Spinal CK2 regulates nociceptive signaling in models of inflammatory pain.
Casein kinase 2 (CK2) is a widely expressed protein kinase. Over the last several years a long list of protein substrates has evolved, many of which have proven or hypothesized roles in nociceptive signal transmission. However, CK2 has not itself been demonstrated to participate in nociception prior to this time. We set out to test the hypothesis that spinal CK2 regulates nociception using several pain models. Our first studies focused on the ability of the selective CK2 inhibitors 4,5,6,7-tetrabromobenzotriazole (TBBT) and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) to reduce formalin-stimulated pain behaviors in mice. Both phases of the response to subcutaneous formalin were strongly inhibited by intrathecal administration of TBBT or DRB in dose-dependent fashion. Likewise, using the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, TBBT was observed to strongly reduce mechanical allodynia. The inhibition of spinal CK2 with either inhibitor did not, however, alter withdrawal latencies in the hotplate thermal pain model while intrathecal morphine was very effective. Immunohistochemical studies demonstrated all three known CK2 subunits, alpha, alpha' and beta to be expressed in spinal cord tissue as did real-time PCR experiments. While mRNA levels for each of the subunits was transiently enhanced after formalin or CFA hindpaw injection, overall spinal cord protein levels were not elevated in a sustained fashion. Our results indicate that CK2 participates in inflammatory nociception both in the acute and chronic phases. Simple changes in the abundance of spinal CK2 subunits do not likely underlie these phenomena, however.
Li
Xiangqi
X
Veterans Affairs Palo Alto Health Care System and Stanford University Department of Anesthesiology, Anesthesiology, 112A, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
Shi
Xiaoyou
X
Liang
De-Yong
DY
Clark
J David
JD
D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D004195:Disease Models, Animal; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission; D014018:Tissue Distribution
D005557:Formaldehyde; D047390:Casein Kinase II