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Chronic opioid antagonist treatment selectively regulates trafficking and signaling proteins in mouse spinal cord.
- Source :
-
Synapse (New York, N.Y.) [Synapse] 2003 Oct; Vol. 50 (1), pp. 67-76. - Publication Year :
- 2003
-
Abstract
- Chronic opioid antagonist treatment produces functional supersensitivity and mu-opioid receptor (muOR) upregulation. Studies suggest a role for G-protein receptor kinases (GRKs) and dynamin (DYN), but not signaling proteins (e.g., G(ialpha2)), in regulation of muOR density following opioid treatment. Therefore, this study examined muOR density, agonist potency, and the abundance and gene expression of GRK-2, DYN-2, and G(ialpha2) in mouse spinal cord after opioid antagonist treatment. Mice were implanted with a 15 mg naltrexone (NTX) or placebo pellet and 8 days later pellets were removed. At 24 and 192 h following NTX treatment, mice were tested for spinal DAMGO analgesia. Other mice were sacrificed at 0 or 192 h following NTX treatment and G(ialpha2), GRK-2, and DYN-2 protein and mRNA levels determined. [(3)H] DAMGO binding studies were also conducted. Immediately following NTX treatment (0 h), muOR density was increased (+ approximately 135%), while 192 h following NTX treatment muOR density was unchanged. NTX increased DAMGO analgesic potency (3.1-fold) 24 h following NTX treatment, while there was no effect at 192 h. NTX decreased protein and mRNA abundance of GRK-2 (-32%; -48%) and DYN-2 (-25%; -29%) in spinal cord at 0 h. At 192 h following 8-day NTX treatment, GRK-2 protein and mRNA were at control levels, while DYN-2 protein remained decreased (-31%) even though DYN-2 mRNA had returned to control levels. G(ialpha2) was unaffected by NTX treatment. These data suggest that opioid antagonist-induced mu-receptor upregulation is mediated by changes in abundance and gene expression of proteins implicated in receptor trafficking, which may decrease constitutive receptor cycling.<br /> (Copyright 2003 Wiley-Liss, Inc.)
- Subjects :
- Animals
Cyclic AMP-Dependent Protein Kinases genetics
Cyclic AMP-Dependent Protein Kinases metabolism
Dynamin II genetics
Dynamin II metabolism
GTP-Binding Protein alpha Subunit, Gi2
GTP-Binding Protein alpha Subunits, Gi-Go genetics
GTP-Binding Protein alpha Subunits, Gi-Go metabolism
Gene Expression Regulation drug effects
Gene Expression Regulation genetics
Male
Mice
Neurons metabolism
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
RNA, Messenger drug effects
RNA, Messenger metabolism
Receptors, Opioid, mu drug effects
Receptors, Opioid, mu metabolism
Spinal Cord metabolism
Up-Regulation drug effects
Up-Regulation genetics
beta-Adrenergic Receptor Kinases
Cyclic AMP-Dependent Protein Kinases drug effects
Dynamin II drug effects
GTP-Binding Protein alpha Subunits, Gi-Go drug effects
Naltrexone pharmacology
Narcotic Antagonists pharmacology
Neurons drug effects
Proto-Oncogene Proteins drug effects
Spinal Cord drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0887-4476
- Volume :
- 50
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Synapse (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 12872295
- Full Text :
- https://doi.org/10.1002/syn.10246