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A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice
S G Khasar1, Y H Lin, A Martin
1Department of Internal Medicine and Oral Surgery, National Institutes of Health/University of California, USA.
Abstract:
There is great interest in discovering new targets for pain therapy since current methods of analgesia are often only partially successful. Although protein kinase C (PKC) enhances nociceptor function, it is not known which PKC isozymes contribute. Here, we show that epinephrine-induced mechanical and thermal hyperalgesia and acetic acid-associated hyperalgesia are markedly attenuated in PKCepsilon mutant mice, but baseline nociceptive thresholds are normal. Moreover, epinephrine-, carrageenan-, and nerve growth factor- (NGF-) induced hyperalgesia in normal rats, and epinephrine-induced enhancement of tetrodotoxin-resistant Na+ current (TTX-R I(Na)) in cultured rat dorsal root ganglion (DRG) neurons, are inhibited by a PKCepsilon-selective inhibitor peptide. Our findings indicate that PKCepsilon regulates nociceptor function and suggest that PKCepsilon inhibitors could prove useful in the treatment of pain.
Insights
Protein kinase C epsilon (PKCepsilon) plays a key role in pain signaling. Inhibiting PKCepsilon may offer a new strategy for pain therapeutics, as it reduces hyperalgesia without affecting normal pain sensation.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Current analgesics have limited efficacy, driving the search for novel pain therapy targets.
- Protein kinase C (PKC) is known to enhance nociceptor function, but specific isozymes involved remain unidentified.
Purpose of the Study:
- To identify the specific PKC isozymes involved in nociceptor function and hyperalgesia.
- To investigate the potential of targeting PKCepsilon for pain treatment.
Main Methods:
- Utilized PKCepsilon mutant mice to assess hyperalgesia responses.
- Administered a PKCepsilon-selective inhibitor peptide in normal rats and cultured dorsal root ganglion (DRG) neurons.
- Measured mechanical, thermal, and chemical hyperalgesia, as well as tetrodotoxin-resistant Na+ current (TTX-R I(Na)).
Main Results:
- PKCepsilon mutant mice showed significantly reduced epinephrine-, acetic acid-, carrageenan-, and nerve growth factor- (NGF-) induced hyperalgesia.
- Baseline nociceptive thresholds were unaffected in mutant mice.
- A PKCepsilon-selective inhibitor peptide successfully inhibited hyperalgesia and epinephrine-induced enhancement of TTX-R I(Na) in DRG neurons.
Conclusions:
- PKCepsilon is a critical regulator of nociceptor function and mediates various forms of hyperalgesia.
- Targeting PKCepsilon with selective inhibitors presents a promising therapeutic strategy for managing pain and hyperalgesia.