Nociceptor subpopulations involved in hyperalgesic priming

doi:10.1016/j.neuroscience.2009.11.029

Neuroscience

Volume 165, Issue 3, 3 February 2010, Pages 896-901

https://doi.org/10.1016/j.neuroscience.2009.11.029 Get rights and content

Abstract

We have previously developed a model in the rat for the transition from acute to chronic pain, hyperalgesic priming, in which a long-lasting neuroplastic change in signaling pathways mediates a prolongation of proinflammatory cytokine-induced nociceptor sensitization and mechanical hyperalgesia, induced at the site of a previous inflammatory insult. Induction of priming is mediated by activation of protein kinase Cε (PKCε) in the peripheral terminal of the primary afferent nociceptor. Given that hyperalgesic mediator-induced PKCε translocation occurs in isolectin B4 (IB4)(+)-nonpeptidergic but not in receptor tyrosine kinase (TrkA)(+)-peptidergic nociceptors, we tested the hypothesis that hyperalgesic priming was restricted to the IB4(+) subpopulation of nociceptors. After recovery from nerve growth factor (NGF)- and GDNF-induced hyperalgesia, a proinflammatory cytokine, prostaglandin E₂ (PGE₂) induced, PKCε-dependent, markedly prolonged hyperalgesia, two features that define the development of the primed state. Thus, hyperalgesic priming occurs in both the IB4(+)-nonpeptidergic and TrkA(+)-peptidergic subpopulations of nociceptive afferents. Of note, however, while attenuation of PKCε prevented NGF-induced priming, the hyperalgesia induced by NGF is PKCε independent. We propose that separate intracellular pools of PKCε, in the peripheral terminals of nociceptors, mediate nociceptor sensitization and the induction of hyperalgesic priming.

Section snippets

Animals

Experiments were performed on adult male Sprague–Dawley rats (250–350 g; Charles River, Hollister, CA, USA). Animals were housed three per cage, under a 12 h light/dark cycle, in a temperature and humidity controlled environment at the University of California, San Francisco (UCSF) animal care facility. Food and water were available ad libitum. All testing was done between 10:00 am and 4:00 pm. Experimental protocols, approved by the UCSF Committee on Animal Research, conformed to National

GDNF and NGF induce hyperalgesic priming

In the primed state induced by local injection of carrageenan, a single injection of prostaglandin E₂, which in normal tissue induces a brief mechanical hyperalgesia that is no longer present at 4 h, now induces prolonged hyperalgesia present four, and even 24, hours after injection (Aley et al., 2000, Parada et al., 2003a). Following this protocol, we tested if the intradermal injection of GDNF or NGF, in place of carrageenan, induces hyperalgesic priming. The intradermal injection of GDNF (10

Discussion

Hyperalgesic priming is a neuroplastic change in the primary afferent nociceptor in which proinflammatory mediators, for example prostaglandin E₂, serotonin and adenosine, now produce markedly prolonged hyperalgesia, which requires activation of a novel isoform of PKC, PKCε (Aley et al., 2000, Parada et al., 2005). Since translocation of PKCε from the cytoplasm to the plasma membrane, a marker of PKCε activation (Cesare et al., 1999, Dorn and Mochly-Rosen, 2002) in response to a hyperalgesic

Conclusion

In summary, based on the observation that PKCε translocation to the plasma membrane occurs in IB4(+)-nonpeptidergic but not TrkA(+)-peptidergic subpopulations of nociceptive afferents, and that NGF, which induces hyperalgesia by action on the TrkA(+)-peptidergic subpopulation of nociceptive afferents, we tested the hypothesis that hyperalgesic priming, a model of the transition from acute to chronic pain, occurs in the IB4(+)-nonpeptidergic but not TrkA(+)-peptidergic subpopulation of

Acknowledgments

This study was funded by the National Institutes of Health (NIH)AR048821, NS053709, NS053880, and AR052106. We thank Dr. Robert Gear for assistance with statistical analysis.

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Pain MechanismResearch PaperNociceptor subpopulations involved in hyperalgesic priming

Abstract

Section snippets

Animals

GDNF and NGF induce hyperalgesic priming

Discussion

Conclusion

Acknowledgments

Neuron

J Biol Chem

J Biol Chem

Neurosci Lett

Neuron

Trends Neurosci

Neuron

J Biol Chem

Pain

Pain

Neuroscience

Brain Res

J Biol Chem

J Pain

Neuroscience

Neuroscience

Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors

J Neurosci

Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C

J Neurosci

NGF and GDNF differentially regulate TRPV1 expression that contributes to development of inflammatory thermal hyperalgesia

Eur J Neurosci

Pain Mechanism
Research Paper
Nociceptor subpopulations involved in hyperalgesic priming