European journal of pharmacology
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Mechanical ventilation is an indispensable supportive intervention for acute respiratory failure. However, mechanical ventilation can provoke ventilator-induced lung injury, which remains one of the major causes of morbidity and mortality in critically ill patients. Excessive inflammatory response characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators contributes to the pathogenesis of ventilator-induced lung injury. ⋯ Accumulating evidence suggests that HO-1 system may function as a crucial negative regulator in the modulation of inflammatory process. This anti-inflammatory action of HO-1 is mediated essentially by the regulation of the key cells involved in inflammation and restoration of the balance between pro-inflammatory and anti-inflammatory mediators. Therefore, HO-1 system represents a promising therapeutic target for intervention of ventilator-induced lung injury.
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Although some studies have shown the essential role of descending serotonergic pathways and spinal 5-HT(1A), 5-HT(2A), or 5-HT(3) receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced analgesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT(7) receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending serotonergic pathways and spinal 5-HT(7) receptors compared with 5-HT(3) and 5-HT(2A) receptors in the antinociceptive and antihyperalgesic effects of paracetamol. ⋯ Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10 μg) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10 μg) did not. Our findings suggest that systemic administration of paracetamol may activate descending serotonergic pathways and spinal 5-HT(7) receptors to produce a central antinociceptive and antihyperalgesic effects.
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Our previous clinical study reported that isoflurane preconditioning and high-dose propofol posttreatment attenuated myocardial ischemia/reperfusion injury of patients in surgery with cardiopulmonary bypass (CPB). This study was designed to confirm this cardiac protection by use of a dog CPB model and to elucidate the related mechanism. Adult mongrel male dogs undergoing standard CPB were assigned into 4 groups: Sham group, Propofol group, Isoflurane (Iso) group and isoflurane in combination of propofol (pre-Iso+P) group. ⋯ Linear regression analysis showed that cardiac function performance and oxidative stress status were inversely correlated, indicating the improved cardiac function was in closed association with the attenuation of oxidative stress. In addition, the cardiac oxygen consumption (VO(2)) was found to be significantly associated with the above cardiac function and oxidative stress parameters, suggesting VO(2) was predictive for the levels of cardiac damage and oxidative stress. Therefore, we conclude that alternative use of isoflurane and propofol confers superior cardioprotection against postischemic myocardial injury and dysfunction, and this protection was probably mediated by attenuation of cardiac oxidative damage.
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Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor-α (PPAR-α) ligand, exerts antinociceptive and anti-inflammatory effects. PEA (3 and 6 nmol) was microinjected in the ventrolateral periaqueductal grey (VL PAG) of male rats and effects on nociceptive responses and ongoing and tail flick-related activities of rostral ventromedial medulla (RVM) ON and OFF cells were recorded. Intra-PAG microinjection of PEA reduced the ongoing activity of ON and OFF cells and produced an increase in the latency of the nociceptive reaction. ⋯ AM251 and I-RTX, instead, enhanced these latter effects. In conclusion, intra-VL PAG PEA induces antinociceptive effects associated with a decrease in RVM ON and OFF cell activities. PPAR-α receptors mediate, and CB(1) and TRPV(1) receptors antagonise, PEA-induced effects within the PAG-RVM circuitry.
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Numerous studies revealed that spinal inflammation and immune response play an important role in neuropathic pain. In this study, we investigated the effects of intrathecal injection of a Toll-like receptor (TLR4) inhibitor epigallocatechin gallate (EGCG) on neuropathic pain induced by chronic constriction injury of the sciatic nerve (CCI). A total of 120 rats were randomly assigned into 4 groups: sham-operated group, CCI group, CCI plus normal saline group and CCI plus EGCG group. ⋯ When compared with the sham group, both mechanical and heat pain thresholds were significantly decreased, and the mRNA and protein expressions of TLR4 and HMGB1, the contents of TNF-α, IL-1β and IL-10 in the spinal cords and NF-κB expression in the spinal dorsal horn were markedly increased in CCI rats (P<0.05). After intrathecal injection of EGCG (1mg/kg) once daily from 1day before to 3days after CCI surgery, the expressions of TLR4, NF-κB, HMGB1, TNF-α and IL-1β were markedly decreased while the content of IL-10 in the spinal cord increased significantly accompanied by dramatical improvement of pain behaviors in CCI rats (P<0.05). These results show that the TLR4 signaling pathway plays an important role in the occurrence and development of neuropathic pain, and the therapy targeting TLR4 might be a novel strategy in the treatment of neuropathic pain.