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Comparison of naltrexone and 6β‐naltrexol in morphine‐naive and morphine‐dependent mice
Author(s) -
Divin Mary F.,
Ko M.C. Holden,
Traynor John R.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a239-b
Subject(s) - naltrexone , morphine , agonist , inverse agonist , pharmacology , chemistry , μ opioid receptor , opioid , opioid receptor , receptor , antagonism , antagonist , medicine , biochemistry
It has been proposed that upon chronic morphine treatment the μ‐opioid receptor becomes constitutively active. In morphine‐dependent mice naltrexone (NTX) precipitates more severe withdrawal behavior than 6β‐naltrexol (Wang et.al., JPET 308: 512), leading to the suggestion that NTX is an inverse agonist and 6β‐naltrexol is a neutral antagonist. To test the hypothesis that these compounds have different efficacies, we compared them in vitro in C6 glioma cells expressing a μ‐opioid receptor (C6μ) and in vivo in naïve and morphine‐dependent NIH Swiss mice. In C6μ cells NTX and 6β‐naltrexol had similar affinities for the μ‐opioid receptor, and in naïve mice the compounds had similar potencies to antagonize morphine‐induced antinociception in the warm‐water tail‐withdrawal assay. In morphine‐dependent mice both compounds were able to precipitate withdrawal jumping measured during 20 min after withdrawal induction, but NTX was 100‐fold more potent than 6β‐naltrexol. At equal doses (1 mg/kg), both compounds reversed antinociception induced by the long‐lasting, efficacious μ‐opioid agonist BU72 in the warm‐water tail‐withdrawal assay, but antagonism by NTX was rapid in onset, reducing antinociception by 50% in less than 0.5 h, whereas a similar reduction by 6β‐naltrexol required greater than 1.5 h. Since the compounds have similar affinity for the μ‐opioid receptor these data suggest that the differences observed between the ability of NTX and 6β‐naltrexol to precipitate withdrawal may be due to different rates of access to the receptor. Supported by NIH grants GM07767, DA19276 (MFD), and DA04087 (JRT).