ArticleFrontiers in neuroscience2019
Mitogen-Activated Protein Kinase Signaling Mediates Morphine Induced-Delayed Hyperalgesia.
Article in Frontiers in neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor hyperactivity.The Journal of clinical investigation · 2026Article
- Alpha-pinene modulates hippocampal MAPKs/c-Fos pathways during morphine dependence and withdrawal in rats.Psychopharmacology · 2026Article
- Role of Central Inflammatory and Oxidative Pathways in the Morphine Exacerbation of Cardiovascular Effects of Sepsis in Rats.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Opioids and Vitamin C: Known Interactions and Potential for Redox-Signaling Crosstalk.Antioxidants (Basel, Switzerland) · 2022Review
- Blocking of Caveolin-1 Attenuates Morphine-Induced Inflammation, Hyperalgesia, and Analgesic Tolerance via Inhibiting NLRP3 Inflammasome and ERK/c-JUN Pathway.Journal of molecular neuroscience : MN · 2022Article
- PKCζ-Mitogen-Activated Protein Kinase Signaling Mediates Crotalphine-Induced Antinociception.Toxins · 2021Article
- Acute morphine blocks spinal respiratory motor plasticity via long-latency mechanisms that require toll-like receptor 4 signalling.The Journal of physiology · 2021Article
- Role of intracellular signaling pathways and their inhibitors in the treatment of inflammation.Inflammopharmacology · 2021Review
- Magnesium Citrate Increases Pain Threshold and Reduces TLR4 Concentration in the Brain.Biological trace element research · 2021Article
- Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1.Frontiers in pharmacology · 2020Review
- Epigenetic regulation in opioid induced hyperalgesia.Neurobiology of pain (Cambridge, Mass.)Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The use of morphine, the standard opioid drug, is limited by its undesirable effects, such as tolerance, physical dependence, and hyperalgesia (increased pain sensitivity). Clinical and preclinical studies have reported development of hyperalgesia after prolonged opioid administration or after a single dose of intrathecal (i.t.) morphine in uninjured rats. However, whether a single standard systemic morphine dose is sufficient to decrease the nociceptive threshold in rats is unknown. Here, we showed that a single morphine subcutaneous injection induces analgesia followed by a long-lasting delayed hyperalgesia in uninjured and PGE2 sensitized rats. The i.t injection of extracellular signal-regulated kinase (ERK) inhibitor blocked morphine-induced analgesia, without interfering with the morphine-induced hyperalgesia. However, i.t. injection of SB20358, a p38 inhibitor and SP660125, a JNK inhibitor, decreased the morphine-induced hyperalgesia. Consistently with the behavioral data, Western Blot analysis showed that ERK is more phosphorylated 1 h after morphine, i.e., when the analgesia is detected. Moreover, phospho-p38 and phospho-JNK levels are upregulated 96 h after morphine injection, time that coincides with the hyperalgesic effect. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to cAMP-responsive element binding protein (CREB) attenuated morphine-induced hyperalgesia. Real-time polymerase chain reaction (RT-PCR) analysis showed that CREB downstream genes expressions were significantly up-regulated 96 h after morphine injection in spinal cord. Together, our data suggest that central ERK is involved in the analgesic and hyperalgesic effects of morphine while JNK, p38, and CREB are involved in the morphine-induced delayed hyperalgesia.
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