ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
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- The cumulative analgesic effect of repeated electroacupuncture is modulated by Adora3 in the SCDH of mice with neuropathic pain.Animal models and experimental medicine · 2025Article
- Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization.Cell & bioscience · 2025Article
- To reveal biomarkers related to macrophage and lactic acid metabolism in renal fibrosis and explore their mechanisms.Frontiers in immunology · 2025Article
- Electroacupuncture Relieves Neuropathic Pain via Adenosine 3 Receptor Activation in the Spinal Cord Dorsal Horn of Mice.International journal of molecular sciences · 2024Article
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- Migraine signaling pathways: purine metabolites that regulate migraine and predispose migraineurs to headache.Molecular and cellular biochemistry · 2023Review
- Adenosine Receptors as Potential Therapeutic Analgesic Targets.International journal of molecular sciences · 2023Review
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- Adenosine signaling mediate pain transmission in the central nervous system.Purinergic signalling · 2023Review
- Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury.Frontiers in molecular neuroscience · 2023Article
- Adenosine AInternational journal of molecular sciences · 2022Article
- The role of botulinum toxin type A related axon transport in neuropathic pain induced by chronic constriction injury.The Korean journal of pain · 2022Article
- Selective activation of Gαob by an adenosine ANature communications · 2022Article
- Single-cell RNA sequencing reveals distinct transcriptional features of the purinergic signaling in mouse trigeminal ganglion.Frontiers in molecular neuroscience · 2022Article
- The Histamine HBiomolecules · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
Abstract
More than 1.5 billion people worldwide suffer from chronic pain, yet current treatment strategies often lack efficacy or have deleterious side effects in patients. Adenosine is an inhibitory neuromodulator that was previously thought to mediate antinociception through the A1 and A2A receptor subtypes. We have since demonstrated that A3AR agonists have potent analgesic actions in preclinical rodent models of neuropathic pain and that A3AR analgesia is independent of adenosine A1 or A2A unwanted effects. Herein, we explored the contribution of the GABA inhibitory system to A3AR-mediated analgesia using well-characterized mouse and rat models of chronic constriction injury (CCI)-induced neuropathic pain. The deregulation of GABA signaling in pathophysiological pain states is well established: GABA signaling can be hampered by a reduction in extracellular GABA synthesis by GAD65 and enhanced extracellular GABA reuptake via the GABA transporter, GAT-1. In neuropathic pain, GABAAR-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Here, we demonstrate that A3AR agonists (IB-MECA and MRS5698) reverse neuropathic pain via a spinal mechanism of action that modulates GABA activity. Spinal administration of the GABAA antagonist, bicuculline, disrupted A3AR-mediated analgesia. Furthermore, A3AR-mediated analgesia was associated with reductions in CCI-related GAD65 and GAT-1 serine dephosphorylation as well as an enhancement of KCC2 serine phosphorylation and activity. Our results suggest that A3AR-mediated reversal of neuropathic pain increases modulation of GABA inhibitory neurotransmission both directly and indirectly through protection of KCC2 function, underscoring the unique utility of A3AR agonists in chronic pain.
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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.