PMID- 37751532
OWN - NLM
STAT- MEDLINE
DCOM- 20240215
LR  - 20240310
IS  - 1872-6623 (Electronic)
IS  - 0304-3959 (Print)
IS  - 0304-3959 (Linking)
VI  - 165
IP  - 3
DP  - 2024 Mar 1
TI  - Intranasal CRMP2-Ubc9 inhibitor regulates Na V 1.7 to alleviate trigeminal 
      neuropathic pain.
PG  - 573-588
LID - 10.1097/j.pain.0000000000003053 [doi]
AB  - Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons 
      contributes to chronic pain conditions, including trigeminal neuropathic pain. We 
      previously reported that chronic pain results in part from increased SUMOylation 
      of collapsin response mediator protein 2 (CRMP2), leading to an increased 
      CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. 
      Targeting this feed-forward regulation, we developed compound 194 , which 
      inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We 
      further demonstrated that 194 effectively reduces the functional activity of Na V 
      1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and 
      neuropathic pain. Here, we used a comprehensive array of approaches, encompassing 
      biochemical, pharmacological, genetic, electrophysiological, and behavioral 
      analyses, to assess the functional implications of Na V 1.7 regulation by CRMP2 
      in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a , Dpysl2 
      , and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 
      and Na V 1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting 
      CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/Na V 1.7 interaction, 
      impeded Na V 1.7 diffusion on the plasma membrane, and subsequently diminished Na 
      V 1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. 
      Finally, when intranasally administered to rats with chronic constriction injury 
      of the infraorbital nerve, 194 significantly decreased nociceptive behaviors. 
      Collectively, our findings underscore the critical role of CRMP2 in regulating Na 
      V 1.7 within TG neurons, emphasizing the importance of this indirect modulation 
      in trigeminal neuropathic pain.
CI  - Copyright (c) 2023 International Association for the Study of Pain.
FAU - Loya-Lopez, Santiago I
AU  - Loya-Lopez SI
AUID- ORCID: 0000-0001-6207-8370
AD  - Department of Molecular Pathobiology, College of Dentistry, New York University, 
      New York, NY, United States.
AD  - NYU Pain Research Center, New York, NY, United States.
FAU - Allen, Heather N
AU  - Allen HN
AD  - Department of Molecular Pathobiology, College of Dentistry, New York University, 
      New York, NY, United States.
AD  - NYU Pain Research Center, New York, NY, United States.
FAU - Duran, Paz
AU  - Duran P
AD  - Department of Molecular Pathobiology, College of Dentistry, New York University, 
      New York, NY, United States.
AD  - NYU Pain Research Center, New York, NY, United States.
FAU - Calderon-Rivera, Aida
AU  - Calderon-Rivera A
AD  - Department of Molecular Pathobiology, College of Dentistry, New York University, 
      New York, NY, United States.
AD  - NYU Pain Research Center, New York, NY, United States.
FAU - Gomez, Kimberly
AU  - Gomez K
AD  - Department of Molecular Pathobiology, College of Dentistry, New York University, 
      New York, NY, United States.
AD  - NYU Pain Research Center, New York, NY, United States.
FAU - Kumar, Upasana
AU  - Kumar U
AD  - Center for Orofacial Pain and Temporomandibular Disorders, Department of 
      Diagnostic Sciences, Rutgers School of Dental Medicine, Newark, NJ, United 
      States.
FAU - Shields, Rory
AU  - Shields R
AD  - Rutgers School of Graduate Studies, Newark Health Science Campus, Newark, NJ, 
      United States.
FAU - Zeng, Rui
AU  - Zeng R
AD  - Department of Chemistry, College of Arts and Sciences, New York University, New 
      York, NY, United States.
FAU - Dwivedi, Akshat
AU  - Dwivedi A
AD  - Department of Chemistry, College of Arts and Sciences, New York University, New 
      York, NY, United States.
FAU - Saurabh, Saumya
AU  - Saurabh S
AD  - Department of Chemistry, College of Arts and Sciences, New York University, New 
      York, NY, United States.
FAU - Korczeniewska, Olga A
AU  - Korczeniewska OA
AD  - Center for Orofacial Pain and Temporomandibular Disorders, Department of 
      Diagnostic Sciences, Rutgers School of Dental Medicine, Newark, NJ, United 
      States.
AD  - Rutgers School of Graduate Studies, Newark Health Science Campus, Newark, NJ, 
      United States.
FAU - Khanna, Rajesh
AU  - Khanna R
AUID- ORCID: 0000-0002-9066-2969
AD  - Department of Molecular Pathobiology, College of Dentistry, New York University, 
      New York, NY, United States.
AD  - NYU Pain Research Center, New York, NY, United States.
AD  - Department of Neuroscience and Physiology and Neuroscience Institute, School of 
      Medicine, New York University, New York, NY, United States.
LA  - eng
GR  - R41 CA210857/CA/NCI NIH HHS/United States
GR  - DA042852/DA/NIDA NIH HHS/United States
GR  - R01 NS098772/NS/NINDS NIH HHS/United States
GR  - F32 NS128392/NS/NINDS NIH HHS/United States
GR  - R61 NS126026/NS/NINDS NIH HHS/United States
GR  - R01 NS120663/NS/NINDS NIH HHS/United States
GR  - NS098772 and NS120663/NS/NINDS NIH HHS/United States
GR  - R01 DA042852/DA/NIDA NIH HHS/United States
GR  - NS128392/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20230926
PL  - United States
TA  - Pain
JT  - Pain
JID - 7508686
RN  - 0 (collapsin response mediator protein-2)
RN  - EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
SB  - IM
UOF - bioRxiv. 2023 Jul 17;:. PMID: 37502910
MH  - Animals
MH  - Rats
MH  - *Chronic Pain/drug therapy/metabolism
MH  - Ganglia, Spinal
MH  - Rats, Sprague-Dawley
MH  - Sensory Receptor Cells/metabolism
MH  - *Trigeminal Neuralgia/drug therapy/metabolism
MH  - *Ubiquitin-Conjugating Enzymes/antagonists & inhibitors
MH  - Administration, Intranasal
MH  - *Nerve Tissue Proteins/antagonists & inhibitors
MH  - *Intercellular Signaling Peptides and Proteins
PMC - PMC10922202
MID - NIHMS1923395
COIS- Conflict of Interest R.K. is the founder of Regulonix LLC, a company developing 
      nonopioid drugs for chronic pain. In addition, R.K., has patents US10287334 
      (non-narcotic CRMP2 peptides targeting sodium channels for chronic pain) and 
      US10441586 (SUMOylation inhibitors and uses thereof) issued to Regulonix LLC.
EDAT- 2023/09/26 18:42
MHDA- 2024/02/12 05:09
PMCR- 2025/03/01
CRDT- 2023/09/26 15:12
PHST- 2023/07/11 00:00 [received]
PHST- 2023/07/25 00:00 [accepted]
PHST- 2025/03/01 00:00 [pmc-release]
PHST- 2024/02/12 05:09 [medline]
PHST- 2023/09/26 18:42 [pubmed]
PHST- 2023/09/26 15:12 [entrez]
AID - 00006396-990000000-00412 [pii]
AID - 10.1097/j.pain.0000000000003053 [doi]
PST - ppublish
SO  - Pain. 2024 Mar 1;165(3):573-588. doi: 10.1097/j.pain.0000000000003053. Epub 2023 
      Sep 26.