Activation of G protein gated inwardly rectifying potassium (GIRK) channels in keratinocytes mediates peripheral kappa opioid receptor-mediated antinociception
Open accessAbstract
Kappa opioid receptors (KOR) expressed by peripheral pain-sensing neurons (nociceptors) are a promising target for development of effective and safer analgesics for inflammatory pain that are devoid of central nervous system adverse effects. Here we sought to delineate the signaling pathways that underlie peripheral KOR-mediated antinociception in adult male and female Sprague-Dawley rats. In an inflammatory model of pain, local intraplantar (i.pl.) injection of pertussis toxin prevented antinociception induced by the KOR agonist, U50488, indicating that members of the Gi/o family mediate the antinociceptive response. Furthermore, i.pl. injection of the G protein-coupled inward-rectifying potassium (GIRK) channel blocker, TPNQ, as well as GIRK2 subunit-targeted siRNA abolished U50488-mediated antinociceptive behavioral responses in both male and female rats. Consistent with these data, i.pl. injection of ML297, a direct activator of GIRK1 subunit-containing channels, elicited peripheral antinociceptive behavior. It is well known that intraepidermal nerve fibers (IENF) that innervate the hindpaw propagate nociceptive signals to the spinal cord. However, recent studies suggest that keratinocytes, the major cell type in the epidermis, also play an active role in pain and sensory processing. Results from RT-qPCR, RNAscope and immunohistochemistry experiments confirmed that both KOR and GIRK are expressed in keratinocytes in the epidermal layer of the rat hindpaw. Knockdown of either KOR or GIRK2 subunits selectively in keratinocytes by i.pl. injection of shRNA plasmids, prevented the antinociceptive response to U50488. Taken together, these data suggest that KOR-mediated activation of GIRK channels in keratinocytes is required for peripherally-mediated antinociception.
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A GIRK1-selective opener and other direct activators hyperpolarize hippocampal pyramidal neurons and reduce seizure susceptibility.
“a GIRK1-selective opener and other direct activators hyperpolarize hippocampal pyramidal neurons and reduce seizure susceptibility”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [308]
The Results section ('Direct activation of GIRK channels produces a robust antinociceptive response'; page unavailable) reports that the direct GIRK activator ML297 affected pain responses in rats. The Discussion describes neuronal hyperpolarization following receptor-mediated GIRK activation, and a reference title reports antiepileptic properties of ML297 in mice. Our copy does not establish that a GIRK1-selective opener or other direct activators hyperpolarize hippocampal pyramidal neurons and reduce seizure susceptibility. (LLM, conf=0.78)
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- Authors
- Pando, M. M., Debner, E. K., Jacobs, B. A., Jamshidi, R. J., Jennings, E. M., Clarke, W. P., & Berg, K. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Berg, Kelly A.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2025-05
- Volume
- 268
- Pages
- 110326
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC12986743
- OpenAlex
- W4406853069
- Cited by
- 5
- References
- 95
- Citations by year
- 2026: 4 · 2025: 1
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 275 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuropharmacology (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Dental and Craniofacial Research
- National Institute of Neurological Disorders and Stroke (T32NS082145)
- NIH National Institute of General Medical Sciences (R01 GM106035)
- National Institute on Drug Abuse (R01 DA038645)
- University of Texas Health Science Center at San Antonio (TST128233)
- U.S. Public Health Service
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- kappa opioid receptor, G protein-coupled inwardly rectifying potassium channels, keratinocytes, antinociception, inflammatory pain, nociceptors, Gi/o proteins, pertussis toxin, U50,488, GIRK2, GIRK1, intraepidermal nerve fibers, epidermis, analgesic targets
- MeSH terms
- Analgesics, Animals, Female, Male, Pain, Keratinocytes, Rats, Sprague-Dawley, Receptors, Opioid, kappa, 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Pertussis Toxin, Rats, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Nociception
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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