Activation of the cAMP/PKA/DARPP-32 Signaling Pathway is Required for Morphine Psychomotor Stimulation but not for Morphine Reward

Borgkvist, Anders; Usiello, Alessandro; Greengard, Paul; Fisone, Gilberto

doi:10.1038/sj.npp.1301321

Cited by 43 publications

(36 citation statements)

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“…Locomotor sensitization was measured following a single injection of morphine (2.5 or 5 mg/kg) in wild type or knock-in DARPP-32 mutants (Figure 9). T34A mutant mice displayed a decreased locomotor response to the first injection of morphine (Figure 9A), as previously reported (Borgkvist et al , 2007). No sensitization was observed after the second injection of morphine at the two doses tested (Figure 9A).…”

Section: Resultssupporting

confidence: 89%

“…Similarly, in knockin mutant mice in which Thr-34 was replaced by an alanine (T34A), a mutation, which prevents DARPP-32 from inhibiting protein phosphatase-1, sensitization to a single injection of cocaine was prevented (Valjent et al , 2005), whereas sensitization to repeated injections was increased (Zachariou et al , 2006). It has also been reported that sensitization to repeated injections of morphine was not significantly altered in null or T34A mutant mice (Borgkvist et al , 2007). Because of the apparent differences between sensitization to single and repeated injections in the DARPP-32 mutant mice, we tested TIPS for morphine in these mice.…”

Section: Resultsmentioning

confidence: 87%

“…These mice displayed a decreased locomotor response to 5 mg/kg morphine, but a normal sensitization (Figure 9C). These results indicate that mutation of Thr-34, but not Thr-75 or Ser-130, dramatically disrupts sensitization to morphine in TIPS, whereas other mechanisms compensate for this defect when repeated injections are used (Borgkvist et al , 2007). These results show that TIPS is particularly sensitive to detect behavioral consequences of mutations.…”

Section: Resultsmentioning

confidence: 99%

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Mechanisms of Locomotor Sensitization to Drugs of Abuse in a Two-Injection Protocol

Valjent

Bertran‐Gonzalez

Aubier

et al. 2009

Neuropsychopharmacol

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A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, its mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization revealed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knock-in mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1, but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of protein phosphatase-1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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Mechanisms of Locomotor Sensitization to Drugs of Abuse in a Two-Injection Protocol

Valjent

Bertran‐Gonzalez

Aubier

et al. 2009

Neuropsychopharmacol

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182

191

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“…This response requires D1 receptors, the phosphoprotein DARPP32 (Becker et al, 2001;Borgkvist et al, 2007;Urs et al, 2011) and ERK (Borgkvist et al, 2008;Urs et al, 2011). We, and others, have shown that the locomotor effect of morphine is blunted in mice lacking b-arrestin 2 (Bohn et al, 2003;Urs et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Mittal

Tan

Egbuta

et al. 2012

Neuropsychopharmacol

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The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking b-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by b-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with b-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking b-arrestin 2 (b-arr2À/À) to examine this interaction, we found that b-arr2À/À neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting b-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking b-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of b-arr2À/À mice, to + / + levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in b-arr2À/À mice were also returned to + / + levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in b-arr2À/À mice to + / + levels. In summary, removing b-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of b-arr2À/À mice.

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“…There are three main groups of GPCR subtypes: μ, δ and κ receptors. These have been shown to modulate several signalling pathways such as the cAMP pathway, Akt or MAPK-ERK pathways (Li and Chang, 1996;Borgkvist et al, 2007;Merighi et al, 2013). In the brain, both acute and chronic morphine results in either up-regulation or downregulation of ERK1/2 activity depending on the brain region, and induces c-fos and junB in striatum and nucleus accumbens (Liu et al, 1994;Ortiz et al, 1995;Berhow et al, 1996;Eitan et al, 2003).…”

Section: Tables Of Linksmentioning

confidence: 99%

Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus

Pačesová

Volfová

Červená

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEOpioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling. EXPERIMENTAL APPROACHA time-dependent effect of morphine (1 mg·kg −1 , i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [ KEY RESULTSMorphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN. CONCLUSIONS AND IMPLICATIONSOur data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β. Abbreviations

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Activation of the cAMP/PKA/DARPP-32 Signaling Pathway is Required for Morphine Psychomotor Stimulation but not for Morphine Reward

Cited by 43 publications

References 34 publications

Mechanisms of Locomotor Sensitization to Drugs of Abuse in a Two-Injection Protocol

Mechanisms of Locomotor Sensitization to Drugs of Abuse in a Two-Injection Protocol

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus

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