ABSTRACT
Previous studies have shown that ligands of the sigma-1 receptor chaperone (Sig-1R) regulate pain-related behaviors. Clinical use of chemotherapeutics is often compromised due to their adverse side effects, particularly those related to neuropathy. Previous studies have shown that repeated administration of oxaliplatin and paclitaxel produces neuropathy in rodents. Therefore, the aim of the present study was to clarify the involvement of the Sig-1R in chemotherapeutic-induced neuropathy by examining the effects of oxaliplatin and paclitaxel on the Sig-1R levels in the spinal cord, and by examining the effects of Sig-1R agonist and antagonist on oxaliplatin- and paclitaxel-induced neuropathy in rats. Chemotherapeutic-induced neuropathic pain was accompanied by a significant reduction of the Sig-1R level in the spinal cord. Furthermore, the administration of paclitaxel to CHO cells that stably overexpressed Sig-1Rs induced the clustering of Sig-1Rs. We also found that the Sig-1R agonist SA4503 potently inhibited the neuropathy induced by oxaliplatin- and paclitaxel, whereas this action was abolished by the Sig-1R antagonist NE-100. These results suggest that the reduction of Sig-1R activity is involved in chemotherapeutic-induced neuropathy, and the Sig-1R agonist SA4503 could serve as a potential candidate for the treatment of chemotherapeutic-induced neuropathy.
Subject(s)
Antineoplastic Agents/toxicity , Neuralgia/chemically induced , Neuralgia/metabolism , Organoplatinum Compounds/toxicity , Paclitaxel/toxicity , Receptors, sigma/metabolism , Animals , Anisoles/pharmacology , Blotting, Western , CHO Cells , Cricetulus , Hyperalgesia/chemically induced , Hyperalgesia/metabolism , Male , Microscopy, Fluorescence , Neuralgia/pathology , Oxaliplatin , Piperazines/pharmacology , Propylamines/pharmacology , Rats, Sprague-Dawley , Receptors, sigma/agonists , Receptors, sigma/antagonists & inhibitors , Receptors, sigma/genetics , Sensory System Agents/pharmacology , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/pathology , Touch , Transfection , Sigma-1 ReceptorABSTRACT
Methadone oral tablets initially became available on the Japanese market in MAR－2013. Methadone, which has different pharmacological properties from other opioids including morphine, can cause serious adverse drug reactions such as respiratory depression and QT prolongation. One of the causes of these reactions is its extremely complex pharmacokinetics. Methadone is mostly metabolized in the liver, with a variety of metabolic enzymes, including cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6, being involved. The characteristics of methadone include self-induction of metabolism, delayed excretion due to alkaline urine, and an extremely long half-life requiring a long time to achieve a steady state. Without a full understanding of its complex pharmacokinetics, the blood concentration of methadone is not maintained at a constant level, and serious adverse events could happen due to an unexpected increase in its blood concentration. Herein, for safe clinical use by physicians and pharmacists, we summarize the pharmacokinetics of methadone.
ABSTRACT
Mice exposed to various stresses, especially restrained-stress, revealed the anxiogenic effect detected by the light-dark test. Under this condition, a remarkable decrease in [35S]GTPgammaS binding to membranes from the prefrontal cortex, amygdala and hypothalamus of restrained-stress mice stimulated by the selective 5-HT1A receptor agonist 5-carboxamidotriptamine (5-CT) was clearly observed, whereas a significant increase in [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist was clearly observed in the dorsal raphe nuclei (DRN) of restrained-stress mice. The immunohistochemical study showed a drastic reduction in phosphorylated-CREB-like immunoreactivity in the DRN of restrained-stress mice. Furthermore, we found a drastic reduction in myelin-associated glycoprotein (MAG)-like immunoreactivity (MAG-IR) in the DRN, amygdala and hypothalamus, indicating the direct suppression of synaptic transmission in these regions. It has been accepted that GSK3beta in the Wnt signal pathway plays an important role in various neuronal functions including apoptosis, clustering of synapsin I and early growth and axonal remodeling. In the present study, the increase in protein levels of GSK3beta and phosphorylated-GSK3beta to cytosol fractions of the amygdala was noted in restrained-stress mice. Taken together, these results suggest that restrained stress may directly affect the 5-HT1A receptor-regulated synaptic transmission in the brain, leading to the expression of the anxiogenic effect in mice. It is well known that various stresses induce intracellular oxidative stress. The present study was then undertaken to investigate the effect of the stimulation of 5-HT1A receptors on oxidative stress. Treatment with H2O2 caused the activation of caspase-3-positive cells and the reduction in levels of MAG-IR in the limbic neuron/glia cocultures as compared to medium alone. The stimulation of 5-HT1A receptor by 5-CT produced a dramatic protection against H2O2-triggered activation of caspase-3 and reduction in levels of MAG-IR. These results suggest that 5-HT1A receptors were involved in the modulation of anxiety and the understanding of molecular mechanisms of 5-HT1A receptor-related cascades may pave the way for new therapeutic strategies for affective disorders.
