ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2021
Sex Differences in Protein Kinase A Signaling of the Latent Postoperative Pain Sensitization That Is Masked by Kappa Opioid Receptors in the Spinal Cord.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 24 citations in OpenAlex.
- Progress in pain mechanisms and management.Signal transduction and targeted therapy · 2026Review
- Kappa opioid receptor antagonism in neuropsychiatry: from molecular mechanisms to clinical prospects.European archives of psychiatry and clinical neuroscience · 2026Review
- The actions of morphine on microglia and the underlying effects on associated adverse effects.Psychopharmacology · 2026Review
- Persistent Mu-Opioid Receptor Dysregulation in a Pain-Facilitatory Brain Region Reinstates Hyperalgesia After Resolution of Opioid-Induced Hyperalgesia.Pharmaceuticals (Basel, Switzerland) · 2026Article
- EAE models of neuropathic pain in multiple sclerosis do not require pertussis toxin.Brain research · 2026Article
- Epigenetic mechanisms of HIV and opioid-induced neuropathology: Potential therapies and interventions.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Identification of risk factors and development of predictive models for chronic postsurgical pain after modified radical mastectomy.Annals of medicine · 2025Article
- Long-lasting and fast methylglyoxal-scavenging peptide CycK(Myr)RPain reports · 2025Article
- The pharmacotherapeutic potential of neuropeptide Y for chronic pain.Journal of internal medicine · 2025Review
- Sex differences in the transition to chronic pain.The Journal of clinical investigation · 2025Review
- Tissue damage-induced axon injury-associated responses in sensory neurons: requirements, prevention, and potential role in persistent post-surgical pain.Frontiers in pain research (Lausanne, Switzerland) · 2025Article
- Neuropeptide Y Y2 receptors in acute and chronic pain and itch.Neuropeptides · 2024Review
- Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.Anesthesiology · 2024Article
- Role of EPAC1 in chronic pain.Biochemistry and biophysics reports · 2024Review
- Contribution of µ Opioid Receptor-expressing Dorsal Horn Interneurons to Neuropathic Pain-like Behavior in Mice.Anesthesiology · 2023Article
- Endogenous μ-opioid-Neuropeptide Y Y1 receptor synergy silences chronic postoperative pain in mice.PNAS nexus · 2023Article
- Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Skin/muscle incision and retraction regulates the persistent postoperative pain in rats by the Epac1/PKC-βII pathway.BMC anesthesiology · 2022Article
- Toward understanding the opioid paradox: cellular mechanisms of opioid-induced hyperalgesia.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Latent sensitization (LS) of pain engages pronociceptive signaling pathways in the dorsal horn that include NMDA receptor (NMDAR)→adenylyl cyclase-1 (AC1)→protein kinase A (PKA), and exchange proteins directly activated by cyclic AMP (Epacs). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal κ opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302, which reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but not astrocytes (GFAPs) nor microglia (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission. In both sexes, intrathecal MK-801 (an NMDAR competitive antagonist) prevented LY2456302-evoked reinstatement of hyperalgesia as did AC1 gene deletion or the AC1 inhibitor NB001. NB001 also prevented stimulus-evoked pERK. In both sexes, the Epac inhibitor ESI-09 prevented reinstatement, whereas the Epac activator 8-CPT reinstated hyperalgesia. By contrast, the PKA inhibitor H89 prevented reinstatement only in male mice, whereas the PKA activator 6-bnz-cAMP itself evoked reinstatement at all doses tested (3-30 nmol, i.t.). In neither sex did incision change gene expression of KOR, GluN1, PKA, or Epac1 in dorsal horn. We conclude that sustained KOR signaling inhibits spinal PKA-dependent mechanisms that drive postoperative LS in a sex-dependent manner. Our findings support the development of AC1, PKA, and Epac inhibitors toward a new pharmacotherapy for chronic postoperative pain.
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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.