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Jundishapur J Nat Pharm Prod. Morphine Ketotifen Tolerance Dependence Mice. Morphine is one of the most common drugs for treatment of pain in a clinic, while its successive use leads to development of tolerance and dependence 1 , 2. Drug addiction is a chronic and relapsing disease with implication in brain neurobiology and behavior that is associated with drug seeking and persistence of memory 3. Morphine in high doses causes euphoria, analgesia, respiratory depression, reduction of gastrointestinal motility, miosis, and dependency 4 , 5. It has been well confirmed that continuous administration of morphine affects mesolimbic dopaminergic system and leads to development of tolerance and dependence 6 , 7. One of the problems after stopping morphine administration is drug withdrawal followed by symptoms such as anxiety, sweating, increased respiratory rate and body temperature, piloerection, restlessness, nausea, diarrhea, lacrimation, abdominal pain, and hyperreflexia 7 , 8. In spite of many efforts for exact perception of morphine tolerance and dependence, there are still many questions that are needed to be worked on 1. Based on previous studies, tolerance and dependence include two phases; the induction phase, in which changes occur during administration, and the expression phase, in which changes occur after drug cessation 9. Histamine is one of the first neurotransmitters investigated on morphine tolerance and dependence and studies on it have significantly increased in these years Previous researches demonstrated that subsequent administration of morphine in tolerance phase increases histamine turnover in animal brains 11 , In addition, investigations on histamine receptors H 1 and H 2 showed that histamine H 1 receptors play an important role in morphine tolerance and dependence 13 - Ketotifen is a H 1 receptor antagonist and a mast cell stabilizer is used for asthma, atopic dermatitis, seasonal rhinitis, acute and chronic urticaria, allergic conjunctivitis, and food allergy-related 16 - Nowadays, the use of non-opioid compounds and natural products, especially medicinal plants, has increased in order to avoid unwanted effects of opioids include tolerance, dependence, and euphoria Accordingly, this research was designed to investigate the role of ketotifen, as a non-opioid drug, in morphine tolerance and dependence in mice. All mice were used only once, and in order to reduce stress response, the animals were located in the experimental environment 2 days before starting of study. The used drugs including morphine sulfate Darupakhsh Pharmaceutical Co, Tehran, Iran was injected subcutaneously s. We used Eddy and Leimbach's method for study of pain reflexes in reaction to heating stimulus in the hot-plate test The response latency was assessed based on either hind licking or jumping reaction, whichever occurred sooner, after first contact with the plate. The cut-off time was set as 20 seconds to prevent damage to the animal. The hot-plate latency was calculated twice before drug injection and twice after; then, the average of the two values was applied to baseline and drug data. The hot-plate test was carried out on each group at 15, 30, 60, and 90 minutes followed by drug administration. Morphine tolerance was assessed in a hot plate model of antinociception. Ketotifen effects were examined in two acute and chronic studies to evaluate the role of ketotifen in the induction and expression of morphine tolerance and dependence Figure 1. Schematic represents timeline induction of morphine tolerance and dependence in mice and treatment with ketotifen. On the 6th day of the experiment, the hot-plate test was immediately performed after the last dose of morphine. The degree of tolerance was determined according to the measured latency time reduction in the hot-plate test. Ketotifen, in an acute study was administered in day six of the experiment 30 minutes before morphine and in chronic study before each dose of morphine except on the 6th day. For measurement jumping, each mouse was placed on a platform 40 cm length, 25 cm width and 45 cm high during 30 minutes and the frequency of jumps was recorded. In addition, The Mice's body weight variations were evaluated 1h after the naloxone administration. AUC is the area under the curve relevant to respective graph. Moreover, we found out these effects were dose dependent Figure 2. Antinociceptive effect of ketotifen in hot-plate test. AUC is the area under the curve relevant to above graph. Significant difference with VEH. Ketotifen effect on antinociceptive effect of single dose of morphine. The acute administration of ketotifen resulted in significant prevention of morphine tolerance Figure 4. The results confirmed that ketotifen increase latency time, significantly. This suggests that ketotifen reverses morphine tolerance in mice Figure 4. Effect of acute and chronic administration of ketotifen on morphine tolerance. Effects of acute and chronic administration of ketotifen on jumping number. Effects of acute and chronic administration of ketotifen on weight loss in morphine dependent mice. Tolerance is a reduction of pharmacological response to a drug after its long term or repeated use and dose increasing is required to obtain the previous response 22 , Dependency can be defined as an altered physiologically state that requires repeated usage or administration for prevention of abstinence and withdrawal syndrome Morphine is used for pain relief in cancer patients and people with chronic pain, however, it has a potential ability to create dependency 4 , In this study, we investigated the effect of ketotifen on morphine tolerance and dependence in mice and resulted in novel findings on improvement of morphine tolerance and dependence. Histamine and its H 1 and H 2 receptors have a key role in the development of morphine tolerance and dependence It has been reported that H 1 receptor antagonists increase the antinociceptive effect of morphine In confirmation, histamine H 1 receptor agonist led to increase of morphine tolerance and dependence Histamine H 2 receptor antagonist resulted in inhibition of antinociceptive induced by morphine administration Therefore, we find that histamine shares a possible interaction with morphine in opioids tolerance and dependence. The use of opioids increases dopamine release from ventral tegmental area VTA to nucleus accumbens NAc in mesolimbic, a reward pathway that lead to euphoria and pleasure. The chronic administration of opioids leads to demanding more opioid for releasing the same amount of dopamine from VTA brain cells to NAc through the reward system and ultimately leads to tolerance of opioid. However, during the absence of opioids, the high activity of LC leads to manifestation of panic, anxiety, muscle cramps, and diarrhea 27 , Moreover, evaluation of dopamine level followed by naloxone-induced withdrawal syndrome showed occurrence of symptoms of withdrawal for example; jumping associated with increasing of dopamine level in the brain In addition, it was confirmed that histamine is a stimulatory agent for noradrenergic neurons in the LC It well confirmed N-methyl-d-aspartate NMDA receptor antagonist, memantine reduce expression, and induction of morphine-dependence Furthermore, histamine potentiates the NMDA currents in same concentrations that activates H 1 and H 2 histamine receptors 32 , Thus, modulation of morphine actions by NMDA receptors and the regulatory properties of histamine on NMDA receptors can affect initiation and maintenance of tolerance and dependence 34 , Moreover, histamine H 1 receptor antagonists resulted in dopamine reduction in the neostriatum and NAc Histamine may enhance glutamate signaling through NMDA receptors, which will increase the dopamine extracellular level. These evidences can support effects of ketotifen in improvement of morphine tolerance and dependence. Most of the inputs to the NAc are glutamatergic, and these excitatory inputs can result in releasing of dopamine from striatatum. Histamine H 1 receptor antagonists have an inhibitory effect on dopamine activity and monoamine reuptake Morphine causes oxidative stress and triggering formation and release of free radicals through opioids receptors 37 and implications of histamine release well marked by free radicals In this respect, the use of ketotifen can affect the physiopathology of opioids addiction and lead to development of an agent for the treatment of opioids tolerance and dependence. It has been reported that mast cells could be of interest in the resolving of opioids dependence and attenuation of withdrawal signs due to the fact that the number of degranulated mast cells in thalamus significantly increase by naloxone in chronic morphine treated mice Toll like receptors TLRs are important regulators of the innate immune system and activation of mast cells TLRs are involved in neuropathological process of opioids tolerance as well as hyperalgesia and activation of glial by opioids and releasing of pro-inflammatory factors and cytokines Thus, activation of TLRs stimulates the nerves and their inhibition by TLR antagonists reduces neuropathic pain and could relieve us from unwanted effects of opioids including tolerance, dependence, and reward due to opioids 41 , This confirms that ketotifen, as an antagonist of TLRs-4 43 , like naloxone can resolve the unwanted effects of opioids. Morphine tolerance implicates the NMDA receptors activation and subsequent formation of nitric oxide by neuronal nitric oxide synthase Histamine activates and increases NMDA currents Overall, histamine is involved in the development of morphine tolerance and dependence, which can be blocked by ketotifen. Finally, we propose that attenuation of tolerance and withdrawal signs can express the modulatory effects of ketotifen and the possible role of histamine in the induction and expression of morphine tolerance and dependence. Thus, ketotifen can be used in conjunction with opioids to prevent tolerance and dependence to opioids and it can also be used in opioids addicted people to prevent withdrawal signs or resolve dependence. Bhargava HN. Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome, and self-administrative behavior. Pharmacol Rev. Bekhit MH. Opioid-induced hyperalgesia and tolerance. Am J Ther. Learning and memory in addiction. Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence. Przewlocki R. Opioid abuse and brain gene expression. Eur J Pharmacol. Neurobiology of drug addiction. Stages and pathways of drug involvement: examining the gateway hypothesis. New York: Cambridge University Press; Zarrindast MR, Farzin D. Nicotine attenuates naloxone-induced jumping behaviour in morphine-dependent mice. Morphine analgesia and acute physical dependence: rapid onset of two opposing, dose-related processes. Brain Res. Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice. Brit J Pharmacol. The effects of chronic morphine treatment on histamine concentration and histidine decarboxylase activity in rat brain. Prog Neuro Psychopharmacol. Morphine-induced changes in histamine dynamics in mouse brain. J Neurochem. Histamine turnover in the brain of morphine-dependent mice. Naunyn Schmiedebergs Arch Pharmacol. The possible role of brain histamine and H1 and H2 receptors in the development of morphine tolerance and physical dependence in mice. Agents Actions. The effects of L-histidine and of specific histamine receptor agonists, on the expression of morphine tolerance and physical dependence in mice. Inhibition of morphine antinociception by centrally administered histamine H2 receptor antagonists. Craps L. Ketotifen in the oral prophylaxis of bronchial asthma: a review. Prophylaxis of asthma with ketotifen in children and adolescents: a review. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders. Thymus daenensis extract and essential oils effects on morphine withdrawal signs in mice. Eddy NB. Heroin Diacetylmorphine : laboratory and clinical evaluation of its effectiveness and addiction liability. Bull Narcotics. Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin. Pharmacol Biochem Behav. AAPS J. Definitions related to the use of opioids for the treatment of pain: consensus statement of the american academy of pain medicine, the american pain society, and the american society of addiction medicine. American Society of Addiction Medicine,. Basic and clinical pharmacology lange basic science. McGraw-Hill Education; Relationships among morphine metabolism, pain and side effects during long-term treatment: an update. J Pain Symptom Manage. Effect of H1 blockers alone and in combination with morphine to produce antinociception in mice. The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect. Akaoka H, Aston-Jones G. Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input. J Neurosci. Elevation of brain dopamine during naloxone-precipitated withdrawal in morphine-dependent mice and rats. J Pharmacol Exp Ther. Histamine excites noradrenergic neurons in locus coeruleus in rats. Popik P, Skolnick P. The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence. Histamine potentiates N-methyl-D-aspartate receptors by interacting with an allosteric site distinct from the polyamine binding site. The physiology of brain histamine. Prog Neurobiol. Imankhah T, Ghanbarzadeh S. Effect of clonidine and ketotifen on tolerance induced to morphine antinociception in mice. Res Pharmaceutical Sc. Modulation of opioid actions by nitric oxide signaling. Dopaminergic effects of histamine administration in the nucleus accumbens and the impact of H1-receptor blockade. Morphine as a potential oxidative stress-causing agent. Mini Rev Org Chem. Mannaioni P, Masini E. The release of histamine by free radicals. Free Radic Biol Med. Naloxone-induced morphine withdrawal increases the number and degranulation of mast cells in the thalamus of the mouse. Toll-like receptor-mediated activation of mast cells: implications for allergic disease? Int Arch Allergy Immunol. Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance. Med Hypotheses. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. We use cookies to provide you with the best possible experience. They also allow us to analyze user behavior in order to constantly improve the website for you. Abstract Background: Morphine is one of the most common drugs for intense pain relief in a clinic, however, its chronic use and repeated administration leads to morphine tolerance and dependence. Objectives: In this study, effects of ketotifen as histamine H 1 receptor antagonist and mast cell stabilizer have been investigated on the induction and expression of morphine tolerance and dependence in mice. Methods: At first, antinociceptive effects of ketotifen were measured using hot-plate test to find out the subeffective doses of ketotifen. Morphine tolerance was evaluated in hot plate model of antinociception. Ketotifen effects were assessed in two methods of acute and chronic administration to define its role in the expression and induction of morphine tolerance and dependence, respectively. Co-administration of ketotifen with morphine in the induction phase attenuated morphine tolerance and reduced withdrawal signs. Conclusions: Accordingly, ketotifen can be used in conjunction with opioids to reduce opioid tolerance and dependence. It can also be considered in treating people addicted to opioids. Background Morphine is one of the most common drugs for treatment of pain in a clinic, while its successive use leads to development of tolerance and dependence 1 , 2. Methods 2. Drugs The used drugs including morphine sulfate Darupakhsh Pharmaceutical Co, Tehran, Iran was injected subcutaneously s. The Mouse Hot-Plate Test We used Eddy and Leimbach's method for study of pain reflexes in reaction to heating stimulus in the hot-plate test Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. References 1. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4. Leave a comment here:. Cookie Setting We use cookies to provide you with the best possible experience.

Investigation on the Effect of Ketotifen Upon Morphine Tolerance and Dependence in Mice

How can I buy cocaine online in Ahvaz

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How can I buy cocaine online in Ahvaz