Pharmacol Rep
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Comparative Study
Inhibition of intracellular signaling pathways NF-κB and MEK1/2 attenuates neuropathic pain development and enhances morphine analgesia.
Neuropathic pain is clinically challenging because it is resistant to alleviation by morphine. The nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways may be involved in the development of neuropathic pain. The aim of our study was to examine the influence of a chronic, intrathecal administration of parthenolide (PTL, inhibitor of NF-κB) and U0126 (inhibitor of MEK1/2) on nociception and morphine effectiveness in a rat model of neuropathy. ⋯ These results indicate that the inhibition of the NF-κB pathway has better analgesic effects. Both inhibitors similarly potentiate morphine analgesia, which parallels the up-regulation of both mor and dor mRNAs expression spinal levels of the model of neuropathy.
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Propofol is a commonly used agent in total intravenous anesthesia (TIVA). However, the link between its pharmacokinetics and pharmacodynamics has not been fully characterized in children yet. Our aim was to determine the quantitative relationship between the venous plasma concentration and bispectral index (BIS) effect in a heterogeneous group of pediatric patients undergoing various surgical procedures (ASA status I-III). ⋯ The BIS values in children are highly correlated with the propofol effect compartment concentrations according to the classical Emax concentration-response relationship. Children had slightly lower sensitivity to propofol and slightly higher clearance, as compared with the adult data available in literature. The intra-patient variations in the BIS require the anesthesiologist's attention in using BIS values alone to evaluate the depth of anesthesia in children.
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Activated microglia cells are well recognized as mediators of neuroinflammation, as they release nitric oxide and pro-inflammatory cytokines in various neuroinflammatory diseases. Thus, suppressing microglial activation may alleviate neuroinflammatory and neurodegenerative processes. In the present study, we synthesized and investigated the anti-neuroinflammatory effect of a novel HTB (2-hydroxy-4-trifuoromethylbenzoic acid) derivative in lipopolysaccharide (LPS)-stimulated microglial cells. ⋯ BECT also mitigated the expression of inducible nitric oxide synthase and cyclooxygenase-2 at both the mRNA and protein levels. Further mechanistic studies demonstrated that the HTB derivative inhibited phosphorylation of JNK and p38 mitogen-activated protein kinase and nuclear translocation of nuclear factor kappa-B in LPS-stimulated BV-2 microglial cells. Thus BECT, our novel synthesized compound have anti-inflammatory activity in microglial cells, and may have therapeutic potential for treating neuroinflammatory diseases.
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The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies. ⋯ In summary, the results suggest that when amitriptyline (but not doxepin or venlafaxine) is locally co-administered with morphine the effectiveness under neuropathic pain is enhanced, although additional studies are necessary to explain differential mechanisms of interaction of antidepressant drugs with morphine after local administration.
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Previous studies have shown that unilateral injection of carrageenan into the gastrocnemius muscle produces chronic thermal and mechanical hyperalgesia. ⋯ In the present carrageenan induced chronic pain model we have determined the role of analgesics in the reversal and inhibition of the state of chronic hyperalgesia. While considering the characterization of the present model our observations suggest the importance of a spinal COX-2 mechanism, a spinal action of systemically delivered drugs in the face of peripheral inflammation.