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Antinociceptive activity of the S1P-receptor agonist FTY720.

Coste O, Pierre S, Marian C, Brenneis C, Angioni C, Schmidt H, Popp L, Geisslinger G, Scholich K - J. Cell. Mol. Med. (2008)

Bottom Line: Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2).We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay.Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced.

View Article: PubMed Central - PubMed

Affiliation: Pharmazentrum Frankfurt, ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany.

ABSTRACT
FTY720 is a novel immunosuppressive drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. In its phosphorylated form FTY720 is a potent S1P receptor agonist. Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2). Since prostaglandins are important mediators of nociception, we studied the effects of FTY720 in different models of nociception. We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay. Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced. Surprisingly, intrathecally administered FTY720 reduced the nociceptive behaviour in the formalin assay without altering spinal prostaglandin synthesis, indicating that additional antinociceptive mechanisms beside the inhibition of prostaglandin synthesis are involved. Accordingly, FTY720 reduced also the nociceptive behaviour in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis. In this model the antinociceptive effect of FTY720 was similar to gabapentin, a commonly used drug to treat neuropathic pain. Taken together we show for the first time that FTY720 possesses antinociceptive properties and that FTY720 reduces nociceptive behaviour during neuropathic pain.

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FTY720 (i.th.) decreases the nociceptive behaviour in the formalin assay without altering the prostanoid synthesis. (A) FTY720 (3 μM) or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of 7–10 animals per group. Two-tailed Student's t-test: *P≤ 0.035 as compared to control animals. (B) FTY720 and FTY720-phosphate concentrations were determined in the plasma of animals 1 hr after administering either 0.01 mg/kg i.p. or 3 μM i.th. FTY720. Data are expressed as the mean ± S.E.M. of 4–5 animals per group (nd = not detectable). (C) The number of white blood cells (WBC) were determined before and 1 hr after a single i.th. administration of 3 μM FTY720. Data are presented as mean ± S.E.M. of 4–5 animals. (D) Eicosanoids were extracted 1 hr after formalin injection from spinal cord segments L4–L5. Where indicated FTY720 (3 μM) was given i.th. Data are presented as mean ± S.E.M. (n= 7–10).
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fig02: FTY720 (i.th.) decreases the nociceptive behaviour in the formalin assay without altering the prostanoid synthesis. (A) FTY720 (3 μM) or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of 7–10 animals per group. Two-tailed Student's t-test: *P≤ 0.035 as compared to control animals. (B) FTY720 and FTY720-phosphate concentrations were determined in the plasma of animals 1 hr after administering either 0.01 mg/kg i.p. or 3 μM i.th. FTY720. Data are expressed as the mean ± S.E.M. of 4–5 animals per group (nd = not detectable). (C) The number of white blood cells (WBC) were determined before and 1 hr after a single i.th. administration of 3 μM FTY720. Data are presented as mean ± S.E.M. of 4–5 animals. (D) Eicosanoids were extracted 1 hr after formalin injection from spinal cord segments L4–L5. Where indicated FTY720 (3 μM) was given i.th. Data are presented as mean ± S.E.M. (n= 7–10).

Mentions: To investigate whether the antinociceptive effect of FTY720 has also a central component we administered FTY720 i.th. Rats that received FTY720 i.th. exhibited a significant decrease in their nociceptive behaviour in the formalin assay as compared to rats that received only saline (Fig. 2A). Neither FTY720 nor its phosphorylated form was detected in the plasma after i.th. administration (Fig. 2B) and accordingly, even with the highest dose of FTY720 (80 μM, i.th.) no effect on the number of white blood cells was observed (Fig. 2C). Since i.p. administration of FTY720 decreases the prostaglandin concentrations in the plasma, we compared the prostanoid synthesis in the spinal cord of animals that received FTY720 i.th. with control animals 1 hr after the formalin injection. Out of 14 eicosanoids that were monitored only five eicosanoids were above the detection limit in the spinal cord extracts and for none of these five eicosanoids significant differences between both animal groups were observed (Fig. 2D). This suggests that the antinociceptive effects of FTY720 in the spinal cord are not based on cPLA2 inhibition.


Antinociceptive activity of the S1P-receptor agonist FTY720.

Coste O, Pierre S, Marian C, Brenneis C, Angioni C, Schmidt H, Popp L, Geisslinger G, Scholich K - J. Cell. Mol. Med. (2008)

FTY720 (i.th.) decreases the nociceptive behaviour in the formalin assay without altering the prostanoid synthesis. (A) FTY720 (3 μM) or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of 7–10 animals per group. Two-tailed Student's t-test: *P≤ 0.035 as compared to control animals. (B) FTY720 and FTY720-phosphate concentrations were determined in the plasma of animals 1 hr after administering either 0.01 mg/kg i.p. or 3 μM i.th. FTY720. Data are expressed as the mean ± S.E.M. of 4–5 animals per group (nd = not detectable). (C) The number of white blood cells (WBC) were determined before and 1 hr after a single i.th. administration of 3 μM FTY720. Data are presented as mean ± S.E.M. of 4–5 animals. (D) Eicosanoids were extracted 1 hr after formalin injection from spinal cord segments L4–L5. Where indicated FTY720 (3 μM) was given i.th. Data are presented as mean ± S.E.M. (n= 7–10).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4401143&req=5

fig02: FTY720 (i.th.) decreases the nociceptive behaviour in the formalin assay without altering the prostanoid synthesis. (A) FTY720 (3 μM) or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of 7–10 animals per group. Two-tailed Student's t-test: *P≤ 0.035 as compared to control animals. (B) FTY720 and FTY720-phosphate concentrations were determined in the plasma of animals 1 hr after administering either 0.01 mg/kg i.p. or 3 μM i.th. FTY720. Data are expressed as the mean ± S.E.M. of 4–5 animals per group (nd = not detectable). (C) The number of white blood cells (WBC) were determined before and 1 hr after a single i.th. administration of 3 μM FTY720. Data are presented as mean ± S.E.M. of 4–5 animals. (D) Eicosanoids were extracted 1 hr after formalin injection from spinal cord segments L4–L5. Where indicated FTY720 (3 μM) was given i.th. Data are presented as mean ± S.E.M. (n= 7–10).
Mentions: To investigate whether the antinociceptive effect of FTY720 has also a central component we administered FTY720 i.th. Rats that received FTY720 i.th. exhibited a significant decrease in their nociceptive behaviour in the formalin assay as compared to rats that received only saline (Fig. 2A). Neither FTY720 nor its phosphorylated form was detected in the plasma after i.th. administration (Fig. 2B) and accordingly, even with the highest dose of FTY720 (80 μM, i.th.) no effect on the number of white blood cells was observed (Fig. 2C). Since i.p. administration of FTY720 decreases the prostaglandin concentrations in the plasma, we compared the prostanoid synthesis in the spinal cord of animals that received FTY720 i.th. with control animals 1 hr after the formalin injection. Out of 14 eicosanoids that were monitored only five eicosanoids were above the detection limit in the spinal cord extracts and for none of these five eicosanoids significant differences between both animal groups were observed (Fig. 2D). This suggests that the antinociceptive effects of FTY720 in the spinal cord are not based on cPLA2 inhibition.

Bottom Line: Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2).We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay.Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced.

View Article: PubMed Central - PubMed

Affiliation: Pharmazentrum Frankfurt, ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany.

ABSTRACT
FTY720 is a novel immunosuppressive drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. In its phosphorylated form FTY720 is a potent S1P receptor agonist. Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2). Since prostaglandins are important mediators of nociception, we studied the effects of FTY720 in different models of nociception. We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay. Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced. Surprisingly, intrathecally administered FTY720 reduced the nociceptive behaviour in the formalin assay without altering spinal prostaglandin synthesis, indicating that additional antinociceptive mechanisms beside the inhibition of prostaglandin synthesis are involved. Accordingly, FTY720 reduced also the nociceptive behaviour in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis. In this model the antinociceptive effect of FTY720 was similar to gabapentin, a commonly used drug to treat neuropathic pain. Taken together we show for the first time that FTY720 possesses antinociceptive properties and that FTY720 reduces nociceptive behaviour during neuropathic pain.

Show MeSH
Related in: MedlinePlus