. We employed a twice acid-induced chronic musculoskeletal pain model in rats to evaluate mechanical pain behavior in both male and female groups. We further conducted protein analysis of dissected dorsal root ganglions from both genders. Both male and female rats exhibited a similar pain behavior trend, with females demonstrating a lower pain threshold. Protein analysis of the dorsal root ganglion (DRG) showed a significant increase in phosphorylated ERK after the second acid injection in all groups. However, phosphorylation of ERK was observed in the dorsal root ganglion, with higher levels in the male ipsilateral group compared to the female group. Moreover, there was a no difference between the left and right sides in males, whereas the significant difference was observed in females. In conclusions, the administration of acid injections induced painful behavior in rats, and concurrent with this, a significant upregulation of pERK was observed in the dorsal root ganglia, with a greater magnitude of increase in males than females, and in the contralateral side compared to the ipsilateral side. Our findings shed light on the peripheral mechanisms underlying chronic pain disorders and offer potential avenues for therapeutic intervention.

Astroglial morphological changes in periaqueductal grey in different pain and itch mice models.

BACKGROUND: The periaqueductal gray (PAG) plays a well-established pivotal role in the descending pain modulatory circuit. The objective of this study was to investigate morphological changes in the astroglia in models that are commonly used in pain and itch studies. METHODS: Five different mouse models of pain, as well as two models of chronic itch, were established using complete Freund's adjuvant (CFA), spared nerve injury (SNI), bone cancer pain (BCP), cisplatin (CIS), and paclitaxel (PTX) for pain, and diphenylcyclopropenone (DCP) and acetone and diethyl ether followed by water (AEW) for chronic itch. von Frey tests and video recordings were employed to assess pain and itching behaviors. The immunofluorescence of S100ß, pSTAT3, and glial fibrillary acidic protein (GFAP) was examined. Two- and three-dimensional studies were used to evaluate changes in astrocyte morphology. RESULTS: Significant scratching was caused by DCP and AEW, whereas the administration of CFA, SNI, BCP, CIS, and PTX produced clear mechanical allodynia. The expression of GFAP in the lPAG/vlPAG was upregulated in CFA, SNI, BCP, CIS, PTX, and DCP mice but decreased in AEW mice. According to Sholl analysis, CFA, SNI, PTX, and BCP mice showed substantially higher astrocyte intersections in the vlPAG, whereas CFA, SNI, BCP, CIS, and DCP mice presented longer peak lengths. In three-dimensional analysis, CFA, SNI, PTX, and DCP mice showed increased astrocyte surface areas, while CIS and AEW mice showed both reduced surface areas and/or volumes of astrocytes. CONCLUSION: The findings showed that different pain and itching conditions have different astrocyte morphologies, and these variations in morphological changes help to explain the pathophysiology of these conditions.

Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior.

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

Neuronal Panx1 drives peripheral sensitization in experimental plantar inflammatory pain.

BACKGROUND: The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood. METHODS: Wild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund's adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and ß-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. ß-galactosidase (ß-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice. RESULTS: Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/ß-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca2+ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/ß-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of ß-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG. CONCLUSIONS: The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.

Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain.

Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6-18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test's time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) -3.1 (2.9); -3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively).    Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS. What is Known: • Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations. • Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life. What is New: • Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue. • Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.

Reaction Time in Fibromyalgia Patients.

BACKGROUND: Fibromyalgia has unknown aetiology and is associated with reduced information processing speed and therefore prolonged reaction time. However, the processes underlying this are unknown. OBJECTIVES: First, to compare the reaction time in a cohort of fibromyalgia patients and a matched group of normal controls. Second, to assess whether detailed symptoms of pain and autonomic function, as well as measures of tinnitus, fatigue, daytime sleepiness and Mycoplasma pneumoniae infection are predictors of reaction time in fibromyalgia. METHODS: The between-groups mean serial five-choice reaction time difference was assessed in a cohort of fibromyalgia patients and in a matched group of normal controls in an analytical casecontrolled study. With the mean serial five-choice reaction time as the dependent variable for the fibromyalgia group, a mixed stepwise multiple linear regression was performed with inputs relating to pain, dysautonomia, tinnitus, fatigue, daytime sleepiness and Mycoplasma pneumoniae infection. RESULTS: The mean (standard error) serial five-choice reaction time for the fibromyalgia group was 448.4 (23.0) ms, compared with 386.3 (8.3) ms for the control group (p = 0.007). The final multiple linear regression model (p < 0.001; adjusted R2 = 0.772) contained 13 predictors: eight sensory pain and three affective pain parameters, and Mycoplasma pneumoniae IgG and IgA assay results. CONCLUSION: Certain sensory and affective pain parameters, as well as Mycoplasma pneumoniae infection, appear to be predictors of reaction time in fibromyalgia. Further research into the pathophysiological mechanisms by which they affect information processing is warranted and may shed light on the aetiology of fibromyalgia.

Disentangling pain and fatigue in chronic fatigue syndrome: a resting state connectivity study before and after cognitive behavioral therapy.

BACKGROUND: Fatigue is a central feature of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), but many ME/CFS patients also report comorbid pain symptoms. It remains unclear whether these symptoms are related to similar or dissociable brain networks. This study used resting-state fMRI to disentangle networks associated with fatigue and pain symptoms in ME/CFS patients, and to link changes in those networks to clinical improvements following cognitive behavioral therapy (CBT). METHODS: Relationships between pain and fatigue symptoms and cortico-cortical connectivity were assessed within ME/CFS patients at baseline (N = 72) and after CBT (N = 33) and waiting list (WL, N = 18) and compared to healthy controls (HC, N = 29). The analyses focused on four networks previously associated with pain and/or fatigue, i.e. the fronto-parietal network (FPN), premotor network (PMN), somatomotor network (SMN), and default mode network (DMN). RESULTS: At baseline, variation in pain and fatigue symptoms related to partially dissociable brain networks. Fatigue was associated with higher SMN-PMN connectivity and lower SMN-DMN connectivity. Pain was associated with lower PMN-DMN connectivity. CBT improved SMN-DMN connectivity, compared to WL. Larger clinical improvements were associated with larger increases in frontal SMN-DMN connectivity. No CBT effects were observed for PMN-DMN or SMN-PMN connectivity. CONCLUSIONS: These results provide insight into the dissociable neural mechanisms underlying fatigue and pain symptoms in ME/CFS and how they are affected by CBT in successfully treated patients. Further investigation of how and in whom behavioral and biomedical treatments affect these networks is warranted to improve and individualize existing or new treatments for ME/CFS.

Relación entre las ciencias básicas y clínicas en la modulación central del dolor / Relationship between basic and clinical sciences in central pain modulation

Esta revisión busca proporcionar a los profesionales de la salud una mayor comprensión del dolor para su actividad clínica-asistencial. Basados en la hipóte-sis de neuroplasticidad presentada inicialmente por Ramón y Cajal y la teoría de la compuerta en la vía dolorosa presentada por Melzack y Wall, se ha ela-borado una revisión bibliográfica con el objetivo de abordar la modulación de la vía nociceptiva desde un punto de vista fisiopatológico. Asimismo, se presen-tan los principales resultados obtenidos durante los últimos años en nuestro laboratorio usando ratas Wistar hembras como modelo de dolor experimental. Finalmente, se describe un circuito original de modu-lación central a nivel del subnúcleo caudal del trigé-mino con una visión integral de los componentes del sistema nociceptivo orofacial, para ayudar al clínico a comprender situaciones de sensibilización central con perpetuación del dolor y cómo paulatinamente el sistema nervioso central pone en marcha un sistema de modulación para adaptarse y alcanzar un estado similar al basal (AU)

This review aims to provide health professionals with a better understanding of pain for their clinical-care activity. Based on the neuroplasticity hypothesis initially presented by Ramón and Cajal, and the gate theory in the pain pathway presented by Melzack and Wall, a literature review has been carried out with the aim of addressing the modulation of the nociceptive pathway from a pathophysiological point of view. The main results obtained in recent years in our laboratory using female Wistar rats as an experimental pain model are also presented. Finally, an original central modulation circuit at the level of the caudal trigeminal subnucleus is described with a comprehensive view of the components of the orofacial nociceptive system, to help the clinician to understand situations of central sensitization with perpetuation of pain and how the central nervous system gradually sets in motion a modulation system to adapt and reach a state similar to the basal one (AU)

Mecanismos de modulación central del dolor: revisión de la literatura / Mechanisms of central pain modulation: literature review

RESUMEN: La percepción del dolor resulta de múltiples y dinámicos mecanismos en el sistema nervioso central (SNC) y periférico que inhiben o facilitan el estímulo y respuesta nociceptiva. Sin embargo, la principal capacidad de modulación esta a cargo del SNC. Los estímulos nociceptivos son detectados por terminaciones nerviosas libres de neuronas periféricas que sinaptan con neuronas aferentes secundarias de la médula espinal. Luego estas fibras decusan para formar las vías nociceptivas ascendentes. Una vez alcanzadas las estructuras subcorticales, se activan las neuronas del tálamo, quienes envían el estímulo hacia la corteza somatosensorial, desencadenando la percepción consciente del dolor y activando el sistema inhibitorio descendente. Para que la modulación nociceptiva se realice, es necesaria la participación de diversas sustancias o neurotransmisores que conectan áreas del SNC especializadas. Por lo tanto, el objetivo de este estudio fue realizar una revisión de la literatura respecto de los mecanismos que participan en los procesos de modulación central del dolor.

SUMMARY: Pain perception results from multiple and dynamic mechanisms in the central nervous system (CNS) and peripheral nervous system that inhibit or facilitate stimulation and nociceptive response. However, neuromodulation is mainly a function of the CNS. Nociceptive stimulus is detected by peripheral neurons receptors that synapse with the secondary afferent neurons of the spinal cord. These fibers cross to conform the ascending nociceptive pathways. Once the subcortical structures are reached, the thalamus`s neurons are activated; the thalamus send the stimulus to the somatosensory cortex, triggering the conscious perception of pain and activating the descending inhibitory system. For the nociceptive modulation to be carried out, the participation of various substances or neurotransmitters that connect specialized CNS areas is necessary. Therefore, the aim of this study was to review the literature regarding the mechanisms involved in central pain modulation processes.

Dolor y analgésicos. Algunas consideraciones oportunas / Pain and painkillers. Some timely considerations

RESUMEN El dolor ha acompañado a la humanidad desde épocas remotas hasta la actualidad; síntoma muy frecuente observado en todos los niveles de salud, y en que la medicina presenta éxitos y fracasos, por lo que preocupa y ocupa en forma permanente a los investigadores. Su atención desde el punto de vista asistencial se hace complejo por la variedad de factores que lo condicionan. El enfoque terapéutico de ese síntoma debe apoyarse en el conocimiento de la fisiopatología y el empleo de medios que permitan hacer una valoración de su origen y evolución para adecuar las estrategias analgésicas que correspondan. En este trabajo se realiza una revisión sobre los aspectos antes mencionados en relación con el dolor.

ABSTRACT Pain has accompanied humanity from remote times to the present day; this is a very well- frequent symptom in health levels, where medicine presents successes and failures. For this reason it is a permanent researchers´ concern and occupation. Assisting pain is complex due to the variety of factors which conditions it. Therapeutic approach to this symptom must be based on pathophysiology knowledge and the use of means that allow assessing its origin and progress to adapt the corresponding analgesic strategies. In this work, a review is made on the aforementioned aspects in relation to pain.

Dor em recém-nascidos hospitalizados em unidade de terapia intensiva: aspectos fisiológicos, comportamentais e endócrinos / Pain in newborns hospitalized in an intensive care unit: physiological, behavioral and endocrine aspects

Introdução: recém-nascidos (RN), que passam semanas ou meses na Unidade de Terapia Intensiva Neonatal (UTIN), são submetidos a um número elevado de procedimentos dolorosos. Estes procedimentos podem desencadear uma resposta global, que inclui alterações fisiológicas, endócrinas e comportamentais. Apesar do grande número de escalas validadas nas últimas décadas, até o momento, não existe um método ideal para a avaliação da dor neonatal. Desta forma, outros parâmetros têm sido explorados, como por exemplo, as dosagens de mediadores inflamatórios. Objetivos: avaliar padrões fisiológicos, comportamentais e endócrinos, relacionados a procedimentos dolorosos, nos primeiros três dias de vida em RN, hospitalizados em UTIN. Método: estudo clínico primário, observacional e prospectivo, desenvolvido na UTIN do Hospital Universitário, da Universidade de São Paulo. Foram coletados dados demográficos dos RN, bem como do número e o tipo de procedimentos dolorosos, medidas farmacológicas e não farmacológicas adotadas. Foram coletados ainda sinais vitais e escores de dor registrados em prontuário clínico. Finalmente, foram coletadas três amostras de saliva, por três dias consecutivos (1-3) para a dosagem de 11 citocinas (IFNg, IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17, TNF e VEGF). Resultados: foram incluídos no estudo 90 RN, dos quais 53,33% nasceram de parto cesárea; 62,22% do sexo masculino; 87,78% classificados como adequado para a idade gestacional (AIG); 48,88% são pré-termo e 48,88% de termo; idade gestacional média de 35 semanas; Escore de Apgar médio no 5°min 7,51 (DP=1,95); peso ao nascimento médio 2,56Kg (DP=1,0); o principal diagnóstico registrado foi desconforto respiratório precoce (60%). Tempo médio de permanência na UTIN foi de 54,98 horas (DP=30,61). Os RN foram submetidos ao total de 2.732 procedimentos dolorosos, foram empregadas 540 estratégias não farmacológicas e 216 medidas farmacológicas. Da admissão ao terceiro dia de internação, foram realizados, em média, 30,36 procedimentos dolorosos por RN, com média de 5,98 medidas não farmacológicas e 2,39 medidas farmacológicas. Nas primeiras 24 horas após a admissão, a média de procedimentos foi de 12,78, no primeiro dia, a média foi de 8,1, no segundo e terceiro dias, a média de procedimentos realizados foi de 5,36 e 3,84, respectivamente. O procedimento doloroso mais frequentemente realizado foi a glicemia capilar (20,96%). Registrou-se média de 1,98 medidas não farmacológicas nas primeiras 24 horas após admissão, 1,73 no primeiro dia, sendo média de 1,23 e 0,97 no segundo e terceiro dias, respectivamente. A estratégia não farmacológica mais comumente registrada foi a redução de luminosidade (28,33%). Com relação às medidas farmacológicas, foram adotadas, em média, 0,81 na admissão, 0,66 no primeiro dia, 0,544 no segundo dia e, 0,36 no terceiro dia, sendo o fentanil contínuo (48,83%) a principal medida farmacológica documentada. O escore NIPS e os sinais vitais apresentam variabilidade da admissão ao terceiro dia de internação. Finalmente, observou-se oscilação do nível das 11 citocinas e, destaca-se a presença de correlação positiva das IL-1b (r = 0,52; p<0,05), IL-2 (r = 0,4; p<0,05), IL-6 (r = 0,64; p<0,05) e VEGF (r = 0,44; p<0,05) com o número de procedimentos dolorosos. Conclusões: evidencia-se que da admissão ao terceiro dia de internação na UTIN, os RN foram expostos a número elevado de procedimentos potencialmente dolorosos, sendo insuficiente o manejo da dor. As alterações fisiológicas e comportamentais não refletem necessariamente o número de intervenções nas quais os RN foram submetidos. Destaca-se ainda, que a dosagem dos mediadores inflamatórios nas amostras de saliva pode fornecer fundamentação científica para a avaliação da dor, que juntamente com os parâmetros fisiológicos e comportamentais, amplia as perspectivas para o desenvolvimento de novas pesquisas para investigar a associação entre dor e as citocinas inflamatórias e compreender melhor as características das condições dolorosas.

Introduction: newborns (NB), who spend weeks or months in the Neonatal Intensive Care Unit (NICU), undergo a high number of painful procedures. These procedures can trigger a global response, which includes physiological, endocrine and behavioral changes. Despite the large number of scales validated in recent decades, so far, there is no ideal method for the assessment of neonatal pain. Thus, other parameters have been explored, such as, for example, the dosages of inflammatory mediators. Objectives:to evaluate physiological, behavioral and endocrine patterns, related to painful procedures, in the first three days of life in newborns hospitalized in the NICU. Method: primary, observational and prospective clinical study, developed at the NICU of the University Hospital of the University of São Paulo. Demographic data of newborns were collected, as well as the number and type of painful procedures, pharmacological and non-pharmacological measures adopted. Vital signs and pain scores recorded in clinical records were also collected. Finally, three saliva samples were collected for three consecutive days (1-3) for the measurement of 11 cytokines (IFNg, IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17, TNF e VEGF). Results: 90 newborns were included in the study, of which 53.33% were born by cesarean delivery; 62.22% were male; 87.78% classified as adequate for gestational age (AGA);48.88% are preterm and 48.88% term; average gestational age of 35 weeks;Mean Apgar score in the 5th min 7.51 (SD = 1.95); average birth weight 2.56 kg (SD = 1.0); the main diagnosis recorded was early respiratory distress (60%). The average length of stay in the NICU was 54.98 hours (SD = 30.61). The newborns underwent a total of 2,732 painful procedures, 540 non-pharmacological strategies and 216 pharmacological measures were used. From admission to the third day of hospitalization, an average of 30.36 painful procedures per NB were performed,with an average of 5.98 non-pharmacological measures and 2.39 pharmacological measures. In the first 24 hours, after admission, the average of procedures was 12.78, on the first day, the average was 8.1, on the second and third days, the average of the procedures performed was 5.36 and 3.84, respectively. The most frequently performed painful procedure was capillary glycemia (20.96%).An average of 1.98 non-pharmacological measures was recorded in the first 24 hours after admission, 1.73 on the first day, with an average of 1.23 and 0.97 on the second and third days, respectively.The most commonly registered non-pharmacological strategy was the reduction in brightness (28.33%). Regarding pharmacological measures, an average of 0.81 was taken at admission, 0.66 on the first day, 0.544 on the second day and 0.36 on the third day, with continuous fentanyl (48.83%) being the main pharmacological measure documented. The Neonatal Infant Pain Scale (NIPS) and vital signs show variability from admission to the third day of hospitalization. Finally, there was an oscillation in the level of the 11 cytokines and the presence of a positive correlation of IL-1b (r = 0.52; p <0.05), IL-2 (r = 0.4; p < 0.05), IL-6 (r = 0.64; p <0.05) and VEGF (r = 0.44; p <0.05), with the number of painful procedures. Conclusions: it is evident that from admission to the third day of hospitalization to the NICU,the NBs were exposed to a high number of potentially painful procedures, with insufficient pain management. Physiological and behavioral changes do not necessarily reflect the number of interventions to which newborns have undergone. It is also noteworthy that the dosage of inflammatory mediators in saliva samples can provide a scientific basis for pain assessment,which, together with the physiological and behavioral parameters, expands the perspectives for the development of new research to investigate the association between pain and inflammatory cytokines and to better understand the characteristics of painful condition

Effects of group kinesiotherapy on primary and secondary symptoms of osteoarthrosis

The aim of this study was to investigate the influence of a specific, kinesiotherapy-based rehabilitation program on the various symptoms of osteoarthrosis (OA), following group treatment. Thirty-one individuals, of both sexes, aged over 50 years and with medical diagnosis of OA, underwent 16 sessions, twice a week, totaling eight weeks, of a specific rehabilitation protocol based on group kinesiotherapy. Primary OA symptoms were assessed (directly related to the disease: OA symptoms, trunk flexibility, balance and pain), and so were secondary ones (indirectly related to the disease: signs of depression and anxiety, and quality of life). Data were tested through Student's t test or Wilcoxon's test, and contingencies of categorical data were analyzed using McNemar's test. There was an improvement in all primary symptoms of OA after the kinesiotherapy protocol was applied. Signs of anxiety and depression improved only in contingency, when risk stratification was taken into account. In addition, physical components of quality of life also showed improvement, which did not occur with mental components though. Therefore, the kinesiotherapy-based rehabilitation program was capable of positively influencing all primary symptoms, and only some aspects of secondary OA symptoms.

Dolor en la artrosis de rodilla / Pain in knee osteoarthritis

El dolor constituye el síntoma fundamental de la artrosis, sus características e interpretación permiten el diagnóstico certero y también conocer la magnitud de esa entidad. El objetivo de este trabajo, es profundizar los conocimientos sobre los elementos más esenciales relacionados con el dolor en la artrosis de la rodilla. Se describen las causas mecánicas y bioquímicas del dolor, entre las que resaltan el dolor óseo, sinovial, así como los factores bioquímicos relacionados con ese síntoma. Se hace referencia a las principales estructuras anatómicas responsables del dolor y sus mecanismos de acción. Se mencionan la relación existente entre ese síntoma y las modalidades imagenológicas, así como los patrones del dolor. Para finalizar, se hace referencia a las escalas de dolor usadas.

Pain is the main symptom of osteoarthritis. Determining the distinctive features of pain in knee osteoarthritis allows for an accurate diagnosis. This article gives a review of the results from research work on the typical features of knee osteoarthritic pain. The mechanics and biochemical causes of pain are described including both bone and synovial biochemical symptom-related factors. The relationships between knee pain, various imaging techniques and pain mechanism are also identified. Finally, the used pain scales are presented.

Expression of glycine receptor α3 subunit in neuropathic and inflammatory central pain sensitization

INTRODUCTION: Increasing evidence suggests that changes in the balance of excitatory/inhibitory neurotransmission are involved in the development of the majority of chronic pain forms. In this context, impairment in glycine mediated inhibitory neurotransmission is thought to play a critical role in the disinhibition that accounts for the development and maintenance of central pain hypersensitivity. AIMS: The goal of this study was to evaluate the Glycine Receptor α3 subunit (α3GlyR) expression in neuropathic (Chronic Constriction Injury, CCI) and inflammatory (Zymosan A injected) animal models of chronic pain. RESULTS AND CONCLUSION: RT-qPCR analysis of spinal cord samples showed that glra3 gene expression does not change after 3 days of CCI and 4 hours of Zymosan A injection. However, we found that protein levels evaluated by Western blot increased after inflammatory pain. These data suggest that central sensitization is differentially regulated depending on the type of pain. α3GlyR protein expression plays an important role in the first step of inflammatory pain establishment.