Nociceptor subpopulations involved in hyperalgesic priming.
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 C(epsilon) (PKC(epsilon)) in the peripheral terminal of the primary afferent nociceptor. Given that hyperalgesic mediator-induced PKC(epsilon) 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 E(2) (PGE(2)) induced, PKC(epsilon)-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 PKC(epsilon) prevented NGF-induced priming, the hyperalgesia induced by NGF is PKC(epsilon) independent. We propose that separate intracellular pools of PKC(epsilon), in the peripheral terminals of nociceptors, mediate nociceptor sensitization and the induction of hyperalgesic priming.
Ferrari
L F
LF
Division of Neuroscience, Departments of Medicine and Oral and Maxillofacial Surgery, University of California, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA.
Bogen
O
O
Levine
J D
JD
D000818:Animals; D015232:Dinoprostone; D055785:Gene Knockdown Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D037102:Lectins / Q000378:metabolism; D008297:Male; D020932:Nerve Growth Factor; D009619:Nociceptors / Q000502:physiology*; D010147:Pain Measurement; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D013997:Time Factors
D051100:Glial Cell Line-Derived Neurotrophic Factor; D037102:Lectins; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D051744:Protein Kinase C-epsilon; D015232:Dinoprostone