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Alleviation of behavioral hypersensitivity in mouse models of inflammatory pain with two structurally different casein kinase 1 (CK1) inhibitors.

Kurihara T, Sakurai E, Toyomoto M, Kii I, Kawamoto D, Asada T, Tanabe T, Yoshimura M, Hagiwara M, Miyata A - Mol Pain (2014)

Bottom Line: However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood.TG003, which was originally identified as a cdc2-like kinase inhibitor, had potent inhibitory effects on CK1 isoforms in vitro and in cultured cells.Intrathecal injection of either TG003 (1-100 pmol) or IC261 (0.1-1 nmol) dose-dependently decreased mechanical allodynia and thermal hyperalgesia induced by carrageenan or CFA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan. tkmphm10@m.kufm.kagoshima-u.ac.jp.

ABSTRACT

Background: The phylogenetically highly conserved CK1 protein kinases consisting of at least seven isoforms form a distinct family within the eukaryotic protein kinases. CK1 family members play crucial roles in a wide range of signaling activities. However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood. The aim of this study was to clarify the role of CK1 in the regulation of inflammatory pain in mouse carrageenan and complete Freund's adjuvant (CFA) models.

Results: We have used two structurally different CK1 inhibitors, TG003 and IC261. TG003, which was originally identified as a cdc2-like kinase inhibitor, had potent inhibitory effects on CK1 isoforms in vitro and in cultured cells. Intrathecal injection of either TG003 (1-100 pmol) or IC261 (0.1-1 nmol) dose-dependently decreased mechanical allodynia and thermal hyperalgesia induced by carrageenan or CFA. Bath-application of either TG003 (1 μM) or IC261 (1 μM) had only marginal effects on spontaneous excitatory postsynaptic currents (sEPSCs) recorded in the substantia gelatinosa neurons of control mice. However, both compounds decreased the frequency of sEPSCs in both inflammatory pain models.

Conclusions: These results suggest that CK1 plays an important pathophysiological role in spinal inflammatory pain transmission, and that inhibition of the CK1 activity may provide a novel strategy for the treatment of inflammatory pain.

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Effects of CK1 inhibitors on carrageenan-induced acute inflammatory pain behaviors. (A, B) Effects of intrathecal injection of IC261 on carrageenan (Car)-induced thermal hyperalgesia. IC261 was injected 5 hour after (A) or 30 min before (B) carrageenan injection. (C, D) Effects of intrathecal injection of TG003 on carrageenan (Car)-induced mechanical allodynia (C) and thermal hyperalgesia (D). Paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal stimuli are plotted against the time after carrageenan injection into a hindpaw. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared with pre-drug data (one-way ANOVA followed by Dunnett’s post hoc test).
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Figure 3: Effects of CK1 inhibitors on carrageenan-induced acute inflammatory pain behaviors. (A, B) Effects of intrathecal injection of IC261 on carrageenan (Car)-induced thermal hyperalgesia. IC261 was injected 5 hour after (A) or 30 min before (B) carrageenan injection. (C, D) Effects of intrathecal injection of TG003 on carrageenan (Car)-induced mechanical allodynia (C) and thermal hyperalgesia (D). Paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal stimuli are plotted against the time after carrageenan injection into a hindpaw. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared with pre-drug data (one-way ANOVA followed by Dunnett’s post hoc test).

Mentions: To investigate whether CK1 is involved in the inflammatory pain states, we evaluated the effects of IC261 or TG003 in mouse models of inflammatory pain. I.t. injections of IC261 (0.1-1 nmol) or TG003 (0.1-100 pmol) dose-dependently increased both withdrawal threshold and withdrawal latency of the hind paw ipsilateral to carrageenan or CFA-induced inflammation (Figures 3 and4). Spinal preemptive treatment of IC261 also dose-dependently attenuated the development of thermal hyperalgesia induced by carrageenan (Figure 3B). Thus, blocking the CK1 activity at the spinal level appeared to be effective in reduction of inflammation-induced mechanical allodynia and thermal hyperalgesia. The maximum effects were observed 0.5-1 hour after the injections of both inhibitors and significant analgesic effects were still observed 3-4 hours after the injection of the highest doses used in this study (Figures 3 and4). These inhibitors had no significant effects on the contralateral hind paw (Figures 3 and4). I.t. injection of vehicle (1% DMSO in saline) used as a solvent for the drugs did not show any effects (Figures 3A and4B, data not shown).


Alleviation of behavioral hypersensitivity in mouse models of inflammatory pain with two structurally different casein kinase 1 (CK1) inhibitors.

Kurihara T, Sakurai E, Toyomoto M, Kii I, Kawamoto D, Asada T, Tanabe T, Yoshimura M, Hagiwara M, Miyata A - Mol Pain (2014)

Effects of CK1 inhibitors on carrageenan-induced acute inflammatory pain behaviors. (A, B) Effects of intrathecal injection of IC261 on carrageenan (Car)-induced thermal hyperalgesia. IC261 was injected 5 hour after (A) or 30 min before (B) carrageenan injection. (C, D) Effects of intrathecal injection of TG003 on carrageenan (Car)-induced mechanical allodynia (C) and thermal hyperalgesia (D). Paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal stimuli are plotted against the time after carrageenan injection into a hindpaw. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared with pre-drug data (one-way ANOVA followed by Dunnett’s post hoc test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4008364&req=5

Figure 3: Effects of CK1 inhibitors on carrageenan-induced acute inflammatory pain behaviors. (A, B) Effects of intrathecal injection of IC261 on carrageenan (Car)-induced thermal hyperalgesia. IC261 was injected 5 hour after (A) or 30 min before (B) carrageenan injection. (C, D) Effects of intrathecal injection of TG003 on carrageenan (Car)-induced mechanical allodynia (C) and thermal hyperalgesia (D). Paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal stimuli are plotted against the time after carrageenan injection into a hindpaw. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared with pre-drug data (one-way ANOVA followed by Dunnett’s post hoc test).
Mentions: To investigate whether CK1 is involved in the inflammatory pain states, we evaluated the effects of IC261 or TG003 in mouse models of inflammatory pain. I.t. injections of IC261 (0.1-1 nmol) or TG003 (0.1-100 pmol) dose-dependently increased both withdrawal threshold and withdrawal latency of the hind paw ipsilateral to carrageenan or CFA-induced inflammation (Figures 3 and4). Spinal preemptive treatment of IC261 also dose-dependently attenuated the development of thermal hyperalgesia induced by carrageenan (Figure 3B). Thus, blocking the CK1 activity at the spinal level appeared to be effective in reduction of inflammation-induced mechanical allodynia and thermal hyperalgesia. The maximum effects were observed 0.5-1 hour after the injections of both inhibitors and significant analgesic effects were still observed 3-4 hours after the injection of the highest doses used in this study (Figures 3 and4). These inhibitors had no significant effects on the contralateral hind paw (Figures 3 and4). I.t. injection of vehicle (1% DMSO in saline) used as a solvent for the drugs did not show any effects (Figures 3A and4B, data not shown).

Bottom Line: However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood.TG003, which was originally identified as a cdc2-like kinase inhibitor, had potent inhibitory effects on CK1 isoforms in vitro and in cultured cells.Intrathecal injection of either TG003 (1-100 pmol) or IC261 (0.1-1 nmol) dose-dependently decreased mechanical allodynia and thermal hyperalgesia induced by carrageenan or CFA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan. tkmphm10@m.kufm.kagoshima-u.ac.jp.

ABSTRACT

Background: The phylogenetically highly conserved CK1 protein kinases consisting of at least seven isoforms form a distinct family within the eukaryotic protein kinases. CK1 family members play crucial roles in a wide range of signaling activities. However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood. The aim of this study was to clarify the role of CK1 in the regulation of inflammatory pain in mouse carrageenan and complete Freund's adjuvant (CFA) models.

Results: We have used two structurally different CK1 inhibitors, TG003 and IC261. TG003, which was originally identified as a cdc2-like kinase inhibitor, had potent inhibitory effects on CK1 isoforms in vitro and in cultured cells. Intrathecal injection of either TG003 (1-100 pmol) or IC261 (0.1-1 nmol) dose-dependently decreased mechanical allodynia and thermal hyperalgesia induced by carrageenan or CFA. Bath-application of either TG003 (1 μM) or IC261 (1 μM) had only marginal effects on spontaneous excitatory postsynaptic currents (sEPSCs) recorded in the substantia gelatinosa neurons of control mice. However, both compounds decreased the frequency of sEPSCs in both inflammatory pain models.

Conclusions: These results suggest that CK1 plays an important pathophysiological role in spinal inflammatory pain transmission, and that inhibition of the CK1 activity may provide a novel strategy for the treatment of inflammatory pain.

Show MeSH
Related in: MedlinePlus