μ-opioid receptor endocytosis prevents adaptations in ventral tegmental area gaba transmission induced during naloxone-precipitated morphine withdrawal

Anuradha Madhavan, Li He, Garret D. Stuber, Antonello Bonci, Jennifer Whistler

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of μ-opioid receptor(MOR)trafficking in one of these adaptations, specifically, changes inGABAtransmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3′,5′-(hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 μl), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 μl), directly tying enhanced cAMP-driven GABA release to naloxone- precipitated morphine withdrawal in the VTA.

Original languageEnglish (US)
Pages (from-to)3276-3286
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number9
DOIs
StatePublished - Mar 3 2010
Externally publishedYes

Fingerprint

Ventral Tegmental Area
Opioid Receptors
Naloxone
Endocytosis
Morphine
gamma-Aminobutyric Acid
Recycling
Morphine Dependence
Opioid-Related Disorders
Grooming
mu Opioid Receptor
Dopaminergic Neurons
Tremor
Interneurons
Synaptic Transmission
Adenosine
Dogs

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

μ-opioid receptor endocytosis prevents adaptations in ventral tegmental area gaba transmission induced during naloxone-precipitated morphine withdrawal. / Madhavan, Anuradha; He, Li; Stuber, Garret D.; Bonci, Antonello; Whistler, Jennifer.

In: Journal of Neuroscience, Vol. 30, No. 9, 03.03.2010, p. 3276-3286.

Research output: Contribution to journalArticle

@article{84423969950446308ea60f260409c963,
title = "μ-opioid receptor endocytosis prevents adaptations in ventral tegmental area gaba transmission induced during naloxone-precipitated morphine withdrawal",
abstract = "Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of μ-opioid receptor(MOR)trafficking in one of these adaptations, specifically, changes inGABAtransmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3′,5′-(hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 μl), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 μl), directly tying enhanced cAMP-driven GABA release to naloxone- precipitated morphine withdrawal in the VTA.",
author = "Anuradha Madhavan and Li He and Stuber, {Garret D.} and Antonello Bonci and Jennifer Whistler",
year = "2010",
month = "3",
day = "3",
doi = "10.1523/JNEUROSCI.4634-09.2010",
language = "English (US)",
volume = "30",
pages = "3276--3286",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "9",

}

TY - JOUR

T1 - μ-opioid receptor endocytosis prevents adaptations in ventral tegmental area gaba transmission induced during naloxone-precipitated morphine withdrawal

AU - Madhavan, Anuradha

AU - He, Li

AU - Stuber, Garret D.

AU - Bonci, Antonello

AU - Whistler, Jennifer

PY - 2010/3/3

Y1 - 2010/3/3

N2 - Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of μ-opioid receptor(MOR)trafficking in one of these adaptations, specifically, changes inGABAtransmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3′,5′-(hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 μl), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 μl), directly tying enhanced cAMP-driven GABA release to naloxone- precipitated morphine withdrawal in the VTA.

AB - Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of μ-opioid receptor(MOR)trafficking in one of these adaptations, specifically, changes inGABAtransmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3′,5′-(hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 μl), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 μl), directly tying enhanced cAMP-driven GABA release to naloxone- precipitated morphine withdrawal in the VTA.

UR - http://www.scopus.com/inward/record.url?scp=77749324825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77749324825&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4634-09.2010

DO - 10.1523/JNEUROSCI.4634-09.2010

M3 - Article

C2 - 20203187

AN - SCOPUS:77749324825

VL - 30

SP - 3276

EP - 3286

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 9

ER -