Upregulation of casein kinase 1epsilon in dorsal root ganglia and spinal cord after mouse spinal nerve injury contributes to neuropathic pain.
BACKGROUND
Neuropathic pain is a complex chronic pain generated by damage to, or pathological changes in the somatosensory nervous system. Characteristic features of neuropathic pain are allodynia, hyperalgesia and spontaneous pain. Such abnormalities associated with neuropathic pain state remain to be a significant clinical problem. However, the neuronal mechanisms underlying the pathogenesis of neuropathic pain are complex and still poorly understood. Casein kinase 1 is a serine/threonine protein kinase and has been implicated in a wide range of signaling activities such as cell differentiation, proliferation, apoptosis, circadian rhythms and membrane transport. In mammals, the CK1 family consists of seven members (alpha, beta, gamma1, gamma2, gamma3, delta, and epsilon) with a highly conserved kinase domain and divergent amino- and carboxy-termini.


RESULTS
Preliminary cDNA microarray analysis revealed that the expression of the casein kinase 1 epsilon (CK1epsilon) mRNA in the spinal cord of the neuropathic pain-resistant N- type Ca2+ channel deficient (Cav2.2-/-) mice was decreased by the spinal nerve injury. The same injury exerted no effects on the expression of CK1epsilon mRNA in the wild-type mice. Western blot analysis of the spinal cord identified the downregulation of CK1epsilon protein in the injured Cav2.2-/- mice, which is consistent with the data of microarray analysis. However, the expression of CK1epsilon protein was found to be up-regulated in the spinal cord of injured wild-type mice. Immunocytochemical analysis revealed that the spinal nerve injury changed the expression profiles of CK1epsilon protein in the dorsal root ganglion (DRG) and the spinal cord neurons. Both the percentage of CK1epsilon-positive neurons and the expression level of CK1epsilon protein were increased in DRG and the spinal cord of the neuropathic mice. These changes were reversed in the spinal cord of the injured Cav2.2-/- mice. Furthermore, intrathecal administration of a CK1 inhibitor IC261 produced marked anti-allodynic and anti-hyperalgesic effects on the neuropathic mice. In addition, primary afferent fiber-evoked spinal excitatory responses in the neuropathic mice were reduced by IC261.


CONCLUSIONS
These results suggest that CK1epsilon plays important physiological roles in neuropathic pain signaling. Therefore CK1epsilon is a useful target for analgesic drug development.
Sakurai
Eri
E
Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. e-sakurai.mphm@tmd.ac.jp
Kurihara
Takashi
T
Kouchi
Kasumi
K
Saegusa
Hironao
H
Zong
Shuqin
S
Tanabe
Tsutomu
T
D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000503:physiopathology; D006930:Hyperalgesia / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000201:enzymology / Q000503:physiopathology; D009619:Nociceptors / Q000201:enzymology; D009924:Organ Culture Techniques; D010523:Peripheral Nervous System Diseases / Q000201:enzymology* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology* / Q000503:physiopathology; D013126:Spinal Nerve Roots / Q000201:enzymology / Q000503:physiopathology; D013127:Spinal Nerves / Q000201:enzymology* / Q000293:injuries* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology
D020864:Calcium Channels, N-Type; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D048149:Casein Kinase 1 epsilon