EFFECTS OF ADENOSINE RECEPTOR LIGANDS ON THE NOCICEPTION AND STRESS-INDUCED ANTINOCICEPTION IN MICE

Introduction: It is well known that exposure to different stressors caused a sequence of biochemical, physiological and behavioural changes including analgesia which is realised by activating multiple endogenous pain inhibitory systems. Although the existing data reveal the important role of the adenosine modulatory system in the processing of nociceptive information, scarce data are available for its role in stress-induced changes in nociception. Materials and Methods: Male ICR mice – controls and exposed to acute (120 minutes) restraint stress (RS) were used; Acetic acid-induced nociception (writhing test); Adenosine A1 receptor agonist N6-R phenylisopropil-adenosine (R-PIA, 0.5 mg/kg, intraperitoneally, IP), nonselective adenosine receptor antagonist theophylline (acute 75mg/kg, IP and chronic 75 mg/kg/day/14 days, IP). Results: RS and R-PIA decreased the visceral nociception in mice. Acute and chronic treatment with theophylline did not influence the pain reactions neither in nonstressed nor in stressed animals. R-PIA administered before restraint stress fully reversed stress–induced antinociception. Single dose of theophylline antagonized the effects of R-PIA both in nonstressed and stressed animals. Chronic theophylline did not antagonize the antinociceptive effect of R-PIA, but abolished R-PIA induced reversion of SIA. Conclusion: Endogenous adenosine is not able to change the RS-induced visceral antinociception, as theophylline did not show any effects on the stress. However, adenosine A1 receptors are involved both in the antinociception in the healthy mice and RS-induced antinociception, perhaps by different mechanism

Chronic unpredictable stress regulates visceral adipocyte-mediated glucose metabolism and inflammatory circuits in male rats

Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte-associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high-throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High-throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress-related disease states

Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression

Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy) and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A1/A2A receptors, and has been demonstrated to modulate behavior in classical animal models of depression. Moreover, selective adenosine receptor antagonists are being assessed for their antidepressant effects in animal studies. This review focuses on how caffeine and selective adenosine antagonists can improve different aspects of depression in humans, as well as in animal models. The effects on motivational symptoms of depression such as anergia, fatigue, and psychomotor slowing receive particular attention. Thus, the ability of adenosine receptor antagonists to reverse the anergia induced by dopamine antagonism or depletion is of special interest. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression

Behavioral Characteristics of Normotensive Wistar and Spontaneously Hypertensive Rats with an Experimental Model of Diabetes Mellitus Type 2

Introduction: Modern lifestyle is often characterized by decreased physical activity, regular intake of saturated and trans-fatty acids and increased physical and emotional stress, which are a prerequisite for the increased incidence of type 2 diabetes (diabetes mellitus, DM2). Recently published studies showed a positive correlation between DM2 and spontaneous hypertension in the deterioration of the sensory nerve function and the occurrence of peripheral diabetic neuropathy. The purpose of this study was to characterize the behavioral changes induced by an experimental model of diabetes in normotensive and spontaneously hypertensive rats.Materials and Metods: DM2 was induced by the combination of a high-fat diet (2 months) with a sub diabetogenic dose of streptozotocin (30 mg/kg, intraperitoneally). The experimental model of DM2 was induced in two rat strains: normotensive Wistar and spontaneously hypertensive rats (SHR). The exploratory activity and locomotion were studied by an open field test, the level of anxiety by an elevated plus maze test and working memory was tested by an object recognition test.Results: The present results confirmed that SHRs are characterized by higher motor activity and less anxiety-like behavior compared to normotensive Wistar rats.  DM2 induced a remarkable decrease in motor activity in both strains. However, this effect was more pronounced in SHRs. Moreover, DM2 impaired the working memory in SHRs without affecting this type of memory in normotensive animals. Conclusions: Data from this study showed that SHRs are more vulnerable to DM2 in regard to behavioral alterations provoked by the metabolic disease. The results could provide a basis for further testing of the effects of existing and new antihypertensive and antidiabetic drugs on the comorbid hypertension with diabetes type 2

Effects of the antinociceptive dipeptide L-tyrosine-L-arginine (kyotorphin) on the motivation, anxiety, and memory in rats

Introduction: The endogenous dipeptide L-tyrosine-L-arginine (kyotorphin, KTP) is found in brain structures related to the processing of information for nociception, the control of emotions, and memory formation. Besides the antinociceptive effect of KTP, it has a mild protective activity against the deleterious influence of the brain hypoperfusion and streptozotocin on the behavior and memory. Aim: We aimed to study the effects of the intracerebroventricular injection of effective antinociceptive doses of KTP on the motivational behavior, memory, and blood and hippocampal levels of the carbonylated proteins in healthy male adult Wistar rats.Materials and methods: We used a paw-pressure test for assessment of acute nociception, an open field test for assessment of exploration and habituation to a new environment, elevated plus maze test for the evaluation of anxiety-like behavior, and novel object recognition test for working memory. Carbonylated protein assay was used for the assessment of the oxidative impairment of the proteins. The results were analyzed by ANOVA.Results: The present data showed that all single doses of KTP exerted an antinociceptive effect, but this effect was not observed after chronic administration. Only the highest dose of 100 µg was able to induce anxiolytic and motor inhibiting effects. None of the doses used showed effects on the recognition memory or the level of the carbonylated protein. Conclusion: Our results showed that KTP exerted its antinociceptive effect without affecting negatively the blood and brain carbonylated protein or basic behavioral parameters related to the exploration, motivation, and memory formation in healthy rats

Expression of NADPH-d reactive neurons in hippocampus of Alzheimer`s disease rat model. A histochemical study

Alzheimer`s disease (AD) is a neurodegenerative disorder caused by deposition of the amyloid-beta peptide (Aβ) in senile plaques and cerebral vasculature. Its neurotoxic mechanisms are associated with generation of oxidative stress and reactive astrogliosis that cause neuronal death and memory impairment. The most vulnerable part of the brain is the hippocampus, a key structure with important role in the adult neurogenesis and formation of long term memory. The hippocampus receives connections originating in the areas of cortex also severely affected in AD. The reported sparing of NADPH-d neurons in AD and the potential involvement of NO in the pathology of this disease led us to investigate whether NADPH-diaphorase (NADPH-d), a histochemical marker for NO activity, expression is altered in the hippocampus. Experimental model of AD was induced by intracerebroventricular injection of streptozotocin (STZ 3 mg/kg body weight, twice with an interval of 48 h). The cannulae were implanted in the lateral brain ventricle (AP =-0.8 mm, L=1.6mm, DV=- 4.2 mm) under anesthesia (ketalar 80 mg/kg and xylasine 4 mg/kg) using a stereotaxic apparatus. Four months later the animals were anaesthetized and perfused through the heart with fixative (4% paraformaldehyde in 0.1M phosphate buffer). Brains were removed and sectioned by a freezing microtome. Then a histochemical procedure for NADPH-diaphorase NO activity was estimated. Ten sections were utilized for calculation of the neuronal packing density. Our results showed that NADPH-d positive neurons were significantly less in the hippocampal formation of rats with AD. In conclusion, these findings indicate that NADPH-d expressing neurons are highly susceptible to neurodegeneration and that NO might contribute to the pathogenesis of AD. Clarifying the profiles of nitric oxide in the brain tissues and its participation in pathophysiological processes opens a new avenue for development of new therapeutic strategies.The research was supported by Grant 18/2016 of the Medical University of Sofia, Bulgaria

Intracerebroventricular infusion of an Angiotensin AT2 receptor agonist Novokinin aggravates some diabetes mellitus-induced alterations in Wistar rats

Cumulative data suggest the significant role of the Renin - Angiotensin System in the development of the pathological consequences of diabetes mellitus (DM). Newly synthesized AT2 receptor agonists gained importance as a target for creating new antihypertensives. The aim of the present work was to study the effects of a peptide AT2 agonist Novokinin, infused intracerebroventricularly, on the consequences of the streptozotocin-induced type 1 DM (T1 DM) in Wistar rats. Food and water consumption, body weight, urine excretion (metabolic cages), motor activity (open field test), anxiety (elevated plus maze), nociception (paw pressure analgesimeter test), spatial memory (T-maze alternation test) and plasma levels of glucose and corticosterone (ELISA) were assessed two weeks after the T1 DM induction. Novokinin increased water and food consumption, and urine output and reduced weight gain in the control rats. Diabetic rats demonstrated hyperalgesia, increased level of plasma corticosterone, decreased motor and exploratory activity, impaired spatial memory. Novokinin infusion increased water intake, diuresis and mortality rate, decreased food intake, exacerbated diabetes-induced hyperalgesia and provoked anxiety-like behavior but improved spatial memory in diabetic rats. These initial data suggest that angiotensin AT2 receptors participate in the pathogenesis of T1 DM-induced complications in the function of the nervous system.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author