The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2003
Antiallodynic effects of intrathecal orexins in a rat model of postoperative pain.
Orexin A and B (hypocretin 1 and 2) are the endogenous ligands of orexin receptors, a G-protein-coupled orphan receptor family containing orexin 1 (OX1) and orexin 2 (OX2) types. Orexin A induces analgesia in acute and inflammatory pain models. We further elucidated the possible antiallodynic effect of intrathecal orexins in a rat model of postoperative pain. ⋯ It is concluded that intrathecal orexins reduce incision-induced allodynia through OX1 receptors. Glycine and P2X purinergic receptors, but not opioid receptors, might be involved in the antiallodynic effects of orexins. Endogenous orexin might be released after incision injury to activate the spinal OX1 receptors as an endogenous analgesic protector.
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J. Pharmacol. Exp. Ther. · Nov 2003
Suppression of L-type voltage-gated calcium channel-dependent synaptic plasticity by ethanol: analysis of miniature synaptic currents and dendritic calcium transients.
Intoxicating concentrations of ethanol inhibit N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation, an interaction thought to underlie a major component of the central nervous system actions of ethanol. Another form of synaptic potentiation involving activation of L-type dihydropyridine-sensitive voltage-gated calcium channels (VGCCs) has been described, but very little information concerning ethanol effects on VGCC-dependent synaptic potentiation is available. Here, we assessed ethanol effects on VGCC-dependent synaptic potentiation using whole cell patch-clamp recordings of alpha-amino-3-hydroxy-5-methyl-4-soxazolepropionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in area CA1 of the rat hippocampus. ⋯ Ethanol inhibition of VGCC-dependent synaptic potentiation seemed to occur at the induction step because both the increases in mEPSC frequency and amplitude were affected. To address that question more directly, we used fluorescent imaging of synaptically evoked dendritic calcium events, which displayed a similarly marked ethanol sensitivity. Thus, ethanol modulates fast excitatory synaptic transmission by inhibiting the induction of an NMDA receptor-independent form of synaptic potentiation observed at excitatory synapses on central neurons.
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J. Pharmacol. Exp. Ther. · Nov 2003
Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice.
Glucosamine (2-amino-2-deoxy-d-glucose) and glucosamine-containing products have been reported to have efficacy in the treatment of various musculoskeletal disorders. Glucosamine's efficacy, including reduction of pain, is attributed to disease-modifying properties, specifically to cartilage-rebuilding associated with modulation of interleukin-1-induced activation of chondrocytes and to inhibition of proinflammatory effects of the nuclear factor-kappaB pathway. However, glucosamine has not been shown to have direct analgesic activity. ⋯ Combinations containing racemic ibuprofen and glucosamine in greater than 1:1 ratio (glucosamine/ibuprofen) were synergistic in the test (e.g., ED50 = 11.0 +/- 2.1 for the 9:1 ratio; p < 0.01, analysis of variance). Combinations containing glucosamine and ibuprofen (2:1 and 9:1) yielded plasma levels of ibuprofen that were no different from administration of ibuprofen alone. The possibility that combinations containing certain fixed ratios of glucosamine and certain nonsteroidal anti-inflammatory drugs (NSAIDs) might enhance pain relief in patients with pain or might achieve acceptable levels of pain relief with lower doses of NSAIDs (reduced adverse effects) is presently being pursued in clinical trials.
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J. Pharmacol. Exp. Ther. · Nov 2003
Mechanism-based modeling of the pharmacodynamic interaction of alphaxalone and midazolam in rats.
The objective of the present investigation was to characterize the pharmacodynamic interaction between the synthetic neuroactive steroid alphaxalone and the benzodiazepine midazolam. The time course of the electroencephalographic (EEG) effect (11.5-30 Hz) was determined in rats in conjunction with plasma concentrations. Alphaxalone was administered as a continuous intravenous infusion of 0, 1.2, 2.2, or 5.2 mg over 360 min. ⋯ The final model contained an exponential expression to account for acute functional adaptation to the EEG effect upon continuous infusion of alphaxalone. The mechanism-based analysis showed that this functional adaptation is best explained by a change in the system-specific stimulus-response relationship, rather than the drug-receptor activation process. It is concluded that the pharmacodynamic interaction between alphaxalone and midazolam in vivo is best described using an independent interaction model without allosteric modulation.
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J. Pharmacol. Exp. Ther. · Oct 2003
Contractions to histamine in pulmonary and mesenteric arteries from endotoxemic rabbits: modulation by vascular expressions of inducible nitric-oxide synthase and histamine H1-receptors.
The inducible isoform of nitric-oxide synthase (iNOS) is highly expressed after induction of endotoxemia and contributes to vascular hypocontractility in endotoxemia. Circulating levels of histamine are elevated in animal models of sepsis and in patients with septic shock. This study assessed whether the vascular effects of histamine play a significant role in the pathophysiology of endotoxemic shock despite the hyporesponsiveness to vasoconstrictors associated with iNOS up-regulation. ⋯ This was possibly associated with a dramatic increase in H1-receptor expression at the gene and protein levels, as determined by Northern blot and immunoblot analyses. Furthermore, we found that LPS-induced endotoxemia caused prominent increases in production of histamine through induction of histidine decarboxylase in tissues, including blood vessels. From these results, we propose that histamine may contribute to the development of endotoxin-induced pulmonary hypertension.