Neuropharmacology
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Comparative Study
AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.
Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). ⋯ AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent of these antagonists effects may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.
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Ischemic postconditioning, a series of mechanical interruptions of blood flow immediately after reperfusion, has been described in brain studies. However, hypoxic postconditioning (HPC) has never been reported in transient global cerebral ischemia (tGCI) adult rat model. The purpose of this study is to explore the effects of neuroprotection by delayed HPC against tGCI in adult rats and investigate underlying mechanisms involving the Akt/Forkhead transcription factor, class O (FoxO) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways. ⋯ Inhibiting phosphorylation of MEK and ERK with U0126 attenuated neuronal damage after tGCI. These results suggest that delayed HPC exerts neuroprotection against tGCI-induced injury in adult rats. The activation of Akt/FoxO and inactivation of MEK/ERK pathways by postconditioning contributed to the induction of neuroprotection against tGCI.
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In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. ⋯ Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.
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A series of experiments using technologies of gene mutation and silencing as well as chemical biology have demonstrated that spinal D-amino acid oxidase (DAAO) contributes to the development of central sensitization-mediated chronic pain and might be a potential molecular target for the treatment of chronic pain. DAAO inhibitors are now under clinical investigations for the management of chronic neuropathic pain. This study examined the interactions between morphine and the DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) in pain and analgesia tolerance mainly in the formalin test. ⋯ Bi-daily exposure of CBIO given subcutaneously for 7 days did not produce self-tolerance to analgesia or cross-tolerance to morphine whereas 7-day subcutaneous morphine induced self-tolerance to analgesia but not cross-tolerance to CBIO. More importantly, subcutaneous co-administrations or even single dose of CBIO completely prevented or reversed morphine tolerance to analgesia (exhibited by a single dose or a dose-response curve of morphine) in both formalin-induced acute phase nociception and tonic phase pain. These results, for the first time, identified DAAO as an efficacious molecule mediating morphine tolerance, in addition to clarifying the complex interactions between morphine and DAAO inhibitors probed by CBIO, and provided a pharmacological basis for DAAO inhibitors in combination with morphine to clinically manage pain.
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Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitating diseases, which still remain without a safe and adequate treatment. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. Here, we assessed the effects and the underlying mechanisms of action of euphol in preventing inflammatory and neuropathic pain. ⋯ In addition, the pre-treatment with either CB₁R or CB₂R antagonists, as well as the knockdown gene of the CB₁R and CB₂R, significantly reversed the antinociceptive effect of euphol. Interestingly, even in higher doses, euphol did not cause any relevant action in the central nervous system. Considering that few drugs are currently available for the treatment of chronic pain states, the present results provided evidence that euphol constitutes a promising molecule for the management of inflammatory and neuropathic pain states.