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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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Related in: MedlinePlus

SEW2871 does not alter nociceptive behaviour in the formalin assay.(A) Increasing concentrations of SEW2871 or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The number of flinches from 0–15 (phase I) min, 16–60 min (phase II) are shown. The data are expressed as the mean ± S.E.M. of six animals per group. (B) Same as panel A except that SEW2871 (4 mg/kg, i.p.) or saline were given 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of six animals per group (n.s.;not significant).(C) The number of white blood cells (WBC) were determined before and 1 hr after a single administration of 10μl SEW2871 (80 μM) i.th. or 4 mg/kg SEW2871 i.p.. Data are presented as mean + S.E.M. of at least seven animals. Two-tailed Student's t-test: *P≤ 0.003 as compared to controls.(D) Eicosanoids were determined in the plasma in untreated animals and 1 hr after formalin injection. Where indicated SEW2871 (4mg/kg) was given i.p.. Data are presented as mean ± S.E.M. (n= 7–9). Two-tailed Student's t-test:*P≤ 0.003 as compared to animals treated only with formalin.
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fig03: SEW2871 does not alter nociceptive behaviour in the formalin assay.(A) Increasing concentrations of SEW2871 or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The number of flinches from 0–15 (phase I) min, 16–60 min (phase II) are shown. The data are expressed as the mean ± S.E.M. of six animals per group. (B) Same as panel A except that SEW2871 (4 mg/kg, i.p.) or saline were given 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of six animals per group (n.s.;not significant).(C) The number of white blood cells (WBC) were determined before and 1 hr after a single administration of 10μl SEW2871 (80 μM) i.th. or 4 mg/kg SEW2871 i.p.. Data are presented as mean + S.E.M. of at least seven animals. Two-tailed Student's t-test: *P≤ 0.003 as compared to controls.(D) Eicosanoids were determined in the plasma in untreated animals and 1 hr after formalin injection. Where indicated SEW2871 (4mg/kg) was given i.p.. Data are presented as mean ± S.E.M. (n= 7–9). Two-tailed Student's t-test:*P≤ 0.003 as compared to animals treated only with formalin.

Mentions: Since the immunosuppressive effects of FTY720 are mediated by S1P1[24] wetested which role this receptor plays in mediating the spinal antinociceptive effects of FTY720. Interestingly, neither i.th. or i.p. administration of SEW2871, a selective S1P1 agonist, caused significant effects on the nociceptive behaviour of rats in the formalin assay (Fig. 3A and B). Inaccordance with the above described findings with FTY720, i.th. administered SEW2871 did not alter the white blood cell count even at the highest dose of (80 μM) (Fig. 3C), while as expected i.p. administered SEW2871 significantly decreased the white blood cell count in the peripheral blood. These findings support the notion that the immunosuppressive property of FTY720 seems not to play a major role in mediating its antinociceptive effect. Moreover, i.p. administered SEW2871 increased significantly the plasma concentrations of PGE2 as well as PGF2α (Fig. 3D). Owing to the fact that increased PGE2 levels are connected with increased nociception [17, 22, 23], this finding further speaks against a role of S1P1 in mediating the antinociceptive effects of FTY720.


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)

SEW2871 does not alter nociceptive behaviour in the formalin assay.(A) Increasing concentrations of SEW2871 or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The number of flinches from 0–15 (phase I) min, 16–60 min (phase II) are shown. The data are expressed as the mean ± S.E.M. of six animals per group. (B) Same as panel A except that SEW2871 (4 mg/kg, i.p.) or saline were given 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of six animals per group (n.s.;not significant).(C) The number of white blood cells (WBC) were determined before and 1 hr after a single administration of 10μl SEW2871 (80 μM) i.th. or 4 mg/kg SEW2871 i.p.. Data are presented as mean + S.E.M. of at least seven animals. Two-tailed Student's t-test: *P≤ 0.003 as compared to controls.(D) Eicosanoids were determined in the plasma in untreated animals and 1 hr after formalin injection. Where indicated SEW2871 (4mg/kg) was given i.p.. Data are presented as mean ± S.E.M. (n= 7–9). Two-tailed Student's t-test:*P≤ 0.003 as compared to animals treated only with formalin.
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Related In: Results  -  Collection

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fig03: SEW2871 does not alter nociceptive behaviour in the formalin assay.(A) Increasing concentrations of SEW2871 or saline were given i.th. 15 min prior to the formalin injection in one hind paw. The number of flinches from 0–15 (phase I) min, 16–60 min (phase II) are shown. The data are expressed as the mean ± S.E.M. of six animals per group. (B) Same as panel A except that SEW2871 (4 mg/kg, i.p.) or saline were given 15 min prior to the formalin injection in one hind paw. The data are expressed as the mean ± S.E.M. of six animals per group (n.s.;not significant).(C) The number of white blood cells (WBC) were determined before and 1 hr after a single administration of 10μl SEW2871 (80 μM) i.th. or 4 mg/kg SEW2871 i.p.. Data are presented as mean + S.E.M. of at least seven animals. Two-tailed Student's t-test: *P≤ 0.003 as compared to controls.(D) Eicosanoids were determined in the plasma in untreated animals and 1 hr after formalin injection. Where indicated SEW2871 (4mg/kg) was given i.p.. Data are presented as mean ± S.E.M. (n= 7–9). Two-tailed Student's t-test:*P≤ 0.003 as compared to animals treated only with formalin.
Mentions: Since the immunosuppressive effects of FTY720 are mediated by S1P1[24] wetested which role this receptor plays in mediating the spinal antinociceptive effects of FTY720. Interestingly, neither i.th. or i.p. administration of SEW2871, a selective S1P1 agonist, caused significant effects on the nociceptive behaviour of rats in the formalin assay (Fig. 3A and B). Inaccordance with the above described findings with FTY720, i.th. administered SEW2871 did not alter the white blood cell count even at the highest dose of (80 μM) (Fig. 3C), while as expected i.p. administered SEW2871 significantly decreased the white blood cell count in the peripheral blood. These findings support the notion that the immunosuppressive property of FTY720 seems not to play a major role in mediating its antinociceptive effect. Moreover, i.p. administered SEW2871 increased significantly the plasma concentrations of PGE2 as well as PGF2α (Fig. 3D). Owing to the fact that increased PGE2 levels are connected with increased nociception [17, 22, 23], this finding further speaks against a role of S1P1 in mediating the antinociceptive effects of FTY720.

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