Drugs That Modify Opioid Tolerance, Physical Dependence, and Abstinence Symptoms: Preclinical and Clinical Studies

Bhargava, Hemendra N.

doi:10.1037/e495822006-005

Cited by 51 publications

(86 citation statements)

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“…It is unknown if a single dose of 10 mg/kg of morphine used for conditioning in mice could result in measurable withdrawal as reported by Krystal and Redmond (1983) in monkeys, but such possibility cannot be ruled out. This explanation appears less likely, as Experiment 4 demonstrated that in mice extinguished with chlordiazepoxide, a known anxiolytic and opiate withdrawal blocker (eg Bhargava, 1994), the morphine challenge produced reinstatement of conditioned response. Moreover, Experiment 4 also shows that in mice extinguished with morphine administration (that apparently would diminish purported withdrawal), morphine challenge was able to reinstate conditioned place preference.…”

Section: Discussionmentioning

confidence: 99%

Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine

Popik

Wróbel

Bisaga

2005

Neuropsychopharmacol

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Protection of abstinent individuals from relapse is the main goal of drug dependence treatment. Relapse is frequently precipitated by exposure to small doses of the drug of abuse or exposure to the environment that was previously associated with the drug. Mice exposed to morphine (10 mg/kg) in a unique test-box environment display a conditioned place preference for this environment. Such preference can be extinguished by subsequent pairing of physiological saline administration with the same environment. Once extinguished, the original place preference can be reinstated after a priming dose (1-2.5 mg/kg) of morphine is given. However, mice treated with 7.5 (but not 3.75) mg/kg of memantine (the glutamate/NMDA receptor antagonist) during the extinction phase were insensitive to morphine's ability to reinstate the place preference 2 days after extinction conditionings. Effect of memantine was also observed when priming dose of morphine was given 21 days after extinction conditionings. In contrast, morphine's ability to reinstate conditioned response was not affected by treatment with 10 mg/kg of chlordiazepoxide, 0.5 mg/kg of LSD-25, or 1 mg/kg of morphine given during extinction conditionings. A separate experiment demonstrated that memantine (7.5 mg/kg) treatment did not affect learning. We show for the first time that memantine treatment during extinction conditionings may abolish the ability of drug-related cues to evoke reinstatement, suggesting that this NMDA receptor antagonist can be useful in preventing relapse in opioid dependent individuals.

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Section: Discussionmentioning

confidence: 99%

Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine

Popik

Wróbel

Bisaga

2005

Neuropsychopharmacol

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“…A reduction in a drug response can theoretically be caused by an adaptive change at one of the many points in the cascade leading to the observable response. In fact, the processes underlying opioid tolerance are known to be complex and involve NMDAdependent learning mechanisms, adaptive changes in the release of other neurotransmitters, compensatory changes in neuronal circuits, and desensitization of signal transduction mechanisms (Trujillo and Akil, 1991;Bhargava, 1994;Nestler, 1996). While the full description of each of these components will ultimately be required to understand the consequences of prolonged opioid exposure, the recent cloning of the ,a-, 6-, and K-opioid receptors (see Kieffer, 1995) has opened up the study of the molecular basis of opioid desensitization of the signaling process.…”

mentioning

confidence: 99%

Agonist‐Induced Phosphorylation of the κ‐Opioid Receptor

Appleyard

Patterson

Jin³

et al. 1997

Journal of Neurochemistry

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Antipeptide antibodies against the K-opioid receptor were used to test whether acute or chronic exposure to K agonists altered the phosphorylation state of the K-Opioid receptor. Immunoprecipitation of the K receptor from guinea pig hippocampal slices preincubated in [ 32P]orthophosphoric acid revealed a basal phosphorylation of the K-opioid receptor. The amount of 32P incorporation into the receptor was increased following a 75-mm treatment with the K agonist U50,488H. This effect was blocked by the selective K receptor antagonist norbinaltorphimine. The time course of this change in the phosphorylation state of the receptor correlated with a desensitization of the electrophysiological response to K agofists measured in the dentate gyrus of hippocampal slices. The phosphorylation state of the K-Opioid receptor was also elevated in brain slices from guinea pigs made tolerant to U50,488H by 5 days of continuous exposure and then maintained in K agonist to avoid acute opiate withdrawal. The results of this study show that the Kopioid receptor was phosphorylated in an agonist-dependent manner in brain slices taken from untreated and U50,488H-tolerant animals.

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“…In addition to these molecular changes, a wide range of neurotransmitters or neuromodulators, including serotonin, noradrenaline, dopamine, cholecystokinin, GABA, agmatine, adenosine, and NO have been shown to play different roles in the mechanisms of tolerance and dependence development to opioid analgesics (19,20). It has been suggested that morphine reduces presynaptic neurotransmitter release such as glutamate, and thus lowers the amount of glutamate available for the NMDA receptors.…”

Section: Tab 1 the Analgesic Effects Of Different Doses Of Morphinementioning

confidence: 99%

Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect

Durmuş¹,

Bağcıvan²,

Özdemir³

et al. 2014

BLL

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Abstract:Objectives: It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. Background: Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. Methods: Nociception was evaluated by tail fl ick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. Results: PPIX, SIN-1, SNAP and NOC-18 signifi cantly increased expression of morphine tolerance while ODQ decreased. Conclusion: These data suggested that sGC activators have a signifi cant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29 Morphine and other opioid drugs are widely used for the treatment of moderate to severe intensity pain. However, tolerance development to the antinociceptive effects of opioids continue to be a signifi cant clinical problem. Although a variety of agents including N-methyl-d-aspartate (NMDA) antagonists, nitric oxide synthase (NOS) inhibitors, calcium channel blockers, kinase inhibitors, and cyclooxygenase inhibitors (1, 2) suggested to block the development of tolerance to the antinociceptive tolerance to opioids, the physiological and biochemical mechanisms underlying the development of tolerance are still unclear (3-5).Nitric oxide (NO) is synthesized from L-arginine and oxygen by the NOS enzyme. After production, NO rapidly diffuses across cell membranes and binds to the heme cofactor of guanylyl cyclase (sGC). sGC forms a stable complex with NO leading to signifi cant increases in cyclic guanosine monophosphate (cGMP) levels that directly modulate phosphodiesterases, ion gated channels, or cGMP-dependent protein kinases which in turn regulate the physiological functions (6, 7). Most of the in vivo studies evaluating the relation between morphine and nitric oxide (NO) have focused on the effects of NOS inhibitors, NMDA receptor antagonists or exogenous administration of L-arginine. However the effects of sGC activators or sGC inhibitors on the pharmacodynamics of morphine are unclear. In this study, we aimed to examine the antinociceptive effects of sGC activators and inhibitors and their role on the development of morphine tole...

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Drugs That Modify Opioid Tolerance, Physical Dependence, and Abstinence Symptoms: Preclinical and Clinical Studies

Cited by 51 publications

References 0 publications

Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine

Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine

Agonist‐Induced Phosphorylation of the κ‐Opioid Receptor

Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect

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