title: Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic pain.
abstract: Injuries can induce adaptations in pain processing that result in amplification of signaling. One mechanism may be analogous to long-term potentiation and involve the atypical protein kinase C, PKMζ. The possible contribution of PKMζ-dependent and independent amplification mechanisms to experimental neuropathic pain was explored in rats with spinal nerve ligation (SNL) injury. SNL increased p-PKMζ in the rostral anterior cingulate cortex (rACC), a site that mediates, in part, the unpleasant aspects of pain. Inhibition of PKMζ within the rACC by a single administration of ζ-pseudosubstrate inhibitory peptide (ZIP) reversed SNL-induced aversiveness within 24 hours, whereas N-methyl-d-aspartate receptor blockade with MK-801 had no effects. The SNL-induced aversive state (reflecting "spontaneous" pain), was re-established in a time-dependent manner, with full recovery observed 7 days post-ZIP administration. Neither rACC ZIP nor MK-801 altered evoked responses. In contrast, spinal ZIP or MK-801, but not scrambled peptide, transiently reversed evoked hypersensitivity, but had no effect on nerve injury-induced spontaneous pain. PKMζ phosphorylation was not altered by SNL in the spinal dorsal horn. These data suggest that amplification mechanisms contribute to different aspects of neuropathic pain at different levels of the neuraxis. Thus, PKMζ-dependent amplification contributes to nerve injury-induced aversiveness within the rACC. Moreover, unlike mechanisms maintaining memory, the consequences of PKMζ inhibition within the rACC are not permanent in neuropathic pain, possibly reflecting the re-establishment of amplification mechanisms by ongoing activity of injured nerves. In the spinal cord, however, both PKMζ-dependent and independent mechanisms contribute to amplification of evoked responses, but apparently not spontaneous pain.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA Bio5 Institute, University of Arizona, Tucson, AZ 85724, USA Department of Anesthesiology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: King
authors.forename: Chaoling
authors.initials: C
authors.lastname: Qu
authors.forename: Alec
authors.initials: A
authors.lastname: Okun
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Edward K
authors.initials: EK
authors.lastname: Mandell
authors.forename: Irina Y
authors.initials: IY
authors.lastname: Maskaykina
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.forename: Gregory O
authors.initials: GO
authors.lastname: Dussor
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006179:Gyrus Cinguli / Q000201:enzymology*; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000201:enzymology*; D013127:Spinal Nerves / Q000201:enzymology / Q000293:injuries
chemical_list: D010455:Peptides; D016291:Dizocilpine Maleate; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat