Opioid-Induced GABA Potentiation after Chronic Morphine Attenuates the Rewarding Effects of Opioids in the Ventral Tegmental Area

Madhavan, Anuradha; Bonci, Antonello; Whistler, Jennifer L.

doi:10.1523/jneurosci.3366-10.2010

Cited by 56 publications

(62 citation statements)

References 30 publications

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“…This suggests that the changes in MOR constitutive activity are not a direct response to the chronic administration of morphine itself, but become pronounced later in the withdrawal period. We also observed that the effect of the MOR agonist DAMGO was diminished during morphine withdrawal, as has been reported previously (Madhavan et al, 2010b). This suggests a withdrawal-induced shift toward more constitutively active MORs, allowing for less additional agonist-induced activation.…”

Section: Discussionsupporting

confidence: 89%

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: Discussionsupporting

confidence: 89%

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

et al. 2012

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“…We have previously shown the facilitating internalization and recycling (not degradation) of the MOR in response to morphine can prevent or delay many of the compensatory homeostatic adaptations that contribute to tolerance and dependence to moderate long-term doses of morphine (Finn and Whistler, 2001;He et al, 2002;He and Whistler, 2005;Kim et al, 2008;Madhavan et al, 2010). Thus, the data reported here, together with these previous results, show that receptor internalization has dramatically different effects on the development of analgesic tolerance and dependence, depending on the trafficking of the targeted receptor.…”

Section: Morphine-induced Down-regulation Of Dmor 639supporting

confidence: 76%

“…One key homeostatic adaptation that contributes to morphine tolerance in WT mice is superactivation of adenylyl cyclase signaling (for review, see Nestler, 2004;Berger and Whistler, 2010). The importance of this adaptation not only to second messenger signaling but also to synaptic adaptations and behavioral withdrawal was recently demonstrated in vivo (Madhavan et al, 2010). Superactivation, in turn, may promote additional and diverse changes in gene and protein expression, all of which play a role in the behavioral manifestation of morphine tolerance and dependence.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there has been a tendency to equate desensitization to the effects of the drug (tolerance) to desensitization/down-regulation of the receptor per se. However, cells and circuits can adapt in ways that make them less responsive to the same dose of drug, thus appearing "desensitized," even in the absence of loss of receptor function (Madhavan et al, 2010). Hence, these studies alone do not differentiate between desensitization of receptors and desensitization to drug as the mechanism that produces tolerance.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

Enquist

Kim

Bartlett

et al. 2011

J Pharmacol Exp Ther

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The role of -opioid receptor (MOR) down-regulation in opioid tolerance remains controversial. In this study, we used a novel knock-in mouse to examine how changing the extent of MOR down-regulation alters the development of morphine tolerance. These mice express a mutant MOR, degrading MOR (DMOR), that differs from the wild-type (WT) MOR in two ways: 1) unlike the recycling WT MOR, the mutant DMOR is targeted for degradation after its internalization, thus facilitating down-regulation; and 2) unlike the WT MOR, DMOR is efficiently internalized in response to morphine activation. We found that both WT MOR and DMOR mice develop tolerance to morphine, but DMOR mice exhibit a more rapid onset of tolerance and show receptor down-regulation. WT MOR mice develop morphine tolerance more slowly but even once profoundly tolerant show no receptor down-regulation. Furthermore, WT mice show significantly more morphine dependence than DMOR mice after long-term treatment as indicated by withdrawal. Taken together these data indicate that tolerance mediated by receptor downregulation manifests differently both at the behavioral and biochemical level than does the actual morphine tolerance that occurs in WT mice and that loss of receptor function is not a major contributor to morphine tolerance in WT MOR mice.

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“…GABA receptors are found distributed across both VTA GABA and dopamine cell populations and, consequently, have been proposed to play a crucial role in dopaminergic cell signaling and motivational processes in general (McBride et al 1999;Laviolette and van der Kooy 2001;Macey et al 2001;Walker and Ettenberg 2005;Madhavan et al 2010). For example, both GABA A receptor agonists and antagonists have been reported to produce positive reinforcing properties when microinjected into the VTA (Ikemoto et al 1997(Ikemoto et al , 1998Laviolette and van der Kooy 2001).…”

Section: Vta Gaba Receptorsmentioning

confidence: 99%

The Neurobiology of Opiate Motivation

Ting‐A‐Kee

Kooy

2012

Cold Spring Harbor Perspectives in Medicine

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Opiates are a highly addictive class of drugs that have been reported to possess both dopamine-dependent and dopamine-independent rewarding properties. The search for how, if at all, these distinct mechanisms of motivation are related is of great interest in drug addiction research. Recent electrophysiological, molecular, and behavioral work has greatly improved our understanding of this process. In particular, the signaling properties of GABA A receptors located on GABA neurons in the ventral tegmental area (VTA) appear to be crucial to understanding the interplay between dopamine-dependent and dopamine-independent mechanisms of opiate motivation.

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Opioid-Induced GABA Potentiation after Chronic Morphine Attenuates the Rewarding Effects of Opioids in the Ventral Tegmental Area

Cited by 56 publications

References 30 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

A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

The Neurobiology of Opiate Motivation

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