title: The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.
abstract: Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.
authors.affiliation: Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Institute of Nautical Medicine, Nantong University, Nantong 226001, China Department of Anesthesiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan Anesthesiology Pain Research Group, Anesthesiology Department, University Hospital Center and University of Lausanne CH-1011 Lausanne, Switzerland Department of Cell Biology and Morphology, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
authors.forename: Zhen-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.forename: Yen-Chin
authors.initials: YC
authors.lastname: Liu
authors.forename: Yeong-Ray
authors.initials: YR
authors.lastname: Wen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Decosterd
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005620:Freund's Adjuvant; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000473:pathology* / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency; D010146:Pain / Q000188:drug therapy / Q000209:etiology*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D014404:Tubulin; D005620:Freund's Adjuvant; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8