No abstract

The present study has been designed to pharmacologically investigate the role of opioid and γ -aminobutyric acid receptors on the seizurogenic effect of tramadol. A single injection of pentylenetetrazole (80 mg/kg) was used to elicit seizure activity in mice. Seizures were assessed in terms of the time latency of the onset of Straub's tail phenomenon, onset of jerky movements of whole body, convulsions and death. Tramadol administration (50 mg/kg) caused a marked increase in seizurogenic activity of pentylenetetrazole as measured in terms of a significant decrease in the time latency of the onset of Straub's tail phenomenon, jerky movements of whole body, convulsions and death. Moreover, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, attenuated the seizurogenic activity that tramadol exerted on pentylenetetrazole-treated mice. Furthermore, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, also attenuated the seizurogenic activity exerted by tramadol per se . Therefore, it is suggested that tramadol exerts a seizurogenic effect on mice possibly via an opioid-dependent γ -aminobutyric acid inhibitory pathway., is a centrally acting analgesic used clinically for the treatment of postoperative and cancer pain. Tramadol binds to opioid receptors with low affinity and inhibits reuptake of monoamines such as norepinephrine and serotonin in the central nervous system, resulting in the activation of the descending inhibitory system [1,2]. These actions are believed to primarily contribute to tramadol's antinociceptive effect. At clinically relevant doses, tramadol has been shown to slightly suppress the severity of seizures [3]. However, at relatively higher doses, tramadol has paradoxically been proven to induce seizures [3]. Although γ -aminobutyric acid (GABA) receptors were not affected by tramadol at clinical doses, at higher concentrations tramadol has been shown to exert an inhibitory effect on GABA receptors [4]. Moreover, pharmacological inhibition of GABA receptors has been reported to potentiate the severity of seizures in various animal models [5]. Furthermore, this inhibition of GABA receptors induced by tramadol has been shown to be secondary to its opioid receptor agonist activity. In addition, continued pharmacological opioid receptor agonist activity has been proven to precipitate seizures via a GABA inhibitory pathway [6,7]. Therefore, the present study has been designed to pharmacologically investigate the role of opioid and GABA receptors in the seizurogenic effect of tramadol on pentylenetetrazole-treated mice and on seizure-like behavioural symptomatology precipitated per se by tramadol. Materials and MethodsMale inbred Swiss albino mice, weighing 25 ± 2 g, maintained on a standard laboratory diet (Kisan Feeds Ltd., Mumbai, India) with free access to tap water, were employed in the present study. They were housed in the departmental animal house and were exposed to a 12-hr light:dark cycle. The experiments were conducte...

Diabetes is a metabolic disease afflicting millions of people worldwide. A substantial fraction of world's total healthcare expenditure is spent on treating diabetes. Hypoglycemia is a serious consequence of anti-diabetic drug therapy, because it induces metabolic alterations in the brain. Metabolic alterations are one of the central mechanisms mediating hypoglycemia-related functional changes in the brain. Acute, chronic, and/or recurrent hypoglycemia modulate multiple metabolic pathways, and exposure to hypoglycemia increases consumption of alternate respiratory substrates such as ketone bodies, glycogen, and monocarboxylates in the brain. The aim of this review is to discuss hypoglycemia-induced metabolic alterations in the brain in glucose counterregulation, uptake, utilization and metabolism, cellular respiration, amino acid and lipid metabolism, and the significance of other sources of energy. The present review summarizes information on hypoglycemia-induced metabolic changes in the brain of diabetic and non-diabetic subjects and the manner in which they may affect brain function.

Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence and responds poorly to the available clinical therapies. Studies from various in vivo and in vitro animal models of opioid withdrawal syndrome have led to understanding of its pathobiology which includes complex interrelated pathways leading to adenylyl cyclase superactivation based central excitation. Advancements in the elucidation of opioid withdrawal syndrome mechanisms have revealed a number of key targets that have been hypothesized to modulate clinical status. The present review discusses the neurobiology of opioid withdrawal syndrome and its therapeutic target recptors like calcitonin gene related peptide receptors (CGRP), N-methyl-D-aspartate (NMDA) receptors, gamma aminobutyric acid receptors (GABA), G-proteingated inwardly rectifying potassium (GIRK) channels and calcium channels. The present review further details the potential role of second messengers like calcium (Ca2+) / calmodulin-dependent protein kinase (CaMKII), nitric oxide synthase, cytokines, arachidonic acid metabolites, corticotropin releasing factor, fos and src kinases in causing opioid withdrawal syndrome. The exploitation of these targets may provide effective therapeutic agents for the management of opioid dependence-induced abstinence syndrome.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The present study has been designed to pharmacologically investigate the role of mast cell degranulation in ischemic preconditioning-induced reversal of global ischemia- and reperfusion-induced cerebral injury in mice. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24 h was employed in present study to produce ischemia- and reperfusion-induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water-maze test. Rota-rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor coordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min (ischemic preconditioning) prevented markedly ischemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of memory and motor coordination. Sodium cromoglycate (10 mg/kg, i.p.), a mast cell stabilizer attenuated the neuroprotective effect of ischemic preconditioning. It is concluded that neuroprotective effect of ischemic preconditioning may be due to the degranulation of mast cells.

The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of antidiabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal and reducing hepatic glucose output. TZDs including pioglitazone, rosiglitazone and troglitazone, by activating PPAR-γ have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, troglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics and pharmacogenetics are an important tool in further understand intersubject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.

No abstract