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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

FTY720 decreases the nociceptive behaviour of rats in the formalin assay. (A) Increasing concentrations of FTY720 or saline were given i.p. 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. Two-tailed Student's t-test: *P≤ 0.025, **P≤ 0.01, ***P≤ 0.001 as compared to animals receiving only vehicle. (B,C) The effect of 0.01 mg/kg FTY720 i.p. on motor co-ordination was assessed using the pole test (B) and on pain thresholds using the hot-plate test (C). Data are presented as mean ±S.E.M. of 5–6 animals.(D) The number of white blood cells (WBC) and lymphocytes (LYM) were determined before (baseline, BL) and after a single i.p. administration of FTY720 to the indicated times. Data are presented as mean ± S.E.M. of 4–5 animals. Two-tailed Student's t-test: *P≤ 0.02 as compared to baseline.(E) Eicosanoid concentrations in the plasma 1 hr after i.p. injection of 0.01 mg/kg FTY720. Data are presented as mean ± S.E.M. (n= 8–9). Two-tailed Student's t-test: *P≤ 0.03 as compared to rats that received only vehicle.
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fig01: FTY720 decreases the nociceptive behaviour of rats in the formalin assay. (A) Increasing concentrations of FTY720 or saline were given i.p. 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. Two-tailed Student's t-test: *P≤ 0.025, **P≤ 0.01, ***P≤ 0.001 as compared to animals receiving only vehicle. (B,C) The effect of 0.01 mg/kg FTY720 i.p. on motor co-ordination was assessed using the pole test (B) and on pain thresholds using the hot-plate test (C). Data are presented as mean ±S.E.M. of 5–6 animals.(D) The number of white blood cells (WBC) and lymphocytes (LYM) were determined before (baseline, BL) and after a single i.p. administration of FTY720 to the indicated times. Data are presented as mean ± S.E.M. of 4–5 animals. Two-tailed Student's t-test: *P≤ 0.02 as compared to baseline.(E) Eicosanoid concentrations in the plasma 1 hr after i.p. injection of 0.01 mg/kg FTY720. Data are presented as mean ± S.E.M. (n= 8–9). Two-tailed Student's t-test: *P≤ 0.03 as compared to rats that received only vehicle.

Mentions: To study the effects of FTY720 on nociceptive behaviour we first employed the formalin assay since this assay depends strongly on prostaglandin synthesis and especially on the spinal PGE2 synthesis [17, 22]. Intraperitoneally (i.p.) injected FTY720 significantly reduced, at rather low doses (0.001 and 0.01 mg/kg), the nociceptive behaviour of adult rats (Fig. 1A). Surprisingly the antinociceptive effect disappeared when the doses were further increased (0.1–1 mg/kg; Fig. 1A). The FTY720 dose with the greatest antinociceptive potency (0.01 mg/kg) did not alter motor abilities of treated rats as determined by the pole assay (Fig. 1B) or the basal pain threshold as determined by the hot plate assay (Fig. 1C). Notably, doses from 0.1–10 mg/kg were previously reported to induce the immunosuppressive actions of FTY720 in rats [9]. Accordingly, at the highest dose (1 mg/kg) a significant reduction in the lymphocyte count occurred (Fig. 1D). At the dose with the strongest antinociceptive effect (0.01 mg/kg) a tendency towards a decreased lymphocyte count was seen, but did not reach statistical significance (Fig. 1D). This gives a first indication that the immunosuppressive properties of FTY720 may not play a major role in mediating its antinociceptive effects. In contrast, 1hr after i.p. administration of 0.01 mg/kg FTY720, the plasma concentrations of PGE2, PGD2, PGF2α and thromboxane A2 (TxA2), as determined by its stable metabolite TxB2, were dramatically decreased. Interestingly, not all eicosanoid concentrations were altered by FTY720, since the plasma concentrations of PGI2, as determined by its stable metabolite 6-ketoPGF1α, were unchanged. The dramatic decrease of the eicosanoid level in the plasma, and here especially the decreased PGE2 concentrations, could serve to explain the antinociceptive effect of FTY720, since inhibition of PGE2 synthesis generally reduces the nociceptive behaviour in the formalin assay [17, 22, 23].


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 decreases the nociceptive behaviour of rats in the formalin assay. (A) Increasing concentrations of FTY720 or saline were given i.p. 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. Two-tailed Student's t-test: *P≤ 0.025, **P≤ 0.01, ***P≤ 0.001 as compared to animals receiving only vehicle. (B,C) The effect of 0.01 mg/kg FTY720 i.p. on motor co-ordination was assessed using the pole test (B) and on pain thresholds using the hot-plate test (C). Data are presented as mean ±S.E.M. of 5–6 animals.(D) The number of white blood cells (WBC) and lymphocytes (LYM) were determined before (baseline, BL) and after a single i.p. administration of FTY720 to the indicated times. Data are presented as mean ± S.E.M. of 4–5 animals. Two-tailed Student's t-test: *P≤ 0.02 as compared to baseline.(E) Eicosanoid concentrations in the plasma 1 hr after i.p. injection of 0.01 mg/kg FTY720. Data are presented as mean ± S.E.M. (n= 8–9). Two-tailed Student's t-test: *P≤ 0.03 as compared to rats that received only vehicle.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4401143&req=5

fig01: FTY720 decreases the nociceptive behaviour of rats in the formalin assay. (A) Increasing concentrations of FTY720 or saline were given i.p. 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. Two-tailed Student's t-test: *P≤ 0.025, **P≤ 0.01, ***P≤ 0.001 as compared to animals receiving only vehicle. (B,C) The effect of 0.01 mg/kg FTY720 i.p. on motor co-ordination was assessed using the pole test (B) and on pain thresholds using the hot-plate test (C). Data are presented as mean ±S.E.M. of 5–6 animals.(D) The number of white blood cells (WBC) and lymphocytes (LYM) were determined before (baseline, BL) and after a single i.p. administration of FTY720 to the indicated times. Data are presented as mean ± S.E.M. of 4–5 animals. Two-tailed Student's t-test: *P≤ 0.02 as compared to baseline.(E) Eicosanoid concentrations in the plasma 1 hr after i.p. injection of 0.01 mg/kg FTY720. Data are presented as mean ± S.E.M. (n= 8–9). Two-tailed Student's t-test: *P≤ 0.03 as compared to rats that received only vehicle.
Mentions: To study the effects of FTY720 on nociceptive behaviour we first employed the formalin assay since this assay depends strongly on prostaglandin synthesis and especially on the spinal PGE2 synthesis [17, 22]. Intraperitoneally (i.p.) injected FTY720 significantly reduced, at rather low doses (0.001 and 0.01 mg/kg), the nociceptive behaviour of adult rats (Fig. 1A). Surprisingly the antinociceptive effect disappeared when the doses were further increased (0.1–1 mg/kg; Fig. 1A). The FTY720 dose with the greatest antinociceptive potency (0.01 mg/kg) did not alter motor abilities of treated rats as determined by the pole assay (Fig. 1B) or the basal pain threshold as determined by the hot plate assay (Fig. 1C). Notably, doses from 0.1–10 mg/kg were previously reported to induce the immunosuppressive actions of FTY720 in rats [9]. Accordingly, at the highest dose (1 mg/kg) a significant reduction in the lymphocyte count occurred (Fig. 1D). At the dose with the strongest antinociceptive effect (0.01 mg/kg) a tendency towards a decreased lymphocyte count was seen, but did not reach statistical significance (Fig. 1D). This gives a first indication that the immunosuppressive properties of FTY720 may not play a major role in mediating its antinociceptive effects. In contrast, 1hr after i.p. administration of 0.01 mg/kg FTY720, the plasma concentrations of PGE2, PGD2, PGF2α and thromboxane A2 (TxA2), as determined by its stable metabolite TxB2, were dramatically decreased. Interestingly, not all eicosanoid concentrations were altered by FTY720, since the plasma concentrations of PGI2, as determined by its stable metabolite 6-ketoPGF1α, were unchanged. The dramatic decrease of the eicosanoid level in the plasma, and here especially the decreased PGE2 concentrations, could serve to explain the antinociceptive effect of FTY720, since inhibition of PGE2 synthesis generally reduces the nociceptive behaviour in the formalin assay [17, 22, 23].

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