RESUMEN
Reactive oxygen species (ROS) are generated in nociceptive pathways in response to inflammation and injury. ROS are accumulated within the sensory ganglia following peripheral inflammation, but the functional role of intraganlionic ROS in inflammatory pain is not clearly understood. The aims of this study were to investigate whether peripheral inflammation leads to prolonged ROS accumulation within the trigeminal ganglia (TG), whether intraganglionic ROS mediate pain hypersensitivity via activation of TRPA1, and whether TRPA1 expression is upregulated in TG during inflammatory conditions by ROS. We demonstrated that peripheral inflammation causes excess ROS production within TG during the period when inflammatory mechanical hyperalgesia is most prominent. Additionally, scavenging intraganglionic ROS attenuated inflammatory mechanical hyperalgesia and a pharmacological blockade of TRPA1 localized within TG also mitigated inflammatory mechanical hyperalgesia. Interestingly, exogenous administration of ROS into TG elicited mechanical hyperalgesia and spontaneous pain-like responses via TRPA1, and intraganglionic ROS induced TRPA1 upregulation in TG. These results collectively suggest that ROS accumulation in TG during peripheral inflammation contributes to pain and hyperalgesia in a TRPA1 dependent manner, and that ROS further exacerbate pathological pain responses by upregulating TRPA1 expression. Therefore, any conditions that exacerbate ROS accumulation within somatic sensory ganglia can aggravate pain responses and treatments reducing ganglionic ROS may help alleviate inflammatory pain.
RESUMEN
Nerve injury induces release of peptides and upregulation of receptors such as substance P and transient receptor potential receptor V1 (TRPV1), which contribute to the development and maintenance of chronic pain. Photobiomodulation therapy (PBMT) is a nonpharmacological strategy that promotes tissue repair and reduces pain and inflammation. However, the molecular basis for PBMT effects on neuropathic pain is still unclear. We investigated the effects of PBMT on substance P, TRPV1, and superficial temperature change in a rodent model of neuropathic pain. We evaluated substance P and TRPV1 in dorsal root ganglia (DRG L4 to L6) at baseline, 14 days after chronic constriction injury (CCI) and after PBMT. We also assessed the superficial temperature of tarsal, metatarsal, tibia, and fibula regions before and after PBMT using infrared thermography. Substance P and TRPV1 levels increased in DRG of CCI rats compared to naive and sham rats and decreased after PBMT. Infrared thermography showed increased temperature of tarsal, metatarsal, tibia, and fibula regions in CCI rats, which was decreased after PBMT. There were no statistical differences between CCI rats with PBMT, sham, and naive rats in any assay. PBMT reduces nociceptive mediators and hind paw and leg's temperature in a rodent model of neuropathic pain, suggesting that PBMT may play a modulatory role in thermoregulation, neurogenic inflammation, and thermal sensitivity in peripheral nerve injuries. Therefore, PBMT appears to be a valuable strategy for neuropathic pain treatment in clinical settings.
Asunto(s)
Terapia por Luz de Baja Intensidad , Neuralgia , Animales , Ganglios Espinales , Hiperalgesia , Neuralgia/radioterapia , Nocicepción , Ratas , Ratas Sprague-Dawley , TermografíaRESUMEN
Background. Glial cells are implicated in the development of chronic pain and brain-derived neurotropic factor (BDNF) released from activated microglia contributes to the nociceptive transmission. Neural mobilization (NM) technique is a method clinically effective in reducing pain sensitivity. Here we examined the involvement of glial cells and BDNF expression in the thalamus and midbrain after NM treatment in rats with chronic constriction injury (CCI). CCI was induced and rats were subsequently submitted to 10 sessions of NM, every other day, beginning 14 days after CCI. Thalamus and midbrain were analyzed for glial fibrillary acidic protein (GFAP), microglial cell OX-42, and BDNF using Immunohistochemistry and Western blot assays. Results. Thalamus and midbrain of CCI group showed increases in GFAP, OX-42, and BDNF expression compared with control group and, in contrast, showed decreases in GFAP, OX-42, and BDNF after NM when compared with CCI group. The decreased immunoreactivity for GFAP, OX-42, and BDNF in ventral posterolateral nucleus in thalamus and the periaqueductal gray in midbrain was shown by immunohistochemistry. Conclusions. These findings may improve the knowledge about the involvement of astrocytes, microglia, and BDNF in the chronic pain and show that NM treatment, which alleviates neuropathic pain, affects glial cells and BDNF expression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Terapia por Ejercicio/métodos , Regulación de la Expresión Génica , Neuralgia/rehabilitación , Neuroglía/patología , Análisis de Varianza , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Recuento de Células , Densitometría , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Neuralgia/patología , Neuroglía/metabolismo , Ratas , Ratas Wistar , Tetraspanina 25/metabolismoRESUMEN
We used functional MRI and a longitudinal design to investigate the brain mechanisms in a previously reported estrogen-dependent visceral hypersensitivity model. We hypothesized that noxious visceral stimulation would be associated with activation of the insula, anterior cingulate cortex, and amygdala, and that estrogen-dependent, stress-induced visceral hypersensitivity would both enhance activation of these regions and recruit activation of other brain areas mediating affect and reward processing. Ovariectomized rats were treated with estrogen (17 ß-estradiol, E2) or vehicle (n = 5 per group) and scanned in a 7T MRI at three different time points: pre-stress (baseline), 2 days post-stress, and 18 days post-stress. Stress was induced via a forced-swim paradigm. In a separate group of ovariectomized rats, E2 treatment induced visceral hypersensitivity at the 2 days post-stress time point, and this hypersensitivity returned to baseline at the 18 days post-stress time point. Vehicle-treated rats show no hypersensitivity following stress. During the MRI scans, rats were exposed to noxious colorectal distention. Across groups and time points, noxious visceral stimulation led to activations in the insula, anterior cingulate, and left amygdala, parabrachial nuclei, and cerebellum. A group-by-time interaction was seen in the right amygdala, ventral striatum-pallidum, cerebellum, hippocampus, mediodorsal thalamus, and pontine nuclei. Closer inspection of the data revealed that vehicle-treated rats showed consistent activations and deactivations across time, whereas estrogen-treated animals showed minimal deactivation with noxious visceral stimulation. This unexpected finding suggests that E2 may dramatically alter visceral nociceptive processing in the brain following an acute stressor. This study is the first to examine estrogen-stress dependent interactions in response to noxious visceral stimulation using functional MRI. Future studies that include other control groups and larger sample sizes are needed to fully understand the interactions between sex hormones, stress, and noxious stimulation on brain activity.
Asunto(s)
Estrógenos/farmacología , Hiperalgesia/etiología , Hiperalgesia/patología , Imagen por Resonancia Magnética , Estrés Psicológico/complicaciones , Vísceras/patología , Animales , Colon/efectos de los fármacos , Colon/patología , Colon/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hiperalgesia/fisiopatología , Actividad Motora/efectos de los fármacos , Ratas Sprague-Dawley , Recto/efectos de los fármacos , Recto/patología , Recto/fisiopatología , Vísceras/fisiopatologíaRESUMEN
Neurotrophins are crucial in relation to axonal regrowth and remyelination following injury; and neural mobilization (NM) is a noninvasive therapy that clinically is effective in neuropathic pain treatment, but its mechanisms remains unclear. We examined the effects of NM on the regeneration of sciatic nerve after chronic constriction injury (CCI) in rats. The CCI was performed on adult male rats, submitted to 10 sessions of NM, starting 14 days after CCI. Then, the nerves were analyzed using transmission electron microscopy and western blot for neural growth factor (NGF) and myelin protein zero (MPZ). We observed an increase of NGF and MPZ after CCI and NM. Electron microscopy revealed that CCI-NM samples had high numbers of axons possessing myelin sheaths of normal thickness and less inter-axonal fibrosis than the CCI. These data suggest that NM is effective in facilitating nerve regeneration and NGF and MPZ are involved in this effect.