Higher Cardiovagal Baroreflex Sensitivity Predicts Increased Pain Outcomes After Cardiothoracic Surgery.

Excessive postoperative pain can lead to extended hospitalization and increased expenses, but factors that predict its severity are still unclear. Baroreceptor function could influence postoperative pain by modulating nociceptive processing and vagal-mediated anti-inflammatory reflexes. To investigate this relationship, we conducted a study with 55 patients undergoing minimally invasive cardiothoracic surgery to evaluate whether cardiovagal baroreflex sensitivity (BRS) can predict postoperative pain. We assessed the spontaneous cardiovagal BRS under resting pain-free conditions before surgery. We estimated postoperative pain outcomes with the Pain, Enjoyment, and General Activity scale and pressure pain thresholds on the first (POD1) and second (POD2) postoperative days and persistent pain 3 and 6 months after hospital discharge. We also measured circulating levels of relevant inflammatory biomarkers (C-reactive protein, albumin, cytokines) at baseline, POD1, and POD2 to assess the contribution of inflammation to the relationship between BRS and postoperative pain. Our mixed-effects model analysis showed a significant main effect of preoperative BRS on postoperative pain (P = .013). Linear regression analysis revealed a significant positive association between preoperative BRS and postoperative pain on POD2, even after adjusting for demographic, surgical, analgesic treatment, and psychological factors. Moreover, preoperative BRS was linked to pain interfering with general activity and enjoyment but not with other pain parameters (pain intensity and pressure pain thresholds). Preoperative BRS had modest associations with postoperative C-reactive protein and IL-10 levels, but they did not mediate its relationship with postoperative pain. These findings indicate that preoperative BRS can independently predict postoperative pain, which could serve as a modifiable criterion for optimizing postoperative pain management. PERSPECTIVE: This article shows that preoperative BRS predicts postoperative pain outcomes independently of the inflammatory response and pain sensitivity to noxious pressure stimulation. These results provide valuable insights into the role of baroreceptors in pain and suggest a helpful tool for improving postoperative pain management.

Baroreceptor Modulation of the Cardiovascular System, Pain, Consciousness, and Cognition.

Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain cardiovascular homeostasis by coordinating the responses to external and internal environmental stressors. While it is well known that carotid and cardiopulmonary baroreceptors modulate sympathetic vasomotor and parasympathetic cardiac neural autonomic drive, to avoid excessive fluctuations in vascular tone and maintain intravascular volume, there is increasing recognition that baroreceptors also modulate a wide range of non-cardiovascular physiological responses via projections from the nucleus of the solitary tract to regions of the central nervous system, including the spinal cord. These projections regulate pain perception, sleep, consciousness, and cognition. In this article, we summarize the physiology of baroreceptor pathways and responses to baroreceptor activation with an emphasis on the mechanisms influencing cardiovascular function, pain perception, consciousness, and cognition. Understanding baroreceptor-mediated effects on cardiac and extra-cardiac autonomic activities will further our understanding of the pathophysiology of multiple common clinical conditions, such as chronic pain, disorders of consciousness (e.g., abnormalities in sleep-wake), and cognitive impairment, which may result in the identification and implementation of novel treatment modalities. © 2021 American Physiological Society. Compr Physiol 11:1373-1423, 2021.

Psychological intervention based on psychoneuroimmunology improves clinical evolution, quality of life, and immunity of children with leukemia: A preliminary study.

We conducted a non-randomized, open-label clinical trial to assess whether a psychoneuroimmunology-based intervention enhanced immunity in children with acute lymphoblastic leukemia undergoing chemotherapy. In total, 16 children (44% female) received psychoneuroimmunology-based intervention, whereas 12 (50% female) received health psychoeducation (controls). The primary outcome was immunity markers, being clinical conditions the secondary outcome. Psychoneuroimmunology-based intervention increased immune markers (CD8+ T, B, and natural killer cells, serum immunoglobulin A, and immunoglobulin M) and quality of life, whereas it shortens the duration of fever and use of antipyretics, antibiotics, analgesics, and respiratory therapy. Immunity markers correlated with clinical conditions. Thus, psychoneuroimmunology-based intervention could reduce hospital cost and increase patient well-being.

Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes.

Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain homeostasis by coordinating physiologic responses to external and internal stimuli. While it is recognized that carotid and cardiopulmonary baroreceptor reflexes modulate autonomic output to mitigate excessive fluctuations in arterial blood pressure and to maintain intravascular volume, increasing evidence suggests that baroreflex pathways also project to key regions of the central nervous system that regulate somatosensory, somatomotor, and central nervous system arousal. In addition to maintaining autonomic homeostasis, baroreceptor activity modulates the perception of pain, as well as neuroimmune, neuroendocrine, and cognitive responses to physical and psychologic stressors. This review summarizes the role that baroreceptor pathways play in modulating acute and chronic pain perception. The contribution of baroreceptor function to postoperative outcomes is also presented. Finally, methods that enhance baroreceptor function, which hold promise in improving postoperative and pain management outcomes, are presented.

Impact of two therapeutic interventions in patients with non-specific low back pain / Impacto de dos intervenciones terapéuticas en pacientes con dolor lumbar inespecífico

Abstract Objective: To evaluate the impact of two therapeutic interventions in patients with non-specific low back pain. Materials and methods: Prospective study, in which in 20 subjects from both genders assigned through consecutive sampling of the two interventions: Group 1:10 sessions of conventional physiotherapy treatment (CPT) (Ultrasound, TENS: Transcutaneous Electrical Nervous Stimulation y HWC: Hot Wet Compresses) and Group 2:10 sessions of Motor Control Exercises (MCE). A numerical Pain Scale (NPS) was applied before and after each intervention. Results: In the first group, it was found a 20% decrease the pain scores after 10 sessions compared with the baseline measurements (before the intervention) (p=0.03). Similarly, in the second group, pain score dimished 42% respect to baseline values at the end of the 10 therapeutic sessions (p = 0.03). When comparing the two interventions, the MCE were more effective than the CPT, even from the first treatment session (p <0.05). Discussion: a significant reduction of pain was found in both groups, although this reduction was significantly in the group treated with MCE.

Resumen Objetivo: Evaluar el impacto de dos intervenciones terapéuticas en pacientes con dolor lumbar inespecífico. Materiales y métodos: Estudio prospectivo, en 20 sujetos de ambos sexos asignados a través de muestreo consecutivo a una de las dos intervenciones: Grupo 1:10 sesiones de tratamiento de fisioterapia convencional (TFC) (Ultrasonido TENS: eléctrica transcutánea nerviosa Estimulación y CHC: Compresa húmedo-calientes) y Grupo 2: 10 sesiones de ejercicios de control motor (ECM). Se aplicó la Escala numérica del dolor (NPS) antes y después de cada intervención. Resultados: En el primer grupo, se encontró una disminución del 20% de las puntuaciones de dolor después de 10 sesiones en comparación con las mediciones de referencia (antes de la intervención) (p = 0,03). De forma similar, en el segundo grupo, la puntuación del dolor disminuyó un 42% con respecto a los valores basales al final de las 10 sesiones terapéuticas (p = 0,03). Al comparar las dos intervenciones, los ECM fueron más efectivos que el TFC, incluso desde la primera sesión de tratamiento (p <0.05). Discusión: Se encontró una reducción significativa del dolor en ambos grupos, aunque esta reducción fue significativamente en el grupo tratado con ECM.

[Novel central dopaminergic agents derived from atypical di-substituted 2-aminoindane-4, 7. Synthesis and central pharmacological profile]. / Novedosos agentes dopaminérgicos centrales derivados del 2-aminoindano-4,7 disustituido atipico. Síntesis y perfil farmacológico central.

In recent decades, many compounds with central dopaminergic activity have been designed, synthesized and evaluated pharmacologically. However, it has not been possible to obtain a drug able to improve or cure diseases involving dopaminergic regulation in the central nervous system, such as Parkinson's disease and schizophrenia, among others. Taking into consideration the term "atypical pharmacophore" and from the compound 5, the aralkyl fragment was incorporated, and the compounds 10, 11, 13a-h and 14a-h were synthesized. Both the compounds 10 and 13a-h under its methoxylated form and the compounds 11 and 14a-h under the phenolic form, were evaluated to determine their pharmacologically agonistic and antagonistic effects on central dopaminergic activity. For this, the effect of intracerebroventricular injection of said compounds on the hydromineral balance and stereotyped behavior in rats, was determined. The results of the preliminary pharmacological evaluation show a centrally acting action through dopamine mechanisms, in which the compounds 10, 11, 13d-h and 14a showed responses as agonists, whereas compounds 14b-h, had responses as antagonists.

Reduction of spinal PGE2 concentrations prevents swim stress-induced thermal hyperalgesia.

We evaluated the association between spinal PGE2 and thermal hyperalgesia following repeated stress. Thermal nociception was determined in male Sprague-Dawley rats using the hot-plate test, before and after forced-swimming; non-conditioned rats served as controls. Animals were pretreated with ketoprofen or meloxicam, preferential COX-1 and COX-2 inhibitors, respectively. After the second hot-plate test, we measured serum corticosterone (stress marker), and lumbar spinal PGE2 (neuroinflammation marker) under peripheral inflammation (1% formalin plantar injection). Stressed rats displayed response latencies 40% shorter and inflammatory spinal PGE2 levels 95% higher than controls. Pretreatment with ketoprofen or meloxicam prevented hyperalgesia and elevation of spinal PGE2, increasing the escape behavior time during forced swimming 95% respect to saline-treated rats. Corticosterone levels in stressed rats were 97% higher than controls; COX inhibitors reduced them by 84%. PGE2 could participate in stress-induced hyperalgesia, learned helplessness, and corticosterone production, supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) for persistent pain associated with chronic stress and depression.

Stress-induced hyperalgesia is associated with a reduced and delayed GABA inhibitory control that enhances post-synaptic NMDA receptor activation in the spinal cord.

GABA and glutamate are both affected by stress and are involved in nociception. Thus, we determined whether stress-induced enhancement of inflammatory hyperalgesia is mediated by an imbalance between glutamate and GABA neurotransmission. Male rats were subjected daily to 10 to 20 minutes per day of either forced swimming (FS) or sham swimming for 3 consecutive days; nonconditioned rats served as controls. Some rats were treated i.p. with ketamine (5 mg/kg), diazepam (2 mg/kg), flumazenil (0.1 mg/kg), or vehicle (0.9% NaCl), 30 to 60 minutes before each conditioning session or nociception assessment. Pain behavior, spinal nociceptive neuronal activation and GABA and glutamate release were respectively evaluated by the formalin test, the expression of c-Fos and in vivo microdialysis of superficial laminae of the lumbar spinal cord, 48 hours after the last conditioning session. Nitric oxide metabolites (NO(x)) were determined as markers of post-synaptic NMDA receptor activation. FS stress enhanced formalin-induced hyperalgesia, increased pain-elicited c-Fos expression, decreased basal and delayed pain-induced GABA release, and increased basal and induced glutamate release. Hyperalgesia and c-Fos overexpression were blocked only by prestress treatment with diazepam and post-stress treatment with ketamine, whereas changes in GABA and glutamate release were reversed by prestress treatment with diazepam. Diazepam effects were blocked by flumazenil. NO(x) increased in lumbar spinal cord of FS rats by a mechanism antagonized by ketamine. Thus, stress-induced hyperalgesia is initiated by a decreased and delayed GABA release and GABA-A receptor activation, whereas it is maintained by increased glutamate release and NMDA glutamate receptor activation at the spinal level.

Enhanced central thermal nociception in mildly depressed nonpatients and transiently sad healthy subjects.

UNLABELLED: Evidence of support for sensory changes during minor depression and sadness is scarce and the neural mechanisms are unclear. We assessed central pain processing engaged in nociceptive C-fiber polymodal activity by examining the perception of a non-noxious unpleasant burning sensation induced by a thermal grill illusion, in 26 nonpatients with minor depression (19 females) and 28 healthy subjects (18 females), between 19 and 61 years old and pain free at the study. Controls were also subjected to induction of transient moods. Subjects with depression reported increased pain perception; this increase was more pronounced for the affective dimension of pain (unpleasantness) than for its sensory dimension (intensity). The perception of pain unpleasantness, pain intensity, and overall pain showed positive and linear correlations with depression levels measured by Zung's and Beck's scales. In controls, sad mood induction only increased the scores assigned to negative mood-describing adjectives; the perception of pain intensity, unpleasantness, and overall pain were significantly increased following sad, but not neutral or elevated, mood inductions. Yet, pain intensity and unpleasantness were correlated linearly and reciprocally to positive, instead of negative, mood-describing adjective scores. Thus, there is a central thermal hyperalgesia in subjects with minor depression and sadness. PERSPECTIVE: There is a central thermal hyperalgesia in subjects with minor depression, probably associated with an enhanced central processing of nociceptive C-fiber polymodal activity at anterior cingulate cortex, that is predominately expressed as an increased unpleasantness and that could be in part counteracted by behavioral therapies leading to mood elevation.

[Association between HSV-2 infection and serum anti-rat brain antibodies in patients with autism]. / Infecciones por HSV-2 y su relación con anticuerpos antiencéfalo de rata en suero de pacientes con autismo.

Some cases of autism could be linked to viral infections able to induce autoimmune mechanisms directed against the encephalon. Neurothophic virus infections in animals are associated with clinical signs that are similar to those observed in neurodevelopment disorders. Thus, in this study, we determined the co-existence of antibodies against nerve tissue and viruses with neurothophic competence (HSV-1/2, Epstein-Barr-EBV, cytomegalovirus, measles and rubella) in serum of forty autistic children and forty healthy children. The presence of antibodies against nerve tissue was detected in slices of rat encephalic tissue by indirect immunofluorescence. The levels of anti-viral IgG and IgM antibodies were measured by indirect ELISA. The proportion of autistics with anti-encephalon IgG antibodies (77% anti-amygdala, 70% anti-caudate nucleus, 47.5% anti-cerebellum y anti-brain stem, 45% anti-hippocampus, 40% anti-corpus callosum and 17,5% anti-cortex) was significantly greater than that of controls (10% anti- amygdala y 5% anti- cerebellum) and was directly related to the severity of the autism. The proportion of children with positive levels (greater than 1.1.mg/dL) for anti-HSV IgM antibodies (indicative of acute infection) was significantly greater in autistics (65%) than in healthy children (17.5%). Ninety six percent of the autistics with anti-HSV antibodies also had anti-encephalon antibodies, percentage that was significantly greater than that of autistics negative to the anti-HSV-antibody (43%). In contrast, there were no significant differences for IgG and IgM antibodies for EBV, cytomegalovirus, measles and rubella. This suggests that autoimmunity against encephalic structures elicited by HSV infections could be involved in autism.

Infecciones por HSV-2 y su relación con anticuerpos antiencéfalo de rata en suero de pacientes con autismo / Association between HSV-2 infection and serum anti-rat brain antibodies in patients witn autism

Algunos casos de autismo podrían estar vinculados a infecciones virales capaces de inducir mecanismos autoinmunes dirigidos contra el encéfalo. Las infecciones de virus neurotrópicos en animales se acompañan de síntomas similares a los observados en los trastornos del neurodesarrollo. Así, en este estudio evaluamos la co-existencia de anticuerpos contra tejido nervioso y contra virus con capacidad neurotrópica [HSV-1/2, Epstein-Barr (EBV), citomegalovirus, sarampión y rubéola] en el suero de cuarenta niños autistas y cuarenta niños sanos. La presencia de anticuerpos contra tejido nervioso se detectó en cortes de tejido encefálico de rata mediante inmunofluorescencia indirecta. Los niveles de anticuerpos IgG e IgM anti-virales se midieron por ELISA indirecta. La proporción de autistas con anticuerpos IgG anti-encéfalo (77% anti-amígdala, 70% anti-núcleo caudado, 47,5% anti-cerebelo y anti-tallo cerebral, 45% anti-hipocampo, 40% anti-cuerpo calloso y 17,5% anti-corteza) fue significativamente mayor que aquella de los controles (10% anti-amígdala y 5% anti-cerebelo) y se relacionó directamente con la severidad del autismo. La proporción de niños con niveles positivos (mayores a 1,1 mg/dL) para anticuerpos IgM anti-HSV (indicativo de infección aguda) fue significativamente mayor en autistas (65%) que en sanos (17,5%). El 96% de los autistas con anticuerpos anti-HSV también presentó anticuerpos anti-encéfalo, porcentaje que fue significativamente mayor que el de los autistas negativos al anticuerpo anti-HSV (43%). En contraste, no hubo diferencias significativas para los anticuerpos IgG e IgM para EBV, citomegalovirus, sarampión y rubéola. Esto sugiere que una autoinmunidad contra estructuras encefálicas desencadenada por infecciones por HSV podría estar involucrada en el autismo.

Some cases of autism could be linked to viral infections able to induce autoimmune mechanisms directed against the encephalon. Neurothophic virus infections in animals are associated with clinical signs that are similar to those observed in neurodevelopment disorders. Thus, in this study, we determined the co-existence of antibodies against nerve tissue and viruses with neurothophic competence (HSV-1/2, Epstein-Barr-EBV, cytomegalovirus, measles and rubella) in serum of forty autistic children and forty healthy children. The presence of antibodies against nerve tissue was detected in slices of rat encephalic tissue by indirect immunofluorescence. The levels of anti-viral IgG and IgM antibodies were measured by indirect ELISA. The proportion of autistics with anti-encephalon IgG antibodies (77% anti-amygdala, 70% anti-caudate nucleus, 47.5% anti-cerebellum y anti-brain stem, 45% anti-hippocampus, 40% anti-corpus callosum and 17,5% anti-cortex) was significantly greater than that of controls (10% anti- amygdala y 5% anti- cerebellum) and was directly related to the severity of the autism. The proportion of children with positive levels (greater than 1.1.mg/dL) for anti-HSV IgM antibodies (indicative of acute infection) was significantly greater in autistics (65%) than in healthy children (17.5%). Ninety six percent of the autistics with anti-HSV antibodies also had anti-encephalon antibodies, percentage that was significantly greater than that of autistics negative to the anti-HSV-antibody (43%). In contrast, there were no significant differences for IgG and IgM antibodies for EBV, cytomegalovirus, measles and rubella. This suggests that autoimmunity against encephalic structures elicited by HSV infections could be involved in autism.

Reduced GABA neurotransmission underlies hyperalgesia induced by repeated forced swimming stress.

We determined if cutaneous hyperalgesia and pain-induced c-Fos overexpression in the spinal cord produced by repeated forced swimming (FS) stress in the rat were related to changes in GABA neurotransmission by studying spinal release of GABA and the effect of positive modulation of GABA-A receptors with diazepam. Male rats were daily submitted to 10-20 min of either forced swimming or sham swimming (SS) for 3 consecutive days. Two days later, spinal GABA release was estimated by in vivo microdialysis. In other set of rats, either diazepam (2 mg/kg, i.p.) or saline was administered 1h before either SS or FS and inflammatory nociception was assessed with the formalin test; it was followed by removal of lumbar spinal cords for c-Fos immunocytochemistry. Basal and pain-evoked release of GABA in the spinal cord was lower in FS rats than in SS rats. In contrast, pain scores during formalin test late phase and pain-induced c-Fos expression in laminae I-VI of ipsilateral dorsal horn were significantly higher in FS rats than in SS rats. In FS rats, diazepam did not have effect on GABA release but reduced pain scores and overexpression of c-Fos whereas flumazenil (0.1 mg/kg, i.p.), an antagonist of the benzodiazepine binding site, reversed these effects. When diazepam was given only 1h before the formalin test, it slightly but significantly reduced pain scores during late phase in FS rats but not in SS rats. In conclusion, stress-induced reduction in GABA-A receptor activation is involved in the development of FS stress-induced hyperalgesia.

Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans.

Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to synthesize N-[2-(4,5-dihydroxyphenyl)-methyl-ethyl]-4,5-dihydroxy-2-aminoindan hydrobromide (3), planned to be a dopamine ligand, and to evaluate its dopaminergic action profile. This compound was assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinary response, after central administration. The pharmacological results showed that compound 3 significantly blocked the apomorphine-induced stereotypy and dopamine-induced diuresis and natriuresis in rats. Thus, compound 3 demonstrated an inhibitory effect on dopaminergic-induced behavior and renal action. N-[2-(-Methyl-ethyl)]-4,5-dihydroxy-2-aminoindan hydrobromide (4) was previously reported as an inotropic agent, and in the present work it was also re-evaluated as a diastereoisomeric mixture for its possible central action on the behavior parameters such as stereotypy and dopamine-induced diuresis and natriuresis in rats. Our results indicate that compound 4 produces an agonistic response, possibly through dopaminergic mechanisms. To better understand the experimental results we performed molecular dynamics simulations of two complexes: compound 3/D(2)DAR (dopamine receptor) and compound 4/D(2)DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.

Autescala de Zung para depresión como predictor de la respuesta sensorial y autonómica al dolor / The Zung's autoscale for depression as predictor of sensorial and autonomic alterations to pain

Evidencia clínica y experimental apoyan una relación entre la susceptibilidad al dolor crónico y la depresión subyacente. Sin embargo, no está claro si los instrumentos de evaluación clínica para depresión que existen permiten vincular ambos trastornos. Así, se evaluó la autoescala para depresión de Zung y sus diferentes categorías: afectiva, fisiológica, motora y psicológica como posible predictor de alteraciones sensoriales y autonómicas, así como su vulnerabilidad a dolores clínicos crónicos. A 32 controles sanos y 11 sujetos con depresión menor sin tratamiento, se les indujo isquemia mediante un torniquete sobre el brazo dominante, y luego seguido de parestesias durante la reperfusión del brazo al ser liberado el torniquete. El dolor muscular isquémico, las parestesias post-isquémicas y la respuesta cardiovascular fueron monitoreadas durante el procedimiento. El puntaje de la categoría afectiva se correlacionó linealmente en forma individual con el mayor número de variables y se ajustó a un modelo de regresión múltiple que explicaba casi un 100 por ciento la varianza, con una contribución de las variables sensoriales y autonómicas de un 70 por ciento y 30 por ciento, respectivamente. Además, la categoría afectiva fue un 50 por ciento mayor en los sujetos con dolor clínico persistente. El índice total de Zung y las otras categorías tuvieron un menor número de correlaciones lineales individuales y modelos de correlación múltiple que solo explicaban entre 30-70 por ciento de la varianza, con una contribución más predominante de las variables autonómicas (20-50 por ciento), especialmente en la categoría psicológica. Esto sugiere que la categoría afectiva puede predecir alteraciones sensoriales cutáneo-musculares con mayor eficacia que el índice total de Zung.

[The Zung's autoscale for depression as predictor of sensorial and autonomic alterations to pain]. / Autescala de Zung para depresión como predictor de la respuesta sensorial y autonómica al dolor.

Clinical and experimental evidence support a relationship between susceptibility to chronic pain and a subjacent depression. Nevertheless, it's not clear if the currently available clinical evaluation instruments for depression allow for linking both disorders. Thus, we evaluated a Zung's autoscale for depression and its different categories: affective, physiological, motor and psychological, as possible predictors of sensorial and autonomic alterations and vulnerability to clinical chronic pain. In 32 healthy controls and 11 subjects with minor depression and free of treatment, ischemic pain was first induced by applying a tourniquet on the dominant arm, and then followed by paresthesias during the reperfusion of arm as the tourniquet is released. Ischemic muscular pain, post-ischemic paresthesias and associated cardiovascular responses were recorded throughout the experimental procedure. The affective category's score was correlated linearly in individual form with the greatest number of variables and it was adjusted to a model of multiple regressions that almost explained the variance in 100% with a contribution of the sensorial and autonomic variables of a 70% and 30%, respectively. In addition, the affective category was 50% greater in subjects with persistent clinical pain. The Zung's index and the other categories had a smaller number of individual linear correlations and models of multiple correlations that only explained between 30-70% of the variance, with a more predominant contribution of the autonomic variables (20-50%), especially in the psychological category. This suggests that the affective category predicts cutaneous-muscular sensorial alterations with greater effectiveness than the Zung's total index.

Stress-induced muscle and cutaneous hyperalgesia: differential effect of milnacipran.

We previously demonstrated that repeated swim stress produces long-term cutaneous hyperalgesia in rats. We have now determined the effect of stress upon muscle nociception and the anti-nociceptive efficacy of the norepinephrine-serotonin reuptake inhibitor, milnacipran (MIL) in this model. Rats were subjected to either 10-20 min daily sessions of forced swimming (FS) for 3 days, or sham swimming (SS) or control (CT). Maximal forelimb grip strength and hot plate response latencies were estimated before and after the conditioning to assess muscle and thermal nociception, respectively. MIL (1-30 mg/kg/i.p.) or vehicle was started 7 days before the conditioning protocol. There were significant reductions in maximal grip strength and hot plate latencies only in FS/vehicle rats. Subsequent carrageenan administration (2 mg/75 microl each triceps) diminished grip strength in all groups 24 h later, with grip strength lower in FS/vehicle and SS/vehicle rats than in CT/vehicle rats. Treatment with MIL before the stress prevented the reduction in grip strength in all groups but it was ineffective in preventing FS-induced reductions in hot plate response latencies. Thus, repeated stress produces muscle hyperalgesia that can be pharmacologically dissociated from cutaneous hyperalgesia, suggesting that different mechanisms may underlie these two phenomena.

Role of mu-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia.

Repeated exposure to swimming stress induces a long-lasting hyperalgesia in the rat by mechanisms to be elucidated. Since opioid and glutamate neurotransmitter systems modulate pain, we now evaluated the effect of pharmacological blockade of opioid and glutamate receptors subtypes on forced swimming stress-induced hyperalgesia. Male rats were daily subjected to 10-20 min of forced or sham swimming for 3 days and thermal nociception was estimated twice, before each behavioral conditioning and 24 h after the last, using hot plate test. Selective opioid and NMDA receptor antagonists were administered i.p. either before each conditioning session or before the second nociception assessment. Unlike sham swimming rats, forced swimming rats showed significant reductions in hot plate response latencies (hyperalgesia) after the last swimming session, as compared to pre-stress values. Rats treated with the opioid receptor antagonists naloxone (0.1 mg/kg, non-subtype-selective) and naloxonazine (5 mg/kg, mu(1)-subtype-selective), before each forced swimming, did not become hyperalgesic, whereas those treated before the second post-stress assessment of nociception developed hyperalgesia. Naltrindole (0.5 mg/kg, delta-subtype-selective) and nor-binaltorphimine (0.5mg/kg, kappa-subtype-selective) were inactive in both administration schedules. The efficacy of morphine (3-7.5 mg/kg) to produce analgesia in forced swimming rats was lower than in sham swimming rats. Rats treated with the NMDA antagonist ketamine (5 mg/kg) before the forced swimming or the second post-stress assessment of nociception did not have hyperalgesia. Thus, swim stress-induced hyperalgesia might be initiated by the repeated stimulation of mu-opioid and NMDA receptors but maintained only by the activity of NMDA receptors.

Anti-inflammatory, antinociceptive, and antipyretic effects of Lantana trifolia Linnaeus in experimental animals.

Lantana trifolia L. (Verbenaceae) is traditionally used as an anti-inflammatory medicinal plant in Venezuela. The methanol extract of the aerial parts of L. trifolia were assessed for the anti-inflammatory, anti-nociceptive and anti-pyretic properties. The extract produced an inhibition of carrageenan-induced edema in the rat paw over a dose range of 10-300 mg/kg i.p.; the dose-response curve was bell-shaped with a maximal effect at 100 mg/kg. The extract also produced a small but significant increase in the response latency of rats subjected to the hot plate, a thermal pain test that only detects analgesia by high-efficacy agents. The extract did not exhibit antipyretic activity. Thus, the L. trifolia extract could have therapeutically relevant anti-inflammatory and analgesic properties in humans.

Anti-inflammatory, antinociceptive, and antipyretic effects of Lantana trifolia linnaeus in experimental animals

Lantana trifolia Linnaeus (Verbenaceae) es tradicionalmente utilizada en Venezuela como una planta medicinal antiinflamatoria. Nosotros indagamos si el extracto metanólico de la parte aérea de L. trifolia posee propiedades antiinflamatoria, antinociceptiva y antipirética. El extracto produjo inhibición del edema inducido por carragenina en la pata trasera derecha de las ratas, en dosis de 10-300 mg/Kg de peso del animal., administradas vía i.p. La curva dosis-respuesta exhibe un máximo a la dosis de 100 mg/Kg. El extracto también produjo un leve pero significativo incremento en la respuesta de latencia de las ratas sometidas al plato caliente, una prueba que sólo detecta analgesia en agentes altamente eficaces. El extracto no exhibió actividad antipirética. El extracto de L. trifolia pudiera tener propiedades terapéuticas antiinflamatorias y analgésicas relevantes en humanos

Repeated swim stress increases pain-induced expression of c-Fos in the rat lumbar cord.

We have previously demonstrated that repeated swim stress produces a long-lasting cutaneous hyperalgesia in rats. We have now looked at c-Fos expression in the spinal lumbar cord of male Sprague-Dawley rats subjected to 10-20 min daily sessions of forced swimming for 3 consecutive days. Control rats were subjected to sham swimming or were completely naive. Forty-eight hours later, nociception was assessed by recording for 90 min the nociceptive behavior evoked the injection of 1% formalin in the hind paw. Thirty min later, the rats' spinal cords were removed for c-Fos immunocytochemistry. Total pain scores were 45% higher in swim stressed rats compared to control animals due an increased nociceptive behavior during last 70 min of the recording period. In addition, the number of c-Fos-immunoreactive nuclei was 40% higher in the lumbar ipsilateral dorsal horn (L4-L5) of swim stressed rats than in controls, being the highest relative increase, relative to the control groups, observed in laminae III-IV, followed by laminae V-VI, with the smallest difference in laminae I-II. c-Fos expression in the contralateral dorsal horn was higher in swim stressed rats than in sham and nai;ve rats. In the absence of a nociceptive stimulus, a low level of c-Fos expression was observed mainly in laminae I, II, V, and VI, being higher in swim stressed rats than in sham rats. These findings suggest that repeated inescapable and uncontrollable stress could induce a sensitization and activation of sensory neurons at the spinal level.