Limits...
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.

Show MeSH

Related in: MedlinePlus

FTY720 decreases nociceptive behaviour in the SNI model for neuropathic pain. The nociceptive behaviour in the SNI model for neuropathic pain was determined ipsilateral (full symbols) and contralateral (empty symbols) before the operation (BL) and at the indicated times after the operation. The animals received gabapentin (red), FTY720 (blue, dotted line) or vehicle (black). Sham operated animals are shown in grey. FTY720 (1x daily, 0.01 mg/kg i.p.) and gabapentin (2x daily 25 mg/kg) were given starting at day 7 after the operation. The mechanical threshold was determined using a plantar aesthesiometer (A) or von Frey hairs (B). Thermal allodynia was determined using the cold plate test (C) or the acetone test (D). Data are presented as mean + S.E.M. of six animals per group.(E) FTY720 was applied to adult rats for 14 days (1x daily, 0.01 mg/kg i.p.) and the number of white blood cells (WBC) and lymphocytes (LYM) was determined at the indicated times. After day 14 administration of FTY720 was discontinued. Data are presented as mean + S.E.M. of five animals. Two-tailed Student's t-test:*P≤ 0.5, **P≤ 0.01, ***P≤ 0.001 as compared to animals not receiving FTY720 or gabapentin.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4401143&req=5

fig04: FTY720 decreases nociceptive behaviour in the SNI model for neuropathic pain. The nociceptive behaviour in the SNI model for neuropathic pain was determined ipsilateral (full symbols) and contralateral (empty symbols) before the operation (BL) and at the indicated times after the operation. The animals received gabapentin (red), FTY720 (blue, dotted line) or vehicle (black). Sham operated animals are shown in grey. FTY720 (1x daily, 0.01 mg/kg i.p.) and gabapentin (2x daily 25 mg/kg) were given starting at day 7 after the operation. The mechanical threshold was determined using a plantar aesthesiometer (A) or von Frey hairs (B). Thermal allodynia was determined using the cold plate test (C) or the acetone test (D). Data are presented as mean + S.E.M. of six animals per group.(E) FTY720 was applied to adult rats for 14 days (1x daily, 0.01 mg/kg i.p.) and the number of white blood cells (WBC) and lymphocytes (LYM) was determined at the indicated times. After day 14 administration of FTY720 was discontinued. Data are presented as mean + S.E.M. of five animals. Two-tailed Student's t-test:*P≤ 0.5, **P≤ 0.01, ***P≤ 0.001 as compared to animals not receiving FTY720 or gabapentin.

Mentions: Next, we tested the antinociceptive actions of FTY720 in the spared nerve injury (SNI) model for neuropathic pain, a pain model that has a different pathophysiological mechanism as compared to the formalin assay and is known to be independent of prostaglandin synthesis [19, 20]. Mechanical and thermal allodynia were allowed to develop over 7 days after surgery before the animals received intraperitoneally FTY720, gabapentin (positive control) or phosphate-buffered saline over 2 weeks. Mechanical allodynia as determined by a plantar aesthesiometer (Fig. 4A) and von Frey hair testing (Fig. 4B) as well as thermal allodynia as determined by cold plate (Fig. 4C) and acetone test (Fig. 4D), were significantly decreased after the treatment with FTY720. Interestingly, the antinociceptive effect of FTY720 was similar to that of gabapentin, a commonly prescribed drug for the treatment of neuropathic pain (Fig. 4A–D) [25]. The chronic daily administration of the low doses of FTY720 caused a statistically significant decrease in the number of peripheral blood lymphocytes (Fig. 4E). However, the number of lymphocytes was still within the range that is found in normal, healthy rats [26].


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 nociceptive behaviour in the SNI model for neuropathic pain. The nociceptive behaviour in the SNI model for neuropathic pain was determined ipsilateral (full symbols) and contralateral (empty symbols) before the operation (BL) and at the indicated times after the operation. The animals received gabapentin (red), FTY720 (blue, dotted line) or vehicle (black). Sham operated animals are shown in grey. FTY720 (1x daily, 0.01 mg/kg i.p.) and gabapentin (2x daily 25 mg/kg) were given starting at day 7 after the operation. The mechanical threshold was determined using a plantar aesthesiometer (A) or von Frey hairs (B). Thermal allodynia was determined using the cold plate test (C) or the acetone test (D). Data are presented as mean + S.E.M. of six animals per group.(E) FTY720 was applied to adult rats for 14 days (1x daily, 0.01 mg/kg i.p.) and the number of white blood cells (WBC) and lymphocytes (LYM) was determined at the indicated times. After day 14 administration of FTY720 was discontinued. Data are presented as mean + S.E.M. of five animals. Two-tailed Student's t-test:*P≤ 0.5, **P≤ 0.01, ***P≤ 0.001 as compared to animals not receiving FTY720 or gabapentin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401143&req=5

fig04: FTY720 decreases nociceptive behaviour in the SNI model for neuropathic pain. The nociceptive behaviour in the SNI model for neuropathic pain was determined ipsilateral (full symbols) and contralateral (empty symbols) before the operation (BL) and at the indicated times after the operation. The animals received gabapentin (red), FTY720 (blue, dotted line) or vehicle (black). Sham operated animals are shown in grey. FTY720 (1x daily, 0.01 mg/kg i.p.) and gabapentin (2x daily 25 mg/kg) were given starting at day 7 after the operation. The mechanical threshold was determined using a plantar aesthesiometer (A) or von Frey hairs (B). Thermal allodynia was determined using the cold plate test (C) or the acetone test (D). Data are presented as mean + S.E.M. of six animals per group.(E) FTY720 was applied to adult rats for 14 days (1x daily, 0.01 mg/kg i.p.) and the number of white blood cells (WBC) and lymphocytes (LYM) was determined at the indicated times. After day 14 administration of FTY720 was discontinued. Data are presented as mean + S.E.M. of five animals. Two-tailed Student's t-test:*P≤ 0.5, **P≤ 0.01, ***P≤ 0.001 as compared to animals not receiving FTY720 or gabapentin.
Mentions: Next, we tested the antinociceptive actions of FTY720 in the spared nerve injury (SNI) model for neuropathic pain, a pain model that has a different pathophysiological mechanism as compared to the formalin assay and is known to be independent of prostaglandin synthesis [19, 20]. Mechanical and thermal allodynia were allowed to develop over 7 days after surgery before the animals received intraperitoneally FTY720, gabapentin (positive control) or phosphate-buffered saline over 2 weeks. Mechanical allodynia as determined by a plantar aesthesiometer (Fig. 4A) and von Frey hair testing (Fig. 4B) as well as thermal allodynia as determined by cold plate (Fig. 4C) and acetone test (Fig. 4D), were significantly decreased after the treatment with FTY720. Interestingly, the antinociceptive effect of FTY720 was similar to that of gabapentin, a commonly prescribed drug for the treatment of neuropathic pain (Fig. 4A–D) [25]. The chronic daily administration of the low doses of FTY720 caused a statistically significant decrease in the number of peripheral blood lymphocytes (Fig. 4E). However, the number of lymphocytes was still within the range that is found in normal, healthy rats [26].

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