The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Oct 2014
Treatment with a heme oxygenase 1 inducer enhances the antinociceptive effects of µ-opioid, δ-opioid, and cannabinoid 2 receptors during inflammatory pain.
The administration of µ-opioid receptor (MOR), δ-opioid receptor (DOR), and cannabinoid 2 receptor (CB2R) agonists attenuates inflammatory pain. We investigated whether treatment with the heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the local effects and expression of MOR, DOR, or CB2R during chronic inflammatory pain. In mice with inflammatory pain induced by the subplantar administration of complete Freund's adjuvant, we evaluated the effects of the intraperitoneal administration of 10 mg/kg CoPP on the antiallodynic and antihyperalgesic actions of locally administered MOR (morphine), DOR (DPDPE {[d-Pen(2),d-Pen(5)]-enkephalin}), or CB2R [JWH-015 {(2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone}] agonists and its reversion with the HO-1 inhibitor, tin protoporphyrin IX (SnPP). ⋯ CoPP treatment, apart from inducing the expression of HO-1, also enhanced the expression of MOR, did not alter CB2R, and avoided the decreased expression of DOR induced by inflammatory pain. This study shows that the HO-1 inducer (CoPP) increased the local antinociceptive effects of MOR, DOR, and CB2R agonists during inflammatory pain by altering the peripheral expression of MOR and DOR. Therefore, the coadministration of CoPP with local morphine, DPDPE, or JWH-015 may be a good strategy for the management of chronic inflammatory pain.
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J. Pharmacol. Exp. Ther. · Sep 2014
Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons.
Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (Kvs). Here we examined the influence of gambierol on intact cerebrocortical neurons. ⋯ In addition, 2-aminoethoxydiphenylborane, an inositol 1,4,5-trisphosphate receptor inhibitor, and U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal potassium channel inhibitor. Considered together, these data demonstrate that gambierol alters both Ca(2+) signaling and neurite outgrowth in cerebrocortical neurons as a consequence of blockade of Kv channels.
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J. Pharmacol. Exp. Ther. · Aug 2014
AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects.
The metabotropic glutamate receptor 5 (mGluR5) antagonists fenobam, MPEP (2-methyl-6-(phenylethynyl)pyridine), and MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) were previously shown to not cause N-methyl-D-aspartate antagonist-like psychoactive effects in phencyclidine (PCP) drug discrimination studies, but to cause MTEP-like discrimination in rats, suggesting that the psychoactive and psychotomimetic effects reported with fenobam in humans were likely mediated by mGluR5 antagonist mechanisms. The present study was designed to characterize AZD9272 (3-fluoro-5-(3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol5-yl)benzonitrile) and AZD2066 [4-(5-{(1R)-1-[5-(3-chlorophenyl)isoxazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine], two mGluR5 antagonists taken to clinical development for analgesia. AZD9272 was evaluated in several groups of rats trained to discriminate cocaine, PCP, chlordiazepoxide, (-)-Δ(9)-tetrahydrocannabinol [(-)-Δ(9)-THC], or MTEP from no drug. ⋯ It is concluded that the discriminative effects of AZD9272 and AZD2066 are similar to those of previously investigated mGluR5 antagonists and dissimilar to those of cocaine, PCP, chlordiazepoxide, and (-)-Δ(9)-THC. The discriminative half-life of AZD9272 is approximately 7-fold longer than for MTEP. These data support and extend previous findings suggesting that mGluR5 antagonism causes psychoactive effects selectively mediated by mGluR5 mechanisms.
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J. Pharmacol. Exp. Ther. · Aug 2014
Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds.
The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. ⋯ Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases-the enzymes that metabolize and inactivate OP compounds-they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans.
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J. Pharmacol. Exp. Ther. · Aug 2014
Casein kinase II regulates N-methyl-D-aspartate receptor activity in spinal cords and pain hypersensitivity induced by nerve injury.
Increased N-methyl-d-aspartate receptor (NMDAR) activity and phosphorylation in the spinal cord are critically involved in the synaptic plasticity and central sensitization associated with neuropathic pain. However, the mechanisms underlying increased NMDAR activity in neuropathic pain conditions remain poorly understood. Here we show that peripheral nerve injury induces a large GluN2A-mediated increase in NMDAR activity in spinal lamina II, but not lamina I, neurons. ⋯ In addition, inhibition of CK2 or CK2β knockdown at the spinal level substantially reverses pain hypersensitivity induced by nerve injury. Our study indicates that neuropathic pain conditions with different etiologies do not share the same mechanisms, and increased spinal NMDAR activity is distinctly associated with traumatic nerve injury. CK2 plays a prominent role in the potentiation of NMDAR activity in the spinal dorsal horn and may represent a new target for treatments of chronic pain caused by nerve injury.