Journal article
Extracellular signal-regulated kinase 1/2 activation counteracts morphine tolerance in the periaqueductal gray of the rat
The Journal of pharmacology and experimental therapeutics, Vol.331(2), pp.412-418
11/2009
Handle:
https://hdl.handle.net/2376/108167
PMCID: PMC2775267
PMID: 19684256
Abstract
Repeated administration of opioids produces long-lasting changes in micro-opioid receptor (MOR) signaling that underlie behavioral changes such as tolerance. Mitogen-activated protein kinase (MAPK) pathways, including MAPK extracellular signal-regulated kinases (ERK1/2), are modulated by opioids and are known to produce long-lasting changes in cell signaling. Thus, we tested the hypothesis that ERK1/2 activation contributes to the development and/or expression of morphine tolerance mediated by the periaqueductal gray (PAG). Changes in phosphorylated ERK1/2 expression were assessed with confocal microscopy and compared to behavioral measures of tolerance to the antinociceptive effects of chronic morphine administration. Repeated microinjection of morphine into the PAG produced tolerance and caused a significant increase in ERK1/2 phosphorylation, an effect not evident with acute morphine microinjection. Microinjection of the MAPK/ERK kinase inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene ethanolate (U0126), into the PAG had no effect on antinociception produced by acute morphine administration. However, repeated coadministration of U0126 and morphine into the PAG blocked ERK1/2 phosphorylation and enhanced the development of morphine tolerance. Coadministration of U0126 with morphine only on the test day also enhanced the expression of morphine tolerance. Administration of the irreversible opioid receptor antagonist beta-chlornaltrexamine blocked the activation of ERK1/2 caused by repeated morphine microinjections, demonstrating that ERK1/2 activation was a MOR-mediated event. In summary, these studies show that chronic morphine administration alters ERK1/2 signaling and that disruption of ERK1/2 signaling enhances both the development and expression of morphine tolerance. Contrary to expectations, these data indicate that ERK1/2 activation opposes the development of morphine tolerance.
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Details
- Title
- Extracellular signal-regulated kinase 1/2 activation counteracts morphine tolerance in the periaqueductal gray of the rat
- Creators
- Tara A Macey - Department of Psychology, Washington State University Vancouver, Vancouver, Washington 98686, USAErin N BobeckDeborah M HegartySue A AicherSusan L IngramMichael M Morgan
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.331(2), pp.412-418
- Academic Unit
- Psychology, Department of
- Publisher
- United States
- Grant note
- R01 DA027625 / NIDA NIH HHS DA015498 / NIDA NIH HHS DE012640 / NIDCR NIH HHS R01 DE012640 / NIDCR NIH HHS T32-NS045553 / NINDS NIH HHS F32 DA023318 / NIDA NIH HHS DA023318 / NIDA NIH HHS RR016858 / NCRR NIH HHS T32 NS045553 / NINDS NIH HHS R01 DA015498 / NIDA NIH HHS
- Identifiers
- 99900546754701842
- Language
- English
- Resource Type
- Journal article