The p75NTR signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw

A. Khodorova, Grant Nicol, G. Strichartz

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Nerve growth factor (NGF) augments the excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75NTR) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical protein-kinase C (aPKC), protein-kinase M zeta (PKMζ), are key mediators. Here we examined these same receptor-pathways in vivo for their role in mechanical hyperalgesia from exogenous NGF. Mechanical sensitivity was tested by the number of paw withdrawals in response to 10 stimuli (PWF=n/10) by a 4-g von Frey hair (VFH, testing "allodynia") and by 10 and 15g VFHs (testing "hyperalgesia"). NGF (500ng/10μL) injected into the male rat's plantar hind paw induced long-lasting ipsilateral mechanical hypersensitivity. Mechano-hypersensitivity, relative to baseline responses and to those of the contralateral paw, developed by 0.5-1.5h and remained elevated at least for 21-24h, Acute intraplantar pre-treatment with nSMase inhibitors, glutathione (GSH) or GW4869, prevented the acute hyperalgesia from NGF (at 1.5h) but not that at 24h. A single injection of N-acetyl sphingosine (C2-ceramide), simulating the ceramide produced by nSMase activity, induced ipsilateral allodynia that persisted for 24h, and transient hyperalgesia that resolved by 2h. Intraplantar injection of hydrolysis-resistant mPro-NGF, selective for the p75NTR over the tyrosine kinase (TrkA) receptor, gave very similar results to NGF and was susceptible to the same inhibitors. Hyperalgesia from both NGF and mPro-NGF was prevented by paw pre-injection with blocking antibodies to rat p75NTR receptor. Finally, intraplantar (1day before NGF) injection of mPSI, the myristolated pseudosubstrate inhibitor of PKCζ/PKMζ, decreased the hyperalgesia resulting from NGF or C2-ceramide, although scrambled mPSI was ineffective. The findings indicate that mechano-hypersensitivity from peripheral NGF involves the sphingomyelin signaling cascade activated via p75NTR, and that a peripheral aPKC is essential for this sensitization.

Original languageEnglish
Pages (from-to)312-323
Number of pages12
JournalNeuroscience
Volume254
DOIs
StatePublished - Dec 19 2013

Fingerprint

Nerve Growth Factor Receptor
Hyperalgesia
Nerve Growth Factor
Sphingomyelins
Sphingomyelin Phosphodiesterase
Hypersensitivity
Injections
Ceramides
Protein Kinase C
Sphingosine
Blocking Antibodies
Receptor Protein-Tyrosine Kinases
Sensory Receptor Cells
Hair
Glutathione
Hydrolysis

Keywords

  • APKCs
  • Hyperalgesia
  • Nerve growth factor
  • Pain
  • PKMζ
  • Sphingomyelinase

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The p75NTR signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw. / Khodorova, A.; Nicol, Grant; Strichartz, G.

In: Neuroscience, Vol. 254, 19.12.2013, p. 312-323.

Research output: Contribution to journalArticle

@article{592a4641172d4c048e7f12f14709b666,
title = "The p75NTR signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw",
abstract = "Nerve growth factor (NGF) augments the excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75NTR) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical protein-kinase C (aPKC), protein-kinase M zeta (PKMζ), are key mediators. Here we examined these same receptor-pathways in vivo for their role in mechanical hyperalgesia from exogenous NGF. Mechanical sensitivity was tested by the number of paw withdrawals in response to 10 stimuli (PWF=n/10) by a 4-g von Frey hair (VFH, testing {"}allodynia{"}) and by 10 and 15g VFHs (testing {"}hyperalgesia{"}). NGF (500ng/10μL) injected into the male rat's plantar hind paw induced long-lasting ipsilateral mechanical hypersensitivity. Mechano-hypersensitivity, relative to baseline responses and to those of the contralateral paw, developed by 0.5-1.5h and remained elevated at least for 21-24h, Acute intraplantar pre-treatment with nSMase inhibitors, glutathione (GSH) or GW4869, prevented the acute hyperalgesia from NGF (at 1.5h) but not that at 24h. A single injection of N-acetyl sphingosine (C2-ceramide), simulating the ceramide produced by nSMase activity, induced ipsilateral allodynia that persisted for 24h, and transient hyperalgesia that resolved by 2h. Intraplantar injection of hydrolysis-resistant mPro-NGF, selective for the p75NTR over the tyrosine kinase (TrkA) receptor, gave very similar results to NGF and was susceptible to the same inhibitors. Hyperalgesia from both NGF and mPro-NGF was prevented by paw pre-injection with blocking antibodies to rat p75NTR receptor. Finally, intraplantar (1day before NGF) injection of mPSI, the myristolated pseudosubstrate inhibitor of PKCζ/PKMζ, decreased the hyperalgesia resulting from NGF or C2-ceramide, although scrambled mPSI was ineffective. The findings indicate that mechano-hypersensitivity from peripheral NGF involves the sphingomyelin signaling cascade activated via p75NTR, and that a peripheral aPKC is essential for this sensitization.",
keywords = "APKCs, Hyperalgesia, Nerve growth factor, Pain, PKMζ, Sphingomyelinase",
author = "A. Khodorova and Grant Nicol and G. Strichartz",
year = "2013",
month = "12",
day = "19",
doi = "10.1016/j.neuroscience.2013.09.046",
language = "English",
volume = "254",
pages = "312--323",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - The p75NTR signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw

AU - Khodorova, A.

AU - Nicol, Grant

AU - Strichartz, G.

PY - 2013/12/19

Y1 - 2013/12/19

N2 - Nerve growth factor (NGF) augments the excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75NTR) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical protein-kinase C (aPKC), protein-kinase M zeta (PKMζ), are key mediators. Here we examined these same receptor-pathways in vivo for their role in mechanical hyperalgesia from exogenous NGF. Mechanical sensitivity was tested by the number of paw withdrawals in response to 10 stimuli (PWF=n/10) by a 4-g von Frey hair (VFH, testing "allodynia") and by 10 and 15g VFHs (testing "hyperalgesia"). NGF (500ng/10μL) injected into the male rat's plantar hind paw induced long-lasting ipsilateral mechanical hypersensitivity. Mechano-hypersensitivity, relative to baseline responses and to those of the contralateral paw, developed by 0.5-1.5h and remained elevated at least for 21-24h, Acute intraplantar pre-treatment with nSMase inhibitors, glutathione (GSH) or GW4869, prevented the acute hyperalgesia from NGF (at 1.5h) but not that at 24h. A single injection of N-acetyl sphingosine (C2-ceramide), simulating the ceramide produced by nSMase activity, induced ipsilateral allodynia that persisted for 24h, and transient hyperalgesia that resolved by 2h. Intraplantar injection of hydrolysis-resistant mPro-NGF, selective for the p75NTR over the tyrosine kinase (TrkA) receptor, gave very similar results to NGF and was susceptible to the same inhibitors. Hyperalgesia from both NGF and mPro-NGF was prevented by paw pre-injection with blocking antibodies to rat p75NTR receptor. Finally, intraplantar (1day before NGF) injection of mPSI, the myristolated pseudosubstrate inhibitor of PKCζ/PKMζ, decreased the hyperalgesia resulting from NGF or C2-ceramide, although scrambled mPSI was ineffective. The findings indicate that mechano-hypersensitivity from peripheral NGF involves the sphingomyelin signaling cascade activated via p75NTR, and that a peripheral aPKC is essential for this sensitization.

AB - Nerve growth factor (NGF) augments the excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75NTR) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical protein-kinase C (aPKC), protein-kinase M zeta (PKMζ), are key mediators. Here we examined these same receptor-pathways in vivo for their role in mechanical hyperalgesia from exogenous NGF. Mechanical sensitivity was tested by the number of paw withdrawals in response to 10 stimuli (PWF=n/10) by a 4-g von Frey hair (VFH, testing "allodynia") and by 10 and 15g VFHs (testing "hyperalgesia"). NGF (500ng/10μL) injected into the male rat's plantar hind paw induced long-lasting ipsilateral mechanical hypersensitivity. Mechano-hypersensitivity, relative to baseline responses and to those of the contralateral paw, developed by 0.5-1.5h and remained elevated at least for 21-24h, Acute intraplantar pre-treatment with nSMase inhibitors, glutathione (GSH) or GW4869, prevented the acute hyperalgesia from NGF (at 1.5h) but not that at 24h. A single injection of N-acetyl sphingosine (C2-ceramide), simulating the ceramide produced by nSMase activity, induced ipsilateral allodynia that persisted for 24h, and transient hyperalgesia that resolved by 2h. Intraplantar injection of hydrolysis-resistant mPro-NGF, selective for the p75NTR over the tyrosine kinase (TrkA) receptor, gave very similar results to NGF and was susceptible to the same inhibitors. Hyperalgesia from both NGF and mPro-NGF was prevented by paw pre-injection with blocking antibodies to rat p75NTR receptor. Finally, intraplantar (1day before NGF) injection of mPSI, the myristolated pseudosubstrate inhibitor of PKCζ/PKMζ, decreased the hyperalgesia resulting from NGF or C2-ceramide, although scrambled mPSI was ineffective. The findings indicate that mechano-hypersensitivity from peripheral NGF involves the sphingomyelin signaling cascade activated via p75NTR, and that a peripheral aPKC is essential for this sensitization.

KW - APKCs

KW - Hyperalgesia

KW - Nerve growth factor

KW - Pain

KW - PKMζ

KW - Sphingomyelinase

UR - http://www.scopus.com/inward/record.url?scp=84886440508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886440508&partnerID=8YFLogxK

U2 - 10.1016/j.neuroscience.2013.09.046

DO - 10.1016/j.neuroscience.2013.09.046

M3 - Article

C2 - 24095693

AN - SCOPUS:84886440508

VL - 254

SP - 312

EP - 323

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

ER -