TY - JOUR
T1 - Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic pain
AU - King, Tamara
AU - Qu, Chaoling
AU - Okun, Alec
AU - Melemedjian, Ohannes K.
AU - Mandell, Edward K.
AU - Maskaykina, Irina Y.
AU - Navratilova, Edita
AU - Dussor, Gregory O.
AU - Ghosh, Sourav
AU - Price, Theodore J.
AU - Porreca, Frank
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Aversiveness
KW - Neuropathic pain
KW - PKM
KW - Spinal cord
KW - Spontaneous pain
KW - ZIP
KW - rACC
UR - http://www.scopus.com/inward/record.url?scp=84861199935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861199935&partnerID=8YFLogxK
U2 - 10.1016/j.pain.2012.03.006
DO - 10.1016/j.pain.2012.03.006
M3 - Article
C2 - 22482911
AN - SCOPUS:84861199935
SN - 0304-3959
VL - 153
SP - 1263
EP - 1273
JO - Pain
JF - Pain
IS - 6
ER -