TY - JOUR
T1 - Chronic morphine treatment reduces recovery from opioid desensitization
AU - Dang, Vu C.
AU - Williams, John T.
PY - 2004/9/1
Y1 - 2004/9/1
N2 - Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovey from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-β-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.
AB - Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovey from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-β-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.
KW - Electrophysiology
KW - Intracellular recording
KW - Locus ceruleus
KW - Slices
KW - Tolerance
KW - μ-opioid receptor
UR - http://www.scopus.com/inward/record.url?scp=4444236554&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4444236554&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2499-04.2004
DO - 10.1523/JNEUROSCI.2499-04.2004
M3 - Article
C2 - 15342737
AN - SCOPUS:4444236554
SN - 0270-6474
VL - 24
SP - 7699
EP - 7706
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 35
ER -