ArticleThe Journal of pharmacology and experimental therapeutics2009
Extracellular signal-regulated kinase 1/2 activation counteracts morphine tolerance in the periaqueductal gray of the rat.
Article in The Journal of pharmacology and experimental therapeutics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 46 citations in OpenAlex.
- The Impact of Levetiracetam on Various Symptoms of Morphine Dependence in Mice.Life (Basel, Switzerland) · 2026Article
- Misuse, Abuse and Medication Errors' Adverse Events Associated with Opioids-A Systematic Review.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics.Neuropharmacology · 2023Review
- Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward.Frontiers in systems neuroscience · 2022Review
- Endogenous opioid systems alterations in pain and opioid use disorder.Frontiers in systems neuroscience · 2022Review
- Article
- The Mechanisms Involved in Morphine Addiction: An Overview.International journal of molecular sciences · 2019Review
- Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats.The journal of pain · 2019Article
- Inflammatory mediators of opioid tolerance: Implications for dependency and addiction.Peptides · 2019Review
- The Alpha Isoform of Heat Shock Protein 90 and the Co-chaperones p23 and Cdc37 Promote Opioid Anti-nociception in the Brain.Frontiers in molecular neuroscience · 2019Article
- Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Cyclosporin A attenuating morphine tolerance through inhibiting NO/ERK signaling pathway in human glioblastoma cell line: the involvement of calcineurin.EXCLI journal · 2018Article
- The Contribution of the Descending Pain Modulatory Pathway in Opioid Tolerance.Frontiers in neuroscience · 2018Article
- Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain.The Journal of biological chemistry · 2017Article
- Sequence-Specific Regulation of Endocytic Lifetimes Modulates Arrestin-Mediated Signaling at theMolecular pharmacology · 2017Article
- Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion.Neuroscience · 2017Article
- Sex Differences in GABAA Signaling in the Periaqueductal Gray Induced by Persistent Inflammation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance.Behavioural brain research · 2016Article
- Involvement of neuronal TGF-β activated kinase 1 in the development of tolerance to morphine-induced antinociception in rat spinal cord.British journal of pharmacology · 2015Article
- Change in functional selectivity of morphine with the development of antinociceptive tolerance.British journal of pharmacology · 2015Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.