ArticleMolecular pain2012
Stimulation of peripheral kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway.
Article in Molecular pain, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 77 citations in OpenAlex.
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- Effect of Dezocine and Dexmedetomidine as Adjuvants in Ropivacaine for Incision Subcutaneous Infiltration Anesthesia on Incision Healing in Diabetic Rats.Brain and behavior · 2025Article
- κ-opioid receptor: from analgesic target to neuroimmune hub.Frontiers in pharmacology · 2025Review
- The Utility of Peripherally Restricted Kappa-Opioid Receptor Agonists for Inhibiting Below-Level Pain After Spinal Cord Injury in Mice.Neuroscience · 2023Article
- Parenteral Ready-to-Use Fixed-Dose Combinations Including NSAIDs with Paracetamol or Metamizole for Multimodal Analgesia-Approved Products and Challenges.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.Neural regeneration research · 2023Review
- PI3Kγ/AKT Signaling in High Molecular Weight Hyaluronan (HMWH)-Induced Anti-Hyperalgesia and Reversal of Nociceptor Sensitization.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Lactoferrin and Its Potential Impact for the Relief of Pain: A Preclinical Approach.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Evaluation of the Antinociceptive, Antiallodynic, Antihyperalgesic and Anti-Inflammatory Effect of Polyalthic Acid.Molecules (Basel, Switzerland) · 2021Article
- Antinociceptive and anti-inflammatory effects of hydrazone derivatives and their possible mechanism of action in mice.PloS one · 2021Article
- Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn.Neuropharmacology · 2020Article
- Antinociceptive Effect of the Citrus Flavonoid Eriocitrinon Postoperative Pain Conditions.Journal of pain research · 2020Article
- Dynamic Opioid Receptor Regulation in the Periphery.Molecular pharmacology · 2019Review
- Article
- Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity.World journal of gastroenterology · 2017Article
- Mechanism Governing Human Kappa-Opioid Receptor Expression under Desferrioxamine-Induced Hypoxic Mimic Condition in Neuronal NMB Cells.International journal of molecular sciences · 2017Article
- Antinociceptive Activities of the Methanolic Extract of the Stem Bark ofEvidence-based complementary and alternative medicine : eCAM · 2017Article
- Neuronal plasticity of trigeminal ganglia in mice following nerve injury.Journal of pain research · 2017Article
- Observing Anti-inflammatory and Anti-nociceptive Activities of Glycyrrhizin Through Regulating COX-2 and Pro-inflammatory Cytokines Expressions in Mice.Inflammation · 2015Article
- Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.PLoS neglected tropical diseases · 2015Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundIn addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral μ-opioid receptor (MOR) activation are able to direct block PGE(2)-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE(2)-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated.
resultsLocal (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE(2)-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (≅ 43%).
conclusionsThe present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.
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