The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Apr 2013
Group I mGluRs evoke K-ATP current by intracellular Ca2+ mobilization in rat subthalamus neurons.
We reported previously that Ca(2+) influx through N-methly-d-aspartate-gated channels evokes ATP-sensitive K(+) (K-ATP) currents in rat subthalamic nucleus (STN) neurons. By using whole-cell patch clamp recordings in brain slices, we investigated the ability of (RS)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist, to evoke K-ATP currents. DHPG (20 µM) evoked outward current at -70 mV and was associated with a positive slope conductance of 2.7 nS. ⋯ Voltage recordings showed that tolbutamide prolonged depolarizing plateau potentials and increased the spontaneous firing rate of STN neurons recorded in the presence of DHPG. These results show that group I mGluR stimulation generates K-ATP current by a nitric oxide- and protein kinase G-dependent process that is mediated by release of Ca(2+) from intracellular stores. Because burst firing is linked to symptoms of Parkinson's disease, we suggest that K-ATP channels might provide a physiologically important inhibitory influence on STN neuronal activity.
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J. Pharmacol. Exp. Ther. · Apr 2013
Upregulation of nuclear factor of activated T-cells by nerve injury contributes to development of neuropathic pain.
Nerve injury induces long-term changes in gene expression in the nociceptive circuitry and can lead to chronic neuropathic pain. However, the transcriptional mechanism involved in neuropathic pain is poorly understood. Nuclear factor of activated T-cells (NFATc) is a transcriptional factor regulated by the Ca(2+)-dependent protein phosphatase calcineurin. ⋯ In addition, treatment with FK-506 or 11R-VIVIT significantly reduced the mRNA levels of NFATc4 and CCR2 but not large-conductance Ca(2+)-activated K(+) channels, in the DRG after nerve injury. Our findings suggest that peripheral nerve injury causes a time-dependent change in NFATc1-c4 expression in the DRG. Calcineurin-NFATc-mediated expression of pronociceptive cytokines contributes to the transition from acute to chronic pain after nerve injury.
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J. Pharmacol. Exp. Ther. · Mar 2013
The antinociceptive effect of milnacipran in the monosodium iodoacetate model of osteoarthritis pain and its relation to changes in descending inhibition.
Osteoarthritis (OA) is a chronic joint disorder whose principal symptom is chronic pain. Current analgesics are inadequate and the mechanisms contributing to this pain are poorly understood but likely to include both local joint changes and central consequences. These studies used monoamine receptor agents combined with behavioral studies and single-unit dorsal horn recordings to examine whether descending noradrenergic and serotonergic inhibitions are altered in the monosodium iodoacetate model of OA pain, and whether increasing these inhibitions with the serotonin/noradrenaline reuptake inhibitor milnacipran can attenuate the attendant hypersensitivity. ⋯ An opioidergic mechanism behind the effects of milnacipran was indicated by a partial reversal of these effects with naloxone. These studies demonstrate antinociceptive effects for milnacipran in a model of OA pain, whose effects come via descending serotonergic and noradrenergic, as well as opioidergic, pathways. Variations in the activity of these pathways over the course of this model may contribute to the presence of behavioral hypersensitivity and determine through which endogenous systems milnacipran exerts its effects.
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J. Pharmacol. Exp. Ther. · Mar 2013
A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine.
The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. ⋯ In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
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J. Pharmacol. Exp. Ther. · Feb 2013
The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients.
Cardiotoxicity from the antitumor anthracycline doxorubicin correlates with doxorubicin cardiac levels, redox activation to superoxide anion (O(2)(.-)) and hydrogen peroxide (H(2)O(2)), and formation of the long-lived secondary alcohol metabolite doxorubicinol. Cardiotoxicity may first manifest during salvage therapy with other drugs, such as the anthracenedione mitoxantrone. Minimal evidence for cardiotoxicity in anthracycline-pretreated patients with refractory-relapsed non-Hodgkin lymphoma was observed with the novel anthracenedione pixantrone. ⋯ In contrast, pixantrone uptake was reduced by prior doxorubicin exposure; moreover, pixantrone lacked redox synergism with doxorubicin, and formed an N-dealkylated product that inhibited metabolism of residual doxorubicin to doxorubicinol. Redox inactivity and inhibition of doxorubicinol formation correlate with the cardiac safety of pixantrone in doxorubicin-pretreated patients. Redox inactivity in the face of high cardiac uptake suggests that pixantrone might also be safe in doxorubicin-naïve patients.