Evidence map›Paper›PMID 39555137›Full record

ArticleNeurology. Genetics2024

TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons.

Mohammad-Reza Ghovanloo, Philip R Effraim, Sidharth Tyagi, Alecia M Aldrich, Xiaoyang Cheng, Jun-Hui Yuan, Betsy R Schulman, Deborah S Jacobs, Sulayman D Dib-Hajj, Stephen G Waxman

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurology. Genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Mohammad-Reza GhovanlooFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0002-2171-0744
Philip R EffraimFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0001-7777-001X
Sidharth TyagiFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0001-6097-0541
Alecia M AldrichFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.
Xiaoyang ChengFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0003-1446-2815
Jun-Hui YuanFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.
Betsy R SchulmanFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0002-9368-9091
Deborah S JacobsFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0002-8587-1184
Sulayman D Dib-HajjFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0002-4137-1655
Stephen G WaxmanFrom the Department of Neurology (M.-R.G., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University School of Medicine, New Haven; Center for Neuroscience and Regeneration Research (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Yale University, New Haven; Neuro-Rehabilitation Research Center (M.-R.G., P.R.E., S.T., A.M.A., X.C., J.-H.Y., B.R.S., S.D.D.-H., S.G.W.), Veterans Affairs Connecticut Healthcare System, West Haven; Department of Anesthesiology (P.R.E.), Yale University School of Medicine, New Haven, CT; and Department of Ophthalmology (D.S.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston.ORCID https://orcid.org/0000-0001-5718-7177

Funding

Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9M
NCATS NIH HHS UL1 TR001863
6 · The paper itself

Abstract

Background and Objectives: Despite extensive efforts, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain following corneal refractive surgery offers a valuable human model for investigating trigeminal axonal injury because laser-assisted in situ keratomileusis (LASIK) severs axons of trigeminal ganglion neurons innervating the cornea. While the majority of patients are pain-free shortly after surgery, a minority endure persistent postoperative ocular pain. Through genomic analysis of patients experiencing persistent postoperative ocular pain, we identified rare variants in genes encoding ion channels and receptors, including TRPM8, which codes for the menthol-sensitive and cold-sensing transient receptor potential cation channel. Methods: We conducted a profiling of 2 TRPM8 mutant variants, D665N and V915M, which were identified in patients suffering from persistent pain after LASIK surgery. We used patch-clamp and multielectrode array (MEA) recordings to investigate the biophysical and pharmacologic properties of mutant vs wild-type (WT) channels. Results: Patch-clamp analysis shows that these mutations shift the activation curves of TRPM8 in a hyperpolarized direction, with this effect being significantly different between WT and D665N channels. In addition, both mutations significantly increase channel sensitivity to the canonical ligand, menthol. MEA recordings from transfected rat trigeminal ganglion neurons indicate that expression of D665N and V915M mutant channels increases spontaneous activity compared with WT channels. Consistent with patch-clamp results, neuronal activity in MEA recordings was increased on exposure to menthol. Discussion: Collectively, our findings suggest that proexcitatory mutations of TRPM8, in the context of axonal injury within the cornea, can produce trigeminal ganglion neuron hyperexcitability that contributes to persistent postoperative ocular pain. In addition to providing additional evidence for a role of TRPM8 in human pain, our results suggest that inhibitors of this channel merit future study.

Identifiers

PMID39555137
PMCPMC11567650

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.