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Kurt Rasmussen - One of the best experts on this subject based on the ideXlab platform.
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The mGlu5 receptor antagonists MPEP and MTEP attenuate behavioral signs of Morphine Withdrawal and Morphine-Withdrawal-induced activation of locus coeruleus neurons in rats.
Neuropharmacology, 2005Co-Authors: Kurt Rasmussen, Heidi Martin, James E. Berger, Matthew A. SeagerAbstract:N-Methyl-d-aspartate (NMDA) antagonists have been demonstrated to suppress the signs of opiate Withdrawal; however, side effects limit their clinical use. Since the metabotropic glutamate (mGlu) 5 receptor has been shown to affect glutamate release and modulate NMDA receptor function, we examined the effects of two selective mGlu5 receptor antagonists, 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), on Morphine Withdrawal. Pretreatment with MPEP or MTEP (1, 3, and 10 mg/kg, i.p.) significantly attenuated behavioral signs of Morphine Withdrawal. Specifically, both MPEP and MTEP attenuated the occurrence/severity of chews, digging, salivation, and weight loss, and increased the occurrence of erections. Neither compound changed the occurrence of wet-dog shakes, ptosis, irritability, or lacrimation. Both MPEP and MTEP produced a modest, but significant, attenuation of Morphine-Withdrawal-induced activation of locus coeruleus neurons in anesthetized rats. These results indicate a role for mGlu5 receptors in Morphine Withdrawal and suggest the potential for mGlu5 antagonists in the treatment of Withdrawal from opiates and other drugs of abuse.
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The selective mGlu2/3 receptor antagonist LY341495 exacerbates behavioral signs of Morphine Withdrawal and Morphine-Withdrawal-induced activation of locus coeruleus neurons.
Neuropharmacology, 2004Co-Authors: Kurt Rasmussen, Mei-ann Hsu, Jim VandergriffAbstract:Abstract Previous research has demonstrated that mGlu2/3 agonists can decrease many behavioral signs and the activation of locus coeruleus (LC) neurons observed during Morphine Withdrawal. However, it is not known if mGlu2/3 receptors are activated during Morphine Withdrawal by endogenous glutamate. Therefore, we investigated the effect of a novel metabotropic glutamate 2, 3 (mGlu2/3) receptor antagonist (LY341495) on naltrexone-precipitated behavioral signs of Morphine Withdrawal and Withdrawal-induced activation of LC neurons. Three levels of severity of Morphine Withdrawal (mild, moderate, and strong) were operationally defined by varying the exposure to Morphine. Pretreatment with LY341495 (1 mg/kg, sc) had no affect on behavioral signs at the mild level of Withdrawal, but significantly increased behavioral signs at the moderate level of Withdrawal. At the strong level of Withdrawal, 3 and 10 mg/kg, but not 1 mg/kg, LY341495 significantly increased the behavioral signs of Withdrawal. In in vivo recordings from anesthetized rats, pretreatment with 1 mg/kg LY341495 did not affect the Morphine-Withdrawal-induced activation of LC neurons at the mild level of Withdrawal. At the moderate level of Withdrawal, 1 and 10 mg/kg LY341495 did not affect Morphine-Withdrawal-induced activation of LC neurons. At the strong level of Withdrawal, both 1 and 10 mg/kg LY341495 significantly increased Morphine-Withdrawal-induced activation of LC neurons. These results indicate that endogenous activation of mGlu2/3 receptors during Morphine Withdrawal acts to reduce the severity of Morphine Withdrawal and demonstrates that mGlu2/3 receptors are activated under a physiologically relevant, pathological condition.
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The selective iGluR1-4 (AMPA) antagonist LY300168 attenuates Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioural signs of Morphine Withdrawal
Neuropharmacology, 2003Co-Authors: Kurt Rasmussen, Jim VandergriffAbstract:Abstract Previously, we have shown that the AMPA (iGluR1-4) antagonist LY293558 attenuates the Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioral signs of Morphine Withdrawal. However, LY293558 has since been shown to also have affinity for one subtype of kainate receptor (iGluR5). In this study, we examined the effects of a selective antagonist of iGluR1-4 receptors, LY300168 (GYKI 53655), and a selective antagonist of iGluR5 receptors, LY382884, on the Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioral signs of Morphine Withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY300168 (0.3–3.0 mg/kg, s.c.), but not LY382884 (at a dose known to have central effects; 100 mg/kg, s.c.) attenuated the Morphine-Withdrawal-induced activation of LC neurons. In unanesthetized, Morphine-dependent rats, pretreatment with LY300168 (0.3–3.0 mg/kg, s.c.), but not LY382884 (100 mg/kg, s.c.), suppressed the severity and occurrence of naltrexone-precipitated Morphine-Withdrawal signs. These results indicate iGluR1-4 (AMPA) receptors, but not iGluR5 receptors, play an important role the Morphine-Withdrawal-induced activation of LC neurons and a subset of behavioral signs of Morphine Withdrawal. In addition, selective AMPA antagonists may have therapeutic effects in man for the treatment of Withdrawal from opiates and other drugs of abuse.
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Morphine Withdrawal as a State of Glutamate Hyperactivity
2002Co-Authors: Kurt RasmussenAbstract:Cessation of the repeated administration of opiates results in a characteristic morbidity in humans, including anxiety, nausea, insomnia, hot and cold flashes, muscle aches, perspiration, and diarrhea (1). Great strides have been made in understanding the neurophysiology underlying these opiate-Withdrawal symptoms. Several neurotransmitter systems have been shown to play an important role in opiate Withdrawal, including the dopaminergic (2–4) and cholinergic (5–7) systems. This chapter will discuss evidence for a role of the glutamate system in Morphine Withdrawal. Specifically, the idea that Morphine Withdrawal is a state of glutamate hyperactivity in defined brain regions will be discussed. One of those brain regions is the locus coeruleus.
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The selective mGlu2/3 receptor agonist LY354740 attenuates Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioral signs of Morphine Withdrawal.
Neuropharmacology, 1999Co-Authors: Jim Vandergriff, Kurt RasmussenAbstract:Naltrexone-precipitated Morphine Withdrawal induces hyperactivity of locus coeruleus (LC) neurons, as well as a plethora of behavioral Withdrawal signs. Previous research has demonstrated that an increased release of glutamate and activation of AMPA receptors, particularly in the LC, play an important role in opiate Withdrawal. LY354740 is a novel Group II metabotropic glutamate mGlu2/3 receptor agonist that decreases the release of glutamate. Therefore, we investigated the effect of LY354740 on naltrexone-precipitated Morphine-Withdrawal-induced activation of LC neurons and behavioral signs of Morphine Withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY354740 (3-30 mg/kg, s.c.) dose-dependently attenuated the Morphine-Withdrawal-induced activation of LC neurons. In unanesthetized, Morphine-dependent animals, pretreatment with LY354740 (3-30 mg/kg, s.c.) dose-dependently suppressed the severity and occurrence of many naltrexone-precipitated Morphine-Withdrawal signs. These results indicate mGlu2/3 receptor agonists: (1) can attenuate the Morphine-Withdrawal-induced activation of LC neurons and many behavioral signs of Morphine Withdrawal; and (2) may have therapeutic effects in man for the treatment of opiate Withdrawal.
Jim Vandergriff - One of the best experts on this subject based on the ideXlab platform.
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The selective mGlu2/3 receptor antagonist LY341495 exacerbates behavioral signs of Morphine Withdrawal and Morphine-Withdrawal-induced activation of locus coeruleus neurons.
Neuropharmacology, 2004Co-Authors: Kurt Rasmussen, Mei-ann Hsu, Jim VandergriffAbstract:Abstract Previous research has demonstrated that mGlu2/3 agonists can decrease many behavioral signs and the activation of locus coeruleus (LC) neurons observed during Morphine Withdrawal. However, it is not known if mGlu2/3 receptors are activated during Morphine Withdrawal by endogenous glutamate. Therefore, we investigated the effect of a novel metabotropic glutamate 2, 3 (mGlu2/3) receptor antagonist (LY341495) on naltrexone-precipitated behavioral signs of Morphine Withdrawal and Withdrawal-induced activation of LC neurons. Three levels of severity of Morphine Withdrawal (mild, moderate, and strong) were operationally defined by varying the exposure to Morphine. Pretreatment with LY341495 (1 mg/kg, sc) had no affect on behavioral signs at the mild level of Withdrawal, but significantly increased behavioral signs at the moderate level of Withdrawal. At the strong level of Withdrawal, 3 and 10 mg/kg, but not 1 mg/kg, LY341495 significantly increased the behavioral signs of Withdrawal. In in vivo recordings from anesthetized rats, pretreatment with 1 mg/kg LY341495 did not affect the Morphine-Withdrawal-induced activation of LC neurons at the mild level of Withdrawal. At the moderate level of Withdrawal, 1 and 10 mg/kg LY341495 did not affect Morphine-Withdrawal-induced activation of LC neurons. At the strong level of Withdrawal, both 1 and 10 mg/kg LY341495 significantly increased Morphine-Withdrawal-induced activation of LC neurons. These results indicate that endogenous activation of mGlu2/3 receptors during Morphine Withdrawal acts to reduce the severity of Morphine Withdrawal and demonstrates that mGlu2/3 receptors are activated under a physiologically relevant, pathological condition.
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The selective iGluR1-4 (AMPA) antagonist LY300168 attenuates Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioural signs of Morphine Withdrawal
Neuropharmacology, 2003Co-Authors: Kurt Rasmussen, Jim VandergriffAbstract:Abstract Previously, we have shown that the AMPA (iGluR1-4) antagonist LY293558 attenuates the Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioral signs of Morphine Withdrawal. However, LY293558 has since been shown to also have affinity for one subtype of kainate receptor (iGluR5). In this study, we examined the effects of a selective antagonist of iGluR1-4 receptors, LY300168 (GYKI 53655), and a selective antagonist of iGluR5 receptors, LY382884, on the Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioral signs of Morphine Withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY300168 (0.3–3.0 mg/kg, s.c.), but not LY382884 (at a dose known to have central effects; 100 mg/kg, s.c.) attenuated the Morphine-Withdrawal-induced activation of LC neurons. In unanesthetized, Morphine-dependent rats, pretreatment with LY300168 (0.3–3.0 mg/kg, s.c.), but not LY382884 (100 mg/kg, s.c.), suppressed the severity and occurrence of naltrexone-precipitated Morphine-Withdrawal signs. These results indicate iGluR1-4 (AMPA) receptors, but not iGluR5 receptors, play an important role the Morphine-Withdrawal-induced activation of LC neurons and a subset of behavioral signs of Morphine Withdrawal. In addition, selective AMPA antagonists may have therapeutic effects in man for the treatment of Withdrawal from opiates and other drugs of abuse.
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The selective mGlu2/3 receptor agonist LY354740 attenuates Morphine-Withdrawal-induced activation of locus coeruleus neurons and behavioral signs of Morphine Withdrawal.
Neuropharmacology, 1999Co-Authors: Jim Vandergriff, Kurt RasmussenAbstract:Naltrexone-precipitated Morphine Withdrawal induces hyperactivity of locus coeruleus (LC) neurons, as well as a plethora of behavioral Withdrawal signs. Previous research has demonstrated that an increased release of glutamate and activation of AMPA receptors, particularly in the LC, play an important role in opiate Withdrawal. LY354740 is a novel Group II metabotropic glutamate mGlu2/3 receptor agonist that decreases the release of glutamate. Therefore, we investigated the effect of LY354740 on naltrexone-precipitated Morphine-Withdrawal-induced activation of LC neurons and behavioral signs of Morphine Withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY354740 (3-30 mg/kg, s.c.) dose-dependently attenuated the Morphine-Withdrawal-induced activation of LC neurons. In unanesthetized, Morphine-dependent animals, pretreatment with LY354740 (3-30 mg/kg, s.c.) dose-dependently suppressed the severity and occurrence of many naltrexone-precipitated Morphine-Withdrawal signs. These results indicate mGlu2/3 receptor agonists: (1) can attenuate the Morphine-Withdrawal-induced activation of LC neurons and many behavioral signs of Morphine Withdrawal; and (2) may have therapeutic effects in man for the treatment of opiate Withdrawal.
M. Luisa Laorden - One of the best experts on this subject based on the ideXlab platform.
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Role of PKC in regulation of Fos and TH expression after naloxone induced Morphine Withdrawal in the heart
Naunyn-Schmiedeberg's Archives of Pharmacology, 2006Co-Authors: Pilar Almela, Manuela Cerezo, M. Victoria Milanés, M. Luisa LaordenAbstract:We previously demonstrated that Morphine Withdrawal induced hyperactivity of the heart by activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. The present study was designed to investigate the role of protein kinase C (PKC) in this process, by estimating whether pharmacological inhibition of PKC would attenuate Morphine Withdrawal induced Fos expression and changes in tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on Morphine was induced on day 8 by an injection of naloxone. Morphine Withdrawal induced Fos expression and increased TH levels and NA turnover in the right and left ventricle. Infusion of calphostin C, a selective PKC inhibitor, did not modify the Morphine Withdrawal-induced increase in NA turnover and TH levels. However, this inhibitor produced a reduction in the Morphine Withdrawal-induced Fos expression. The results of the present study provide new information on the mechanisms that underlie Morphine Withdrawal-induced up-regulation of Fos expression in the heart and suggest that TH is not a target of PKC during Morphine Withdrawal at heart levels.
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Alterations in protein kinase A and different protein kinase C isoforms in the heart during Morphine Withdrawal.
European Journal of Pharmacology, 2005Co-Authors: Manuela Cerezo, M. Victoria Milanés, M. Luisa LaordenAbstract:Abstract The present study was designed to investigate the possible changes of protein kinase A (PKA) and different isoforms of protein kinase C (PKC): PKC α, PKC δ and PKC ζ after naloxone induced Morphine Withdrawal in the heart. Male rats were implanted with placebo (naive) or Morphine (tolerant/dependent) pellets for 7 days. On day 8 rats received saline s.c. or naloxone (5 mg/kg s.c.). The protein levels of PKA, PKC δ and PKC ζ were significantly up-regulated in the heart from Morphine Withdrawal rats. By contrast, Morphine Withdrawal induced down-regulation of PKC α. These results suggest that both PKA and PKC may be involved in the cardiac adaptive changes observed during Morphine Withdrawal.
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Alterations in protein kinase A and different protein kinase C isoforms in the heart during Morphine Withdrawal.
European journal of pharmacology, 2005Co-Authors: Manuela Cerezo, M. Victoria Milanés, M. Luisa LaordenAbstract:The present study was designed to investigate the possible changes of protein kinase A (PKA) and different isoforms of protein kinase C (PKC): PKC alpha, PKC delta and PKC zeta after naloxone induced Morphine Withdrawal in the heart. Male rats were implanted with placebo (naïve) or Morphine (tolerant/dependent) pellets for 7 days. On day 8 rats received saline s.c. or naloxone (5 mg/kg s.c.). The protein levels of PKA, PKC delta and PKC zeta were significantly up-regulated in the heart from Morphine Withdrawal rats. By contrast, Morphine Withdrawal induced down-regulation of PKC alpha. These results suggest that both PKA and PKC may be involved in the cardiac adaptive changes observed during Morphine Withdrawal.
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Increase of tyrosine hydroxylase levels and activity during Morphine Withdrawal in the heart.
European journal of pharmacology, 2004Co-Authors: Ana González-cuello, M. Victoria Milanés, M. Luisa LaordenAbstract:Our previous studies have shown an enhanced activity of the noradrenergic pathways innervating the heart in rats withdrawn from Morphine. However, the possible adaptive changes that can occur in these pathways during Morphine dependence are not known. We studied the alterations in tyrosine hydroxylase (the rate-limiting enzyme in catecholamines biosynthesis) and tyrosine hydroxylase activity in the heart (right and left ventricle) during Morphine Withdrawal. In the same paradigm, we measured Fos expression as a marker of neuronal activation and the normetanephrine/noradrenaline ratio (an index of noradrenaline turnover). We evaluated the levels of tyrosine hydroxylase and Fos by quantitative Western blot analysis, and noradrenaline turnover using high-performance liquid chromatography (HPLC). Dependence on Morphine was induced by a 7-day s.c. implantation of Morphine pellets. Morphine Withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg s.c.). The results show a significant increase in tyrosine hydroxylase levels and activity in the right and left ventricle 30 or 90 min after naloxone precipitated Withdrawal in parallel with an increase in noradrenaline turnover. Morphine Withdrawal also induced an increase in the Fos expression, which indicates an activation of cardiac cellular activity. Our results suggest that an increase in tyrosine hydroxylase protein levels and tyrosine hydroxylase enzyme activity might contribute to the enhanced noradrenergic activity in the heart in response to Morphine Withdrawal.
Loris A. Chahl - One of the best experts on this subject based on the ideXlab platform.
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Sensitization to Morphine Withdrawal in guinea-pigs.
European journal of pharmacology, 2005Co-Authors: Akiko Mizutani, Jenny Arvidsson, Loris A. ChahlAbstract:The aim of this study was to determine whether sensitization occurred to Morphine Withdrawal. Guinea-pigs were treated twice daily with increasing doses of Morphine (10-100 mg/kg s.c.) for 3 days followed by injection of Morphine 100 mg/kg on the fourth day. Sixty min after the last Morphine injection, animals were withdrawn from Morphine with naltrexone, 15 mg/kg s.c., and locomotor activity and all other behaviours scored over 90 min. Animals were then rested for 3 days. This procedure was repeated twice over the next 2 weeks. Control animals were treated with saline for the first two treatment cycles. Guinea-pigs subjected to three cycles of Morphine Withdrawal showed a significant increase in the total number of Withdrawal behaviour counts over the 90-min observation period following the third cycle of Withdrawal compared with the first and second Withdrawal cycles. However, locomotor activity, a major sign of Morphine Withdrawal in guinea-pigs, was not significantly increased. Fos-LI was markedly increased in the repeatedly withdrawn animals in several brain regions, including amygdala, dorsal striatum, thalamus, ventral tegmental area, and ventrolateral periaqueductal gray area. It is concluded that sensitization to Morphine Withdrawal occurs in guinea-pigs.
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Chronic treatment with ascorbic acid inhibits the Morphine Withdrawal response in guinea-pigs.
Neuroscience letters, 1992Co-Authors: P. A. Johnston, Loris A. ChahlAbstract:Abstract The effects of ascorbic acid (AA) were investigated on the Morphine Withdrawal response of guinea-pigs, a species which shares with man the inability to synthesize AA. Chronic pretreatment of guinea-pigs with AA, 1 g/l, in drinking water for 3 days, or AA 200 mg/kg subcutaneously (s.c.) 3 times daily for 3 days, markedly reduced the locomotor and behavioural Withdrawal responses of guinea-pigs given naloxone hydrochloride, 15 mg/kg s.c. 2 h after a single dose of Morphine sulphate, 15 mg/kg s.c. AA, 1 g/kg given intraperitoneally (i.p.) 30 min before Morphine had no significant effect on Morphine Withdrawal. However, intracerebroventricular injection of AA, 1 μmol, 30 min before naloxone significantly enhanced Morphine Withdrawal. It is concluded that chronic but not acute administration of AA inhibits opiate Withdrawal.
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Tachykinin antagonists inhibit the Morphine Withdrawal response in guinea-pigs
Naunyn-Schmiedeberg's Archives of Pharmacology, 1991Co-Authors: P. A. Johnston, Loris A. ChahlAbstract:This study was an investigation of the effects of the tachykinin antagonists, spantide and ( d -Pro^4, d -Trp^7, 9, 10)substance P 4-11, injected intracerebroventricularly (ICV), on the locomotor and behavioural responses of guinea-pigs to substance P (SP) injected ICV and to naloxone-induced Morphine Withdrawal. SP, 50 nmol, produced increased locomotor activity and behaviour that mimicked the response induced by injection of naloxone hydrochloride, 15 mg/kg, in guinea-pigs treated 2 h previously with Morphine sulphate, 15 mg/kg. Spantide or ( d -Pro^4, d -Trp^7, 9, 10)SP4-11, 10 nmol, reduced the locomotor and behavioural responses to SP and to Morphine Withdrawal. The results support the suggestion that SP or a related tachykinin might be a mediator of the opioid Withdrawal response in the central nervous system as has been proposed for the enteric nervous system.
Rosa Paolicelli - One of the best experts on this subject based on the ideXlab platform.
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Morphine Withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability
Nature Neuroscience, 2019Co-Authors: Kristina Valentinova, Anna Tchenio, Massimo Trusel, Joseph Clerke, Arnaud Lalive, Stamatina Tzanoulinou, Alessandro Matera, Imane Moutkine, Luc Maroteaux, Rosa PaolicelliAbstract:The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug Withdrawal. Here we report that Morphine Withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes Morphine Withdrawal-like social deficits. Morphine Withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug Withdrawal.