Generation of a pain memory in the primary afferent nociceptor triggered by PKCε activation of CPEB.
Isolectin B(4)-positive [IB(4)(+)] primary afferent nociceptors challenged with an inflammatory or neuropathic insult develop a PKCε-dependent long-lasting hyperalgesic response to a subsequent challenge by the proinflammatory cytokine prostaglandin E(2) (PGE(2)), a phenomenon known as hyperalgesic priming. Here we demonstrate that the neuroplasticity underlying nociceptor priming requires 72 h to be established; rats that have been challenged with the inflammatory mediator TNFα 24 or 48 h ahead of PGE(2) do not show the enhanced and prolonged hyperalgesic response by which primed IB(4)(+)-nociceptors are being characterized. Moreover, as the underlying plasticity can be interrupted by the peripheral administration of the protein translation inhibitor anisomycin it is reflected by changes in the peripheral protein expression pattern. Finally, the induction of priming by the selective PKCε agonist, psi ε receptor for activated c kinase (ψεRACK) can be prevented, but not reversed by intrathecal injections of antisense oligodeoxynucleotides for the cytoplasmic polyadenylation element binding protein (CPEB) mRNA, a master regulator of protein translation that coimmunoprecipitated with PKCε and is almost exclusively expressed by IB(4)(+)-nociceptors. Our results suggest that CPEB is downstream of PKCε in the cellular signaling cascade responsible for the induction of priming, raising the intriguing possiblity that prion-like misfolding could be a responsible mechanism for the chronification of pain.
Department of Medicine, Division of Neuroscience, University of California at San Francisco, California 94143-0440, USA.
Oliver
O
Bogen
Nicole
N
Alessandri-Haber
Carissa
C
Chu
Robert W
RW
Gear
Jon D
JD
Levine
D000818:Animals; D006930:Hyperalgesia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008568:Memory / Q000502:physiology*; D008959:Models, Neurological; D009475:Neurons, Afferent / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009619:Nociceptors / Q000378:metabolism / Q000502:physiology*; D010146:Pain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D051744:Protein Kinase C-epsilon / Q000378:metabolism* / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
C539243:CPEB1 protein, rat; D016601:RNA-Binding Proteins; D051744:Protein Kinase C-epsilon