title: Spinal protein kinase M ζ underlies the maintenance mechanism of persistent nociceptive sensitization.
abstract: Sensitization of the pain pathway is believed to promote clinical pain disorders. We hypothesized that the persistence of a sensitized state in the spinal dorsal horn might depend on the activity of protein kinase M ζ (PKMζ), an essential mechanism of late long-term potentiation (LTP). To test this hypothesis, we used intraplantar injections of interleukin-6 (IL-6) in mice to elicit a transient allodynic state that endured ∼3 d. After the resolution of IL-6-induced allodynia, a subsequent intraplantar injection of prostaglandin E(2) (PGE(2)) or intrathecal injection of the metabotropic glutamate receptor 1/5 (mGluR1/5) agonist DHPG (dihydroxyphenylglycol) precipitated allodynia and/or nocifensive responses. Intraplantar injection of IL-6 followed immediately by intrathecal injection of a PKMζ inhibitor prevented the expression of subsequent PGE(2)-induced allodynia. Inhibitors of protein translation were effective in preventing PGE(2)-induced allodynia when given immediately after IL-6, but not after the initial allodynia had resolved. In contrast, spinal PKMζ inhibition completely abolished both prolonged allodynia to hindpaw PGE(2) and enhanced nocifensive behaviors evoked by intrathecal mGluR1/5 agonist injection after the resolution of IL-6-induced allodynia. Moreover, spinal PKMζ inhibition prevented the enhanced response to subsequent stimuli following resolution of hypersensitivity induced by plantar incision. The present findings demonstrate that the spinal cord encodes an engram for persistent nociceptive sensitization that is analogous to molecular mechanisms of late LTP and suggest that spinally directed PKMζ inhibitors may offer therapeutic benefit for injury-induced pain states.
authors.affiliation: Department of Pharmacology, The University of Arizona College of Medicine, Tucson, AZ 85721, USA.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Asiedu
authors.forename: Dipti V
authors.initials: DV
authors.lastname: Tillu
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Adia
authors.initials: A
authors.lastname: Shy
authors.forename: Raul
authors.initials: R
authors.lastname: Sanoja
authors.forename: Bryce
authors.initials: B
authors.lastname: Bodell
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D015232:Dinoprostone / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007278:Injections, Spinal; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008818:Mice, Neurologic Mutants; D010147:Pain Measurement / Q000187:drug effects; D058748:Pain Perception / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D015232:Dinoprostone; D051860:Fragile X Messenger Ribonucleoprotein 1; D015850:Interleukin-6; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C497684:Fmr1 protein, mouse