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BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance.

Dobashi T, Tanabe S, Jin H, Mimura N, Yamamoto T, Nishino T, Aoe T - J. Cell. Mol. Med. (2010)

Bottom Line: The activation of glycogen synthase kinase 3b (GSK-3b) was associated with morphine tolerance, because an inhibitor of GSK-3β prevented it.These results suggest that BiP may play an important role in the development of morphine tolerance.Furthermore, we found that a chemical chaperone which improves ER protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba, Japan.

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A chemical chaperone attenuates the development of morphine tolerance. Wild-type mice were injected intraperitoneally with TUDCA together with 20 mg/kg morphine twice a day for 5 days, and the hot plate test was performed to evaluate analgesia at the tenth injection on day 5. (A) The graph represents the response latencies (0–60 sec.) of the mice with saline control (NS, N= 10), morphine alone (M, N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). ‘Pre’ represents control mice evaluated by the hot plate test after the first morphine injection on day 1 (N= 10). The response latencies of the mice receiving both TUDCA (250 mg/kg) and morphine were significantly longer than those of control mice with morphine alone after the tenth treatment. *P < 0.05, **P < 0.01, two-way ANOVA with the Bonferroni post hoc test. (B) The graph represents the distribution of percentage MPE after the treatment of wild-type mice with morphine alone (N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). The mean percentage MPE of mice treated with TUDCA and morphine was significantly larger than that of the mice treated with morphine alone. *P < 0.05, ***P < 0.001, one-way ANOVA with the Bonferroni post hoc test.
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fig08: A chemical chaperone attenuates the development of morphine tolerance. Wild-type mice were injected intraperitoneally with TUDCA together with 20 mg/kg morphine twice a day for 5 days, and the hot plate test was performed to evaluate analgesia at the tenth injection on day 5. (A) The graph represents the response latencies (0–60 sec.) of the mice with saline control (NS, N= 10), morphine alone (M, N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). ‘Pre’ represents control mice evaluated by the hot plate test after the first morphine injection on day 1 (N= 10). The response latencies of the mice receiving both TUDCA (250 mg/kg) and morphine were significantly longer than those of control mice with morphine alone after the tenth treatment. *P < 0.05, **P < 0.01, two-way ANOVA with the Bonferroni post hoc test. (B) The graph represents the distribution of percentage MPE after the treatment of wild-type mice with morphine alone (N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). The mean percentage MPE of mice treated with TUDCA and morphine was significantly larger than that of the mice treated with morphine alone. *P < 0.05, ***P < 0.001, one-way ANOVA with the Bonferroni post hoc test.

Mentions: In order to confirm that an ER chaperone mediates the development of morphine tolerance, we examined the effect of a chemical chaperone on morphine tolerance. Tauroursodeoxycholic acid (TUDCA) is a derivative of endogenous bile acids that is thought to increase ER folding capacity and suppresses the expression of BiP [29, 30]. We administered TUDCA together with 20 mg/kg morphine twice a day for 5 days in wild-type mice, and hot plate tests were performed at the first and the tenth treatments. The response latencies of the mice receiving both TUDCA and morphine were significantly longer than those of control mice with morphine alone after the tenth treatment (Fig. 8A). The mean percentage MPE of mice treated with TUDCA and morphine was significantly greater than that of the mice treated with morphine alone (Fig. 8B). Thus, TUDCA prevented the development of morphine tolerance, suggesting a mechanistic relationship between an ER chaperone and morphine tolerance.


BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance.

Dobashi T, Tanabe S, Jin H, Mimura N, Yamamoto T, Nishino T, Aoe T - J. Cell. Mol. Med. (2010)

A chemical chaperone attenuates the development of morphine tolerance. Wild-type mice were injected intraperitoneally with TUDCA together with 20 mg/kg morphine twice a day for 5 days, and the hot plate test was performed to evaluate analgesia at the tenth injection on day 5. (A) The graph represents the response latencies (0–60 sec.) of the mice with saline control (NS, N= 10), morphine alone (M, N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). ‘Pre’ represents control mice evaluated by the hot plate test after the first morphine injection on day 1 (N= 10). The response latencies of the mice receiving both TUDCA (250 mg/kg) and morphine were significantly longer than those of control mice with morphine alone after the tenth treatment. *P < 0.05, **P < 0.01, two-way ANOVA with the Bonferroni post hoc test. (B) The graph represents the distribution of percentage MPE after the treatment of wild-type mice with morphine alone (N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). The mean percentage MPE of mice treated with TUDCA and morphine was significantly larger than that of the mice treated with morphine alone. *P < 0.05, ***P < 0.001, one-way ANOVA with the Bonferroni post hoc test.
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fig08: A chemical chaperone attenuates the development of morphine tolerance. Wild-type mice were injected intraperitoneally with TUDCA together with 20 mg/kg morphine twice a day for 5 days, and the hot plate test was performed to evaluate analgesia at the tenth injection on day 5. (A) The graph represents the response latencies (0–60 sec.) of the mice with saline control (NS, N= 10), morphine alone (M, N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). ‘Pre’ represents control mice evaluated by the hot plate test after the first morphine injection on day 1 (N= 10). The response latencies of the mice receiving both TUDCA (250 mg/kg) and morphine were significantly longer than those of control mice with morphine alone after the tenth treatment. *P < 0.05, **P < 0.01, two-way ANOVA with the Bonferroni post hoc test. (B) The graph represents the distribution of percentage MPE after the treatment of wild-type mice with morphine alone (N= 10), 250 mg/kg TUDCA alone (N= 10), 100 mg/kg TUDCA and morphine (N= 12), 250 mg/kg TUDCA and morphine (N= 8). The mean percentage MPE of mice treated with TUDCA and morphine was significantly larger than that of the mice treated with morphine alone. *P < 0.05, ***P < 0.001, one-way ANOVA with the Bonferroni post hoc test.
Mentions: In order to confirm that an ER chaperone mediates the development of morphine tolerance, we examined the effect of a chemical chaperone on morphine tolerance. Tauroursodeoxycholic acid (TUDCA) is a derivative of endogenous bile acids that is thought to increase ER folding capacity and suppresses the expression of BiP [29, 30]. We administered TUDCA together with 20 mg/kg morphine twice a day for 5 days in wild-type mice, and hot plate tests were performed at the first and the tenth treatments. The response latencies of the mice receiving both TUDCA and morphine were significantly longer than those of control mice with morphine alone after the tenth treatment (Fig. 8A). The mean percentage MPE of mice treated with TUDCA and morphine was significantly greater than that of the mice treated with morphine alone (Fig. 8B). Thus, TUDCA prevented the development of morphine tolerance, suggesting a mechanistic relationship between an ER chaperone and morphine tolerance.

Bottom Line: The activation of glycogen synthase kinase 3b (GSK-3b) was associated with morphine tolerance, because an inhibitor of GSK-3β prevented it.These results suggest that BiP may play an important role in the development of morphine tolerance.Furthermore, we found that a chemical chaperone which improves ER protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba, Japan.

Show MeSH
Related in: MedlinePlus