μ-Opioid Receptor Endocytosis Prevents Adaptations in Ventral Tegmental Area GABA Transmission Induced during Naloxone-Precipitated Morphine Withdrawal

Madhavan, Anuradha; He, Ling; Stuber, Garret D.; Bonci, Antonello; Whistler, Jennifer L.

doi:10.1523/jneurosci.4634-09.2010

Cited by 44 publications

(61 citation statements)

References 33 publications

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“…A characteristic feature of morphine withdrawal is an increase in GABAergic activity in regions like the VTA (Bagley et al, 2011), leading to enhanced GABAergic neurotransmission onto VTA dopamine neurons (Bonci and Williams, 1997;Madhavan et al, 2010a), associated with detrimental opiate withdrawal symptoms (Madhavan et al, 2010a). Accordingly, we observed that withdrawal from chronic morphine pretreatment (n ϭ 15) increased the frequency of mIPSCs onto VTA dopamine neurons by 66.08% (F (1,48) ϭ 4.09, p Ͻ 0.05, one-way ANOVA; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Reduced dopamine signaling during morphine withdrawal can arise due to increased GABAergic signaling onto VTA dopamine neurons (Bagley et al, 2011). This enhancement of inhibitory signals has been reported to occur as a consequence of morphine withdrawal-induced elevations in cAMP (cAMP superactivation) in GABAergic terminals (Bonci and Williams, 1997;Madhavan et al, 2010a). Together, these findings point to an important role of GABAergic signaling onto VTA dopamine neurons in the occurrence of opiate withdrawal symptoms.…”

Section: Introductionmentioning

confidence: 87%

“…In the VTA, such cAMP superactivation has been reported to increase GABAergic input to VTA dopamine neurons (Bonci and Williams, 1997), and is responsible for negative withdrawal symptoms (Madhavan et al, 2010a). Enhanced MOR constitutive activity could be an adaptive countermeasure to partly suppress the withdrawal-induced cAMP overshoot and concomitant enhanced GABAergic transmission in the VTA.…”

Section: Enhancement Of Camp Levels Increases Inverse Agonistic Effecmentioning

confidence: 99%

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Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

et al. 2012

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-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Enhancement Of Camp Levels Increases Inverse Agonistic Effecmentioning

confidence: 99%

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Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

et al. 2012

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“…The application of forskolin increases GABA IPSCs in morphine-treated brain slices while dideoxyforskolin, which does not have an effect on AC, did not increase GABA IPSC. 136,137 …”

Section: Molecular Changes In the Ventral Tegmental Areamentioning

confidence: 99%

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

Chan

Lutfy

2016

Progress in Molecular Biology and Translational Science

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“…TTX is a highly selective voltagegated sodium channel (VGSC) blocker [4]. TTX have been used for anaesthetic agents [5], reducing opioid withdrawal symptoms [6], preventing ischemia in post stroke patients [7]. Recent studies also show that TTX has anti-metastatic [8] and anti tumor properties [9].…”

mentioning

confidence: 99%

Effect of Tetrodotoxin from Crude Puffer Fish (Tetraodon fluviatilis) Liver Extract on Intracellular Calcium Level and Apoptosis of HeLa Cell Culture

Untario¹,

Dewi²,

Widodo³

et al. 2017

JTLS

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Cervical cancer is the third most commonly diagnosed cancer and fourth leading cause of women death with 8% of total death caused by cancer in women in 2008. Tetrodotoxin (TTX) is a potent neurotoxin found in inner organs puffer fish, with the specific mechanism of sodium channel blocking, and widely used for research purposes. Previous reports claimed that TTX has the capability of inhibiting metastatic process of cancer and apoptotic effect. Studies also show that apoptosis is a process involving increase of intracellular calcium level, yet the connection between TTX and increase of intracellular calcium level, therefore triggering apoptosis, has not been established. This is an experimental study with post-test only control group design, carried out by exposing HeLa cell culture to crude liver extract of a puffer fish species, Tetraodon fluviatilis. Crude puffer fish liver extract is administered into HeLa cell culture well in different concentrations 10 . Intracellular calcium level and apoptosis were then measured after 18 hours of incubation. Measurements of intracellular calcium level were done by using CLSM with Fura-2AM staining, and apoptosis by using flowcytometry with Annexin V/PI. The result shows that there is a significant differences between samples both in intracellular calcium (p < 0.05) and apoptosis (p < 0,05). Both intracellular calcium and apoptosis levels are proportional to liver fish extract concentration. Pearson's correlation test shows correlation between treatment and intracellular calcium levels (p = 0.000), between treatment and apoptosis (p = 0.002), but not between intracellular calcium and apoptosis (p = 0.05). These results suggest that TTX induces an increase in intracellular calcium level and apoptosis, but calcium pathway is not the sole cause of the apoptosis. Cervical cancer is the third most commonly diagnosed cancer and fourth leading cause of women death, contributing to 9% (528,000) from total new cancer cases per year and 8% (257,100) total cancer death for women in 2008 [1]. Conventional strategy for cancer management including surgery, radiotherapy, and chemotherapy with both synthetic agents and natural agents have been established for years [2], yet cancer is still the leading cause of death. Side effects of chemotherapy includes headache, hair loss, nausea and vomiting, sore throat, diarrhea, and many more [3]. This clearly calls for other effective therapeutic agents with less intolerable side effects.Tetrodotoxin (TTX) is a potent neurotoxin found in the inner organs of puffer fish, including Tetraodon fluviatilis. Found in deep water, these fishes are known to be toxic, hence they are are usually returned to the sea by fisherman. TTX is a highly selective voltagegated sodium channel (VGSC) blocker [4]. TTX have been used for anaesthetic agents [5], reducing opioid withdrawal symptoms [6], preventing ischemia in post stroke patients [7]. Recent studies also show that TTX has anti-metastatic [8] and anti tumor properties [9]. Study by Fouda et al. (2005)...

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μ-Opioid Receptor Endocytosis Prevents Adaptations in Ventral Tegmental Area GABA Transmission Induced during Naloxone-Precipitated Morphine Withdrawal

Cited by 44 publications

References 33 publications

Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

Effect of Tetrodotoxin from Crude Puffer Fish (Tetraodon fluviatilis) Liver Extract on Intracellular Calcium Level and Apoptosis of HeLa Cell Culture

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