Activity

Time-Resolved Fluorescence Resonance Energy Transfer revealed that MMIs are weak ligands of human PXR. Collectively, we show that MMIs are ligands and partial agonists of human PXR, which induce PXR-regulated genes in human intestinal cells. As a consequence of the detoxification process, drugs and drug related metabolites can accumulate in the liver, resulting in drug induced liver injury (DILI), which is the major cause for dose limitation. Amitriptyline, a commonly used tricyclic anti-depressant, is known to cause DILI. The mechanism of Amitriptyline induced liver injury is not yet completely understood. However, as it undergoes extensive hepatic metabolism, unraveling the molecular changes in the liver upon Amitriptyline treatment can help understand Amitriptyline’s mode of toxicity. In this study, Amitriptyline treated male rat liver tissue was analyzed using Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI) to investigate the spatial abundances of Amitriptyline, lipids, and bile acids. The metabolism of Amitriptyline in liver tissue was successfully demonstrated, as the spatial distribution of Amitriptyline and its metabolites localize throughout treatment group liver samples. Several lipids appear upregulated, from which nine were identified as distinct phosphatidylcholine (PC) species. The detected bile acids were found to be lower in Amitriptyline treatment group. The combined results from histological findings, Oil Red O staining, and lipid zonation by MSI revealed lipid upregulation in the periportal area indicating drug induced macrovesicular steatosis (DIS). BACKGROUND Spinal cord injury is one of the most common causes of neuropathic pain which is not responsive to common treatments. Owing to the adverse effects of drugs, it seems that the use of Calcitonin Gene-Related Protein (CGRP) receptor antagonist or Morphine and their combination could be an appropriate strategy for pain alleviation. METHOD To achieve the objective, fifty six male Wistar rats were divided into seven groups. CGRP8-37 and Endomorphin-1 alone, and in combinated administration, as bolus and continues dose. Both mechanical and cold allodynia, and mechanical hyperalgesia were evaluated before and also15 and 60 min after injection to indicate the efficacy of the therapies in the acute and chronic circumstances on pain induced by spinal cord compression injury. Sigma-1 receptor experssion, oxidant and antioxidant activity after the seven days of the drug adminestration were evaluated. RESULT The results showed that Endomorphin-1and CGRP8-37 injections were able to reduce neuropathic pain after spinal cord compression injury. Compared to Endomorphin-1, or CGRP8-37 monotherapy, combination therapy did not show more attenuating effects on the pain threshold. Compared to the continous administration of Endomorphin-1 alone, and CGRP8-37 alone, the continous combination therapy did not reduce the pain further. Molecular studies disclosed the increased expression of the Sigma1 receptor, in the spinal cord after administration of Endomorphin-1, and CGRP8-37 alone, as well as combination therapy. Although, an increase in GPx and SOD activity, and decrease in MDA activity was observed in the combination therapy. CONCLUSION Our results demonstrate that either Endomorphin-1 or CGRP receptor antagonist is able to decrease the neuropathic pain after SCI but combination therapy by a CGRP receptor antagonist and Endomorphin-1 did not make any further reduction in pain sensation. V.It is often claimed that merely seeing a graspable object can elicit the implicit representation of a potential grasp. But can this representation affect the explicit execution of an actual grasp, and if so, how? In an open-loop paradigm, we instructed participants to grasp small, medium, or large test disks with the appropriate grip configuration (pincer, tripod, or pentapod). Before the presentation of these tests, we presented congruent or incongruent distractors. To assess interactions between implicit (putatively elicited by the distractors) and explicit (actually executed) sensorimotor processes, we measured preview reaction times (as an index of action preparation) and grasp kinematics (as an indicator of sensorimotor representations for motor control). Results indicate that action preparation is indeed affected by the presentation of preceding distractors. However, costs in action preparation were measured only when the first, implicit process was less precise than that of the actual grasp. We suggest that an interaction occurs at the level of sensorimotor processes through a mechanism which generalizes a precision parameter. We interpret these findings in relation to processes involved in real-time motor control and within the framework of theories of motor cognition. selleck chemical The incentive effects of food and related cues are determined by stimulus properties and the internal state of the organism. Enhanced hedonic reactivity and incentive motivation in energy deficient subjects have been demonstrated in animal models and humans. Defining the neurobiological underpinnings of these state-based modulatory effects could illuminate fundamental mechanisms of adaptive behavior, as well as provide insight into maladaptive consequences of weight loss dieting and the relationship between disturbed eating behavior and substance abuse. This article summarizes research of our laboratory aimed at identifying neuroadaptations induced by chronic food restriction (FR) that increase the reward magnitude of drugs and associated cues. The main findings are that FR decreases basal dopamine (DA) transmission, upregulates signaling downstream of the D1 DA receptor (D1R), and triggers synaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). Selective antagonism of CP-AMPARs decreases excitatory postsynaptic currents in NAc medium spiny neurons of FR rats and blocks the enhanced rewarding effects of d-amphetamine and a D1R, but not a D2R, agonist. These results suggest that FR drives CP-AMPARs into the synaptic membrane of D1R-expressing MSNs, possibly as a homeostatic response to reward loss. FR subjects also display diminished aversion for contexts associated with LiCl treatment and centrally infused cocaine. An encompassing, though speculative, hypothesis is that NAc synaptic incorporation of CP-AMPARs in response to food scarcity and other forms of sustained reward loss adaptively increases incentive effects of reward stimuli and, at the same time, diminishes responsiveness to aversive stimuli that have potential to interfere with goal pursuit.