“…ERK1/2 is known to alter several epigenetic markers and transcription factors including c-fos , brain-derived neurotrophic factor, and cAMP response element binding proteins (CREB) in several brain regions following opioid withdrawal (Wang et al, 2012, Ciccarelli et al, 2013). The adenylyl cyclase-cAMP-CREB pathway is upregulated following prolonged opioid exposure (Cao et al, 2010).…”
Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.
“…ERK1/2 is known to alter several epigenetic markers and transcription factors including c-fos , brain-derived neurotrophic factor, and cAMP response element binding proteins (CREB) in several brain regions following opioid withdrawal (Wang et al, 2012, Ciccarelli et al, 2013). The adenylyl cyclase-cAMP-CREB pathway is upregulated following prolonged opioid exposure (Cao et al, 2010).…”
Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.
“…Within 1 hour after the last administration of morphine, morphine was in vivo precipitated by naloxone. Such precipitation results in different dynamics of H3 phosphorylation and acetylation: H3 phosphorylation was increased significantly while H3 acetylation remained unchanged [84].…”
Section: A Specific Examples Of Exposures and Effects On Histone Modmentioning
Histone modifications play important roles in the epigenetic regulation of gene expression. Recent genomewide profiling of histone modifications with deep sequencingbased methods provides novel insights of crosstalk between histone modifications, leading to recent proposals of histone "language" or "web" as an alternative of "code" to appreciate combinatorial modification patterns. Environmental factor-altered histone modifications now may be addressed dynamically and systematically with the recognition and use of these interesting combinatorial patterns.
“…Despite these effects, no evidence exists to show that opiate consumption causes DNA alteration; however, recent studies have shown that chronic exposure to opiates affects chromatin-related proteins and therefore induces modifications in gene expression patterns. In fact, chronic morphine exposure causes epigenetic modifications (12)(13)(14)(15)(16).…”
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