European journal of pharmacology
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Comparative Study
Spinal anesthesia with diphenhydramine and pheniramine in rats.
The aim of this study was to evaluate the local anesthetic effects of pheniramine and diphenhydramine, two histamine H₁ receptor antagonists, on spinal anesthesia and their comparison with lidocaine, a commonly used local anesthetic. After rats were injected intrathecally with diphenhydramine and pheniramine, the dose-response curves were obtained. The potency and duration of diphenhydramine and pheniramine on spinal anesthesia were compared with lidocaine. ⋯ In equianesthetic doses (ED₂₅, ED₅₀, and ED₇₅), the block duration caused by diphenhydramine was longer than that caused by pheniramine or lidocaine (p<0.01 for the differences). Diphenhydramine, but not pheniramine or lidocaine, elicited longer duration of sensory block than that of motor block at the same dose of 1.75 μmol. These preclinical data reported that diphenhydramine with a more sensory-selective action over motor blockade demonstrated more potent and longer-lasting spinal blockades, compared with pheniramine or lidocaine.
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Amyloid β-protein (Aβ), which is deposited in neurons as neurofibrillary tangles, is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the PI3K/Akt-mediated interaction between Bad and Bcl(XL) plays an important role in maintaining mitochondrial integrity. However, the application of therapeutic drugs, especially natural products in Alzheimer's disease therapy via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway has not aroused extensive attention. ⋯ Further study indicated that hyperoside can activate the PI3K/Akt signaling pathway, resulting in inhibition of the interaction between Bad and Bcl(XL), without effects on the interaction between Bad and Bcl-2. Furthermore, hyperoside inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). These results demonstrate that hyperoside can protect Aβ-induced primary cultured cortical neurons via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway, and they raise the possibility that hyperoside could be developed into a clinically valuable treatment for Alzheimer's disease and other neuronal degenerative diseases associated with mitochondrial dysfunction.
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Recent studies have indicated that nearly half of all surgical patients still have inadequate pain relief; therefore, it is becoming increasingly more important to understand the mechanisms involved in postoperative pain in order to be better treated. Previous studies have shown that incisions can cause mast cell degranulation. Thus, the aim of this study was to investigate the involvement of mast cells in a model of postoperative pain in mice. ⋯ Accordingly, pre-treatment with the mast cell membrane stabilizer cromoglycate (200 μg/paw, i.pl.) prevented mechanical allodynia (inhibition of 96 ± 21%) and an increase in histamine (44 ± 10% of inhibition) and serotonin (73 ± 5% of inhibition) levels induced by plantar surgery. Finally, local treatment with H(1) (promethazine, 100 μg/paw, i.pl.), 5-HT(3) (ondansetron, 10 μg/paw, i.pl.) or 5-HT(2A) (ketanserin, 5 μg/paw, i.pl.) receptor antagonists partially decreased postoperative nociception in mice, but when co-administered together it completely reversed the mechanical allodynia in operated mice. Thus, mast cell activation mechanisms are interesting targets for the development of novel therapies to treat postoperative pain.
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We examined the analgesic effect of the selective kappa opioid receptor agonist SA14867 and the balance of its antinociceptive and sedative effects. The ED(50) values of SA14867 after oral administration for acetic acid-induced writhing, first and second phases of the formalin test, and rotarod test in mice were 6.1, 9.3, 2.7, and 19.5mg/kg, respectively. These values were smaller than those of the conventional kappa receptor agonists asimadoline and U-50488H. ⋯ Subcutaneously administered morphine (0.1-1mg/kg) improved the decreased pain threshold in a SART-stressed model; on the contrary, morphine did not inhibit the arthritis-induced decrease in the pain threshold. Moreover, orally administered SA14867 (0.1-1mg/kg) strongly attenuated mechanical allodynia and thermal hyperalgesia in a sciatic nerve ligation model. These results suggest that SA14867 has analgesic effects on chronic pain and may serve as a new therapeutic agent for pain treatment.