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Role of G iα2 ‐protein in opioid tolerance and μ‐opioid receptor downregulation in vivo
Author(s) -
Yoburn B.C.,
Gomes B.A.,
Rajashekara V.,
Patel C.,
Patel M.
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.10149
Subject(s) - etorphine , downregulation and upregulation , receptor , opioid , μ opioid receptor , morphine , opioid receptor , pharmacology , drug tolerance , chemistry , agonist , endocrinology , medicine , (+) naloxone , biochemistry , gene
Although opioid receptors are G‐protein coupled, the role that specific G‐protein subunits play in the development of opioid tolerance and the regulation of opioid receptor number is not well understood. In the present study, we used a G iα2 antisense oligodeoxynucleotide (ODN) to examine the contribution of G iα2 proteins to μ‐opioid tolerance and receptor downregulation in the mouse. Mice were injected intracerebroventricularly (ICV) and into the spinal intrathecal space (IT) for 4–5 consecutive days (30 μg/site/day), with an antisense ODN or a mismatch ODN directed at mRNA for the G iα2 subunit of G‐proteins. Controls were treated with dH 2 O. On the second day of ODN treatment continuous subcutaneous (SC) infusion of etorphine (200 μg/kg/day) or morphine (40 mg/kg/day + 25 mg pellet) was begun. Control mice were implanted with inert placebo pellets. Three days later, pumps and pellets were removed and mice were tested for morphine analgesia or μ‐opioid receptor density was determined in whole brain. Etorphine produced significant tolerance (ED 50 shift = ∼11‐fold) and downregulation of μ‐opioid receptors (≈25%). Morphine treatment produced significant tolerance (ED 50 shift ≈9‐fold), but no μ‐opioid receptor downregulation. Antisense treatment reduced G iα2 protein levels in striatum and spinal cord by ∼25%. G iα2 antisense reduced the acute potency of morphine. G iα2 antisense blocked the development of tolerance to morphine treatment and reduced the development of tolerance to etorphine treatment. Antisense did not have any effect on etorphine‐induced μ‐opioid receptor downregulation. In another experiment, 7‐day treatment with morphine or etorphine similarly increased G iα2 mRNA and protein abundance in spinal cord. Overall, these results support an important role for G iα2 ‐protein in the acute effects of opioids and opioid tolerance. However, G iα2 is not required for agonist‐induced μ‐opioid receptor density regulation in vivo. Synapse 47:109–116, 2003. © 2002 Wiley‐Liss, Inc.