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Chronic opioid antagonist treatment selectively regulates trafficking and signaling proteins in mouse spinal cord
Author(s) -
Patel Chintan N.,
Rajashekara Vikram,
Patel Kaushal,
Purohit Vishal,
Yoburn Byron C.
Publication year - 2003
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.10246
Subject(s) - damgo , naltrexone , opioid antagonist , antagonist , μ opioid receptor , endocrinology , medicine , pharmacology , chemistry , downregulation and upregulation , agonist , opioid , opioid receptor , receptor , (+) naloxone , biochemistry , gene
Abstract Chronic opioid antagonist treatment produces functional supersensitivity and μ‐opioid receptor (μOR) upregulation. Studies suggest a role for G‐protein receptor kinases (GRKs) and dynamin (DYN), but not signaling proteins (e.g., G iα2 ), in regulation of μOR density following opioid treatment. Therefore, this study examined μOR density, agonist potency, and the abundance and gene expression of GRK‐2, DYN‐2, and G iα2 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 iα2 , GRK‐2, and DYN‐2 protein and mRNA levels determined. [ 3 H] DAMGO binding studies were also conducted. Immediately following NTX treatment (0 h), μOR density was increased (+ ≈135%), while 192 h following NTX treatment μOR 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 iα2 was unaffected by NTX treatment. These data suggest that opioid antagonist‐induced μ‐receptor upregulation is mediated by changes in abundance and gene expression of proteins implicated in receptor trafficking, which may decrease constitutive receptor cycling. Synapse 50:67–76, 2003. © 2003 Wiley‐Liss, Inc.