Kofi 2012-08-19 01:26:06
Mol Pharmacol. 2010 Jul;78(1):58-68. Epub 2010 Apr 12.
Up-regulation of the mu-opioid receptor gene is mediated through
chromatin remodeling and transcriptional factors in differentiated
Hwang CK, Kim CS, Kim do K, Law PY, Wei LN, Loh HH.
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall,
321 Church St. S.E., Minneapolis, MN 55455, USA.
The effects of morphine are mediated mainly through the mu opioid
receptor (MOR). Expression of the MOR is up-regulated during neuronal
differentiation in P19 embryonal carcinoma cells and epigenetic changes
play an important role in MOR up-regulation. This study investigates the
basis for differentiation-dependent alterations of MOR chromatin by
studying the recruitment or dissociation of several factors to the
remodeled chromatin locus. Chromatin immunoprecipitation assays were
used to demonstrate the recruitment of the transcriptional activator Sp1
and the chromatin remodeling factors Brg1 and BAF155 to this promoter,
as well as the dissociation of repressors [histone deacetylases, mSin3A,
Brm, and methyl-CpG-binding protein 2 (MeCP2)]. Histone modifications
(acetylation, induction of histone H3-lys4 methylation, and reduction of
H3-lys9 methylation) were consistently detected on this promoter.
Overexpression of Sp1 strongly enhanced MOR promoter activity, and the
histone deacetylase inhibitor trichostatin A also increased promoter
activity. In vitro DNA CpG-methylation of the promoter partially blocked
binding of the Sp1 factor but induced MeCP2 binding.
Coimmunoprecipitation studies also found novel evidence of an endogenous
MeCP2 interaction with Sp3 but a weaker interaction with Sp1. Overall,
the results suggest that during neuronal differentiation, MeCP2 and DNA
methylation mediate remodeling of the MOR promoter by chromatin
remodeling factors (Brg1 and BAF155) from a compacted state to a
conformation allowing access for transcriptional factors. Subsequent
recruitment of the activating transcription factor Sp1 to the remodeled
promoter results in MOR up-regulation.
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov’t
friendly gut bacteria – lactobacillus acidophilus – found in yoghurt and low-dose naltrexone enhances cannabinoid-induced antinociception (i.e.,
probiotics boosts the synthesis of receptors for mu opioids and
cannabinoids (CB1 and CB2) – our natural painkillers – in human and
rodent gut cells; rats given probiotics experienced a 20% increase in
their pain threshold or twice that if they had irritable bowel syndrome;
the analgesic effect was similar to morphine and suggests the
microbiology of the intestinal tract influences our visceral perception
raised the pain threshold in rats); a high dose has no effect; a
cannabanoid antagonist stopped the combination from working; this
suggests a mechanism of cannabinoid-opioid interaction where activated
opioid receptors couple to Gs-proteins and attenuate cannabinoid-induced
antinociception and/or motor functioning; LDN also enhances the effects
of morphine and other mu opioid agonists [PMID 16286810]
low-dose naltrexone enhances cannabinoid-induced antinociception (i.e.,