European journal of pharmacology
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Role of monoamine neurotransmitters in the modulation of emotional and pain processing in spinal cord and brain regions is not well known. Tapentadol, a norepinephrine reuptake inhibitor with µ-opioid receptor agonistic activity has recently been introduced for the treatment of moderate to severe pain. The objective of the present study was to examine the effects of tapentadol on modulation of monoamines in the prefrontal cortex and dorsal horn using brain microdialysis. ⋯ In the dorsal horn, increase in norepinephrine levels could be due to inhibition of norepinephrine transporter in the spinal cord. Whereas, activation of opioids receptors in non-spinal regions might be responsible for increase in dopamine and serotonin levels. The results from current investigation suggest that clinical efficacy of tapentadol in neuropathic pain is mediated through the enhanced monoaminergic neurotransmission in the spinal cord and regions involved with emotional processing in brain.
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Tramadol is a centrally acting analgesic drug able to prevent nociceptor sensitization when administered into the temporomandibular joint (TMJ) of rats. The mechanism underlying the peripheral anti-inflammatory effect of tramadol remains unknown. ⋯ In conclusion, the results demonstrate that peripheral administration of tramadol has a potential antinociceptive and anti-inflammatory effect. The antinociceptive effect is mediated by activation of the intracellular nitric oxide/cyclic guanosine monophosphate pathway, at least in part, independently from the opioid system.
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Cluster of differentiation 14 (CD14), a pattern recognition receptor expressed on myeloid cells and a critical component of the innate immune system, mediates local and systemic host responses to gram-negative bacterial products, including lipopolysaccharide (LPS). Therefore, CD14 is an attractive target for development of sepsis therapies, and several monoclonal anti-CD14 antibodies have been reported. In this study, we prepared an anti-human CD14 monoclonal antibody, F1024-1-3, which suppressed LPS-induced upregulation of pro-inflammatory cytokines and an adhesion molecule in human peripheral mononuclear cells and human vascular endothelial cells. ⋯ In endotoxemia models generated by three sequential injections of LPS, intravenous administration of F1024-1-3 at 0.3-3mg/kg sharply reduced pro-inflammatory responses in a dose-dependent manner and moderately attenuated pro-coagulant responses; at 1mg/kg, the protein protected rabbits from lethality even when administered 2h after the initial LPS injection. However, F1024-1-3 (10mg/kg) given 2h post-surgery did not prevent death of rabbits in a cecal ligation and puncture model. Thus, suppression of CD14-mediated activation of leukocytes and endothelial cells alone may not be clinically efficacious for the treatment of severe sepsis and septic shock.
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Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. ⋯ Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pKB findings here show that there would be significant antagonism of endothelin-1 contraction in the pulmonary and radial arteries at therapeutic plasma levels. This functional assay confirms in human tissue that much higher plasma concentrations of endothelin-1 receptor antagonists are required to be effective than those predicted from binding or other biochemical assays.
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Several drugs and agents are currently used for the treatment of neuropathic pain. Among them amitriptyline, a tricyclic antidepressant drug, represent a first line treatment. Despite its well-documented clinical efficacy, amitriptyline is ineffective in some animal models of neuropathic pain. ⋯ Additionally, amitriptyline further promoted astrocyte activation in neuropathic mice, as illustrated by the increased expression of glial fibrillary acidic protein (GFAP), that was attenuated by intrathecal injection of the JNK inhibitor. These data indicate astrocyte JNK activation as counteracting pathway to amitriptyline analgesic response. Targeting the JNK pathway in spinal astroglia may present an efficient way to improve the analgesic efficacy of amitriptyline in the neuropathic pain treatment.