ArticlePain2019
An NPY Y1 receptor antagonist unmasks latent sensitization and reveals the contribution of protein kinase A and Epac to chronic inflammatory pain.
Article in Pain, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 47 citations in OpenAlex.
- Trial
- Persistent Mu-Opioid Receptor Dysregulation in a Pain-Facilitatory Brain Region Reinstates Hyperalgesia After Resolution of Opioid-Induced Hyperalgesia.Pharmaceuticals (Basel, Switzerland) · 2026Article
- From nerve to bone: a tale of autonomic nervous system, bone cells, and beyond.Military Medical Research · 2026Review
- Neuropeptide Y signaling in osteoarthritis pain: neuroimmune mechanisms, joint remodeling, and translational opportunities.Frontiers in pain research (Lausanne, Switzerland) · 2026Review
- The pharmacotherapeutic potential of neuropeptide Y for chronic pain.Journal of internal medicine · 2025Review
- De novo expression of neuropeptide Y in sensory neurons does not contribute to peripheral neuropathic pain.The journal of pain · 2025Article
- Action potential-independent spontaneous microdomain CaProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Neuropeptide Y Y2 receptors in acute and chronic pain and itch.Neuropeptides · 2024Review
- CCL2 Potentiates Inflammation Pain and Related Anxiety-Like Behavior Through NMDA Signaling in Anterior Cingulate Cortex.Molecular neurobiology · 2024Article
- Role of EPAC1 in chronic pain.Biochemistry and biophysics reports · 2024Review
- Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic.ACS pharmacology & translational science · 2024Review
- The plasticity of neuropeptide Y-Y1 receptor system onTheranostics · 2024Article
- Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp.JCI insight · 2023Article
- Endogenous μ-opioid-Neuropeptide Y Y1 receptor synergy silences chronic postoperative pain in mice.PNAS nexus · 2023Article
- Kinin BPharmaceutics · 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
- Estrogen metabolites increase nociceptor hyperactivity in a mouse model of uterine pain.JCI insight · 2022Article
- Endogenous µ-opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain.Journal of neuroscience research · 2022Article
- CAV-1 Overexpression Exacerbates the Manifestation in EPAC-1-Induced Chronic Postsurgical Pain in Rats.Pain research & management · 2022Article
- Sex Differences in Protein Kinase A Signaling of the Latent Postoperative Pain Sensitization That Is Masked by Kappa Opioid Receptors in the Spinal Cord.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Peripheral inflammation produces a long-lasting latent sensitization of spinal nociceptive neurons, that is, masked by tonic inhibitory controls. We explored mechanisms of latent sensitization with an established four-step approach: (1) induction of inflammation; (2) allow pain hypersensitivity to resolve; (3) interrogate latent sensitization with a channel blocker, mutant mouse, or receptor antagonist; and (4) disrupt compensatory inhibition with a receptor antagonist so as to reinstate pain hypersensitivity. We found that the neuropeptide Y Y1 receptor antagonist BIBO3304 reinstated pain hypersensitivity, indicative of an unmasking of latent sensitization. BIBO3304-evoked reinstatement was not observed in AC1 knockout mice and was prevented with intrathecal co-administration of a pharmacological blocker to the N-methyl-D-aspartate receptor (NMDAR), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), transient receptor potential cation channel A1 (TRPA1), channel V1 (TRPV1), or exchange protein activated by cAMP (Epac1 or Epac2). A PKA activator evoked both pain reinstatement and touch-evoked pERK expression in dorsal horn; the former was prevented with intrathecal co-administration of a TRPA1 or TRPV1 blocker. An Epac activator also evoked pain reinstatement and pERK expression. We conclude that PKA and Epac are sufficient to maintain long-lasting latent sensitization of dorsal horn neurons that is kept in remission by the NPY-Y1 receptor system. Furthermore, we have identified and characterized 2 novel molecular signaling pathways in the dorsal horn that drive latent sensitization in the setting of chronic inflammatory pain: NMDAR→AC1→PKA→TRPA1/V1 and NMDAR→AC1→Epac1/2. New treatments for chronic inflammatory pain might either increase endogenous NPY analgesia or inhibit AC1, PKA, or Epac.
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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.