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 language | English (US) |
|---|---|
| Pages (from-to) | 3276-3286 |
| Number of pages | 11 |
| Journal | Journal of Neuroscience |
| Volume | 30 |
| Issue number | 9 |
| DOIs | |
| State | Published - Mar 3 2010 |
| Externally published | Yes |
Fingerprint
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 journal › Article
}
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 -