μ-Opioid receptor-regulated adenylate cyclase activity in primary cultures of rat striatal neurons upon chronic morphine exposure

Vliet, Bernard J. Van; Vries, Taco J. De; Wardeh, George; Mulder, Arie H.; Schoffelmeer, Anton N. M.

doi:10.1016/0922-4106(91)90060-u

Cited by 39 publications

(27 citation statements)

References 23 publications

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“…When morphine is discontinued or withdrawal is pharmacologically precipitated, cAMP levels dramatically increase (see Figures 1 and 2 , GABAergic neurons in Withdrawal condition; Nestler and Aghajanian, 1997; Williams et al, 2001). This phenomenon of early inhibition and late positive regulation of adenylyl cyclase by morphine has been demonstrated in several morphine-receptive brain regions (Duman et al, 1988; Nestler and Tallman, 1988; Terwilliger et al, 1991; Van Vliet et al, 1991; Self et al, 1995; Shaw-Lutchman et al, 2002). Upregulation of the cAMP pathway observed during morphine withdrawal activates cAMP-dependent protein kinase A (PKA; Chartoff et al, 2003a, b, 2006).…”

Section: Mor Activation and Intracellular Signalingmentioning

confidence: 74%

Itâ€™s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

2014

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Opioids selective for the G protein-coupled mu opioid receptor (MOR) produce potent analgesia and euphoria. Heroin, a synthetic opioid, is considered one of the most addictive substances, and the recent exponential rise in opioid addiction and overdose deaths has made treatment development a national public health priority. Existing medications (methadone, buprenorphine, and naltrexone), when combined with psychosocial therapies, have proven efficacy in reducing aspects of opioid addiction. Unfortunately, these medications have critical limitations including those associated with opioid agonist therapies (e.g., sustained physiological dependence and opioid withdrawal leading to high relapse rates upon discontinuation), non-adherence to daily dosing, and non-renewal of monthly injection with extended-release naltrexone. Furthermore, current medications fail to ameliorate key aspects of addiction such as powerful conditioned associations that trigger relapse (e.g., cues, stress, the drug itself). Thus, there is a need for developing novel treatments that target neural processes corrupted with chronic opioid use. This requires a basic understanding of molecular and cellular mechanisms underlying effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. The focus of this review is to discuss how crosstalk between MOR-associated G protein signaling and glutamatergic neurotransmission leads to immediate and long-term effects on emotional states (e.g., euphoria, depression) and motivated behavior (e.g., drug-seeking, relapse). Our goal is to integrate findings on how opioids modulate synaptic release of glutamate and postsynaptic transmission via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in the nucleus accumbens and ventral tegmental area with the clinical (neurobehavioral) progression of opioid dependence, as well as to identify gaps in knowledge that can be addressed in future studies.

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Section: Mor Activation and Intracellular Signalingmentioning

confidence: 74%

Itâ€™s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

2014

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“…βarrestin2 was also involved in the desensitization of cyclase responses following sustained exposure of striatal MORs to morphine and DAMGO [65]. However, in spite of its ability to trigger MOR regulation, exposure to morphine induced superactivation of the striatal cAMP cascade [69], suggesting that MOR desensitization when associated to this effector might not be enough to completely avoid cellular compensatory mechanisms.…”

Section: Regulation Of Opioid-mediated Responses In Neuronsmentioning

confidence: 99%

Regulation of opioid receptor signalling: Implications for the development of analgesic tolerance

Nagi

Piñeyro

2011

Molecular Brain

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Opiate drugs are the most effective analgesics available but their clinical use is restricted by severe side effects. Some of these undesired actions appear after repeated administration and are related to adaptive changes directed at counteracting the consequences of sustained opioid receptor activation. Here we will discuss adaptations that contribute to the development of tolerance. The focus of the first part of the review is set on molecular mechanisms involved in the regulation of opioid receptor signalling in heterologous expression systems and neurons. In the second part we assess how adaptations that take place in vivo may contribute to analgesic tolerance developed during repeated opioid administration.

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“…In the case of morphinemediated locomotor stimulation, the dopamine system appears to contribute to the expression, but not the development, of sensitization [148]. Although dopamine receptor levels in the striatum are not altered in sensitized animals [228], D 2 receptors are desensitized and D 1 -mediated signaling is upregulated [229,342]. The findings that sensitization is a persistent process suggests that changes in genetic expression of certain signaling proteins might contribute to this process.…”

Section: Sensitizationmentioning

confidence: 83%

“…Desensitization of MOR-mediated AC inhibition in the thalamus has also been found under treatment conditions that increase phosphorylation of MOR [89]. No change in MOR-inhibited AC has been found in caudate-putamen or NAC following chronic opioid treatment using MORspecific agonists to assess activity [86,236,342]. Decreased MOR-inhibited AC in the striatum has been observed using the non-selective opioid agonist (D-Ala 2 -Met 5 ) enkephalinamide (DAME) [331], but probably reflects desensitization of DOR-inhibited AC [236].…”

Section: Adenylyl Cyclasementioning

confidence: 93%

Regional Differences in Adaptation of CNS Mu Opioid Receptors to Chronic Opioid Agonist Administration

Sim‐Selley¹

2005

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Opioids produce a number of acute effects, notably antinociception and euphoria, whereas chronic use produces tolerance and dependence. Mu opioid receptors (MOR) mediate opioid antinociception and reinforcement and are distributed throughout the CNS in regions consistent with their acute effects, including striatum, thalamus, amygdala, periaqueductal gray (PAG), locus coeruleus (LC), and spinal cord. G-protein-coupled receptor (GPCR) adaptation involves G-protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation with subsequent β-arrestin binding, which uncouples GPCRs from G-protein activation. β-arrestin binding can initiate receptor endocytosis, leading to subsequent degradation or recycling of GPCRs. These processes are reflected experimentally by desensitization (loss of functional response) and downregulation (loss of receptor binding sites). Evaluation of MOR levels following chronic opioid treatment has indicated that MOR downregulation is not required for the expression of tolerance and dependence. In contrast, evaluation of post-receptor events has revealed region-dependent alterations in MOR-G-protein coupling and subsequent effector activity. For example, MOR-mediated G-protein activity and inhibition of adenylyl cyclase are generally decreased in brainstem nuclei following chronic morphine administration, whereas no changes are found in striatum. Similarly, tolerance develops to MOR-mediated potassium channel activation in regions that include LC and PAG. Chronic opioid-mediated effects on adenylyl cyclase affect downstream signaling via regulation of cAMP dependent protein kinase (PKA) and cAMP response element binding protein (CREB), both of which are altered in LC, nucleus accumbens (NAC) and amygdala, regions that might contribute to motivational and physiological signs of withdrawal. Possible explanations for regional differences in MOR adaptation include region-specific co-localization of MOR with signaling proteins and differential distribution of MOR splice variants or oligomers. Moreover, the finding that regional differences exist in neuroadaptation suggests that behavioral adaptations to chronic opioid administration will vary based on the functional neuroanatomy of the MOR system.

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μ-Opioid receptor-regulated adenylate cyclase activity in primary cultures of rat striatal neurons upon chronic morphine exposure

Cited by 39 publications

References 23 publications

Itâ€™s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

Itâ€™s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

Regulation of opioid receptor signalling: Implications for the development of analgesic tolerance

Regional Differences in Adaptation of CNS Mu Opioid Receptors to Chronic Opioid Agonist Administration

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