RESUMEN
The mechanistic interactions among redox status of leukocytes, muscle, and exercise in pain regulation are still poorly understood and limit targeted treatment. Exercise benefits are numerous, including the treatment of chronic pain. However, unaccustomed exercise may be reported as undesirable as it may contribute to pain. The aim of the present review is to evaluate the relationship between oxidative metabolism and acute exercise-induced pain, and as to whether improved antioxidant capacity underpins the analgesic effects of regular exercise. Preclinical and clinical studies addressing relevant topics on mechanisms by which exercise modulates the nociceptive activity and how redox status can outline pain and analgesia are discussed, in sense of translating into refined outcomes. Emerging evidence points to the role of oxidative stress-induced signaling in sensitizing nociceptor sensory neurons. In response to acute exercise, there is an increase in oxidative metabolism, and consequently, pain. Instead, regular exercise can modulate redox status in favor of antioxidant capacity and repair mechanisms, which have consequently increased resistance to oxidative stress, damage, and pain. Data indicate that acute sessions of unaccustomed prolonged and/or intense exercise increase oxidative metabolism and regulate exercise-induced pain in the post-exercise recovery period. Further, evidence demonstrates regular exercise improves antioxidant status, indicating its therapeutic utility for chronic pain disorders. An improved comprehension of the role of redox status in exercise can provide helpful insights into immune-muscle communication during pain modulatory effects of exercise and support new therapeutic efforts and rationale for the promotion of exercise.
Asunto(s)
Analgesia/efectos adversos , Ejercicio Físico , Músculo Esquelético/patología , Nociceptores/patología , Estrés Oxidativo , Dolor/patología , Células Receptoras Sensoriales/patología , Humanos , Músculo Esquelético/metabolismo , Nociceptores/inmunología , Nociceptores/metabolismo , Oxidación-Reducción , Dolor/etiología , Dolor/metabolismo , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/metabolismoRESUMEN
Mammals are subject to colonization by an astronomical number of mutualistic and commensal microorganisms on their environmental exposed surfaces. These mutualistic species build up a complex community, called the indigenous microbiota, which aid their hosts in several physiological activities. In this review, we show that the transition between a non-colonized and a colonized state is associated with modification on the pattern of host inflammatory and behavioral responsiveness. There is a shift from innate anti-inflammatory cytokine production to efficient release of proinflammatory mediators and rapid mobilization of leukocytes upon infection or other stimuli. In addition, host responses to hypernociceptive and stressful stimuli are modulated by indigenous microbiota, partly due to the altered pattern of innate and acquired immune responsiveness of the non-colonized host. These altered responses ultimately lead to significant alteration in host behavior to environmental threats. Therefore, host colonization by indigenous microbiota modifies the way the host perceives and reacts to environmental stimuli, improving resilience of the entire host-microorganism consortium to environmental stresses.
Asunto(s)
Infecciones Bacterianas/inmunología , Infecciones Bacterianas/psicología , Conducta , Inmunidad Innata , Nociceptores/inmunología , Estrés Fisiológico/inmunología , Adaptación Biológica , Animales , Infecciones Bacterianas/microbiología , Interacciones Huésped-Patógeno , Humanos , Inflamación/inmunologíaRESUMEN
In the present study, we used the electronic version of the von Frey test to investigate the role of cytokines (TNF-alpha and IL-1beta) and chemokines (KC/CXCL-1) in the genesis of mechanical hypernociception during antigen-induced inflammation in mice. The nociceptive test consisted of evoking a hindpaw flexion reflex with a hand-held force transducer (electronic anesthesiometer) adapted with a 0.5 mm(2) polypropylene tip. The intraplantar administration of methylated bovine serum albumin (mBSA) in previously immunized (IM), but not in sham-immunized (SI) mice, induced mechanical hypernociception in a dose-dependent manner. Hypernociception induced by antigen was reduced in animals pretreated with IL-1ra and reparixin (a non-competitive allosteric inhibitor of CXCR2), and in TNF receptor type 1 deficient (TNFR1-/-) mice. Consistently, antigen challenge induced a time-dependent release of TNF-alpha, IL-1beta and KC/CXCL-1 in IM, but not in SI, mice. The increase in TNF-alpha levels preceded the increase in IL-1beta and KC/CXCL1. Antigen-induced release of IL-1beta and KC/CXCL1 was reduced in TNFR1-/- mice, and TNF-alpha-induced hypernociception was inhibited by IL-1ra and reparixin. Hypernociception induced by IL-1beta in immunized mice was inhibited by indomethacin, whereas KC/CXCL1-induced hypernociception was inhibited by indomethacin and guanethidine. Antigen-induced hypernociception was reduced by indomethacin and guanethidine and abolished by the two drugs combined. Together, these results suggest that inflammation associated with an adaptive immune response induces hypernociception that is mediated by an initial release of TNF-alpha, which triggers the subsequent release of IL-1beta and KC/CXCL1. The latter cytokines in turn stimulate the release of the direct-acting final mediators, prostanoids and sympathetic amines.
Asunto(s)
Quimiocinas/metabolismo , Citocinas/metabolismo , Hiperalgesia/inmunología , Hipersensibilidad Tardía/inmunología , Neuroinmunomodulación/inmunología , Nociceptores/inmunología , Animales , Quimiocina CXCL1/inmunología , Modelos Animales de Enfermedad , Femenino , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Hipersensibilidad Tardía/genética , Hipersensibilidad Tardía/fisiopatología , Mediadores de Inflamación/farmacología , Interleucina-1beta/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroinmunomodulación/genética , Dimensión del Dolor , Umbral del Dolor , Estimulación Física , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Factor de Necrosis Tumoral alfa/inmunología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
Macrophages secrete a variety of chemical mediators that play a central role in the pathophysiology of inflammatory pain. Therefore, the activation or deactivation of these cells in an inflammatory focus could modulate the intensity of the algogenic response. Based on these premises and on our previous demonstration that the calcium-binding protein MRP-14, highly expressed in neutrophils, deactivates activated macrophages in vitro, we decided to investigate the role of MRP-14 and of neutrophils in the control of inflammatory pain in mice. Our results show that this protein is endowed with antinociceptive activity. When tested in the writhing model it was able to inhibit pain response but did not change the behavior of the animals in the hot plate test. This observation indicates that MRP-14 down-regulates inflammatory but not central pain. Using a model of acute neutrophilic peritonitis induced by glycogen, a close correlation between neutrophil migration and antinociception was detected. Surgical adrenalectomy demonstrated that the antinociceptive response induced by glycogen was not due to endogenous liberation of glucocorticoids. The treatment of animals either with a monoclonal antibody anti-MRP-14 or a monoclonal antibody that depletes the animals of neutrophils reverts the antinociceptive response observed in the glycogen-induced peritonitis. These data define the calcium-binding protein MRP-14 as a novel mediator for the control of inflammatory pain and consequently discloses an anti-inflammatory role for the neutrophil.