Antinociceptive activity of the S1P-receptor agonist FTY720.
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.
Coste
Ovidiu
O
Pharmazentrum Frankfurt, ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany.
Pierre
Sandra
S
Marian
Claudiu
C
Brenneis
Christian
C
Angioni
Carlo
C
Schmidt
Helmut
H
Popp
Laura
L
Geisslinger
Gerd
G
Scholich
Klaus
K
D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D000077206:Gabapentin; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011453:Prostaglandins / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D011409:Propylene Glycols; D011453:Prostaglandins; D049349:Receptors, Lysosphingolipid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine