European Journal of Pharmacology 404 2000 95–102
Antinociception in rat by sarpogrelate, a selective 5-HT receptor
antagonist, is peripheral
, Shigeru Saito, Keiji Ishizaki, Fumio Goto
Department of Anesthesiology and Reanimatology, Gunma UniÕersity, School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan
Received 3 April 2000; received in revised form 14 July 2000; accepted 17 July 2000
The antinociceptive effect of sarpogrelate, a new selective 5-hydroxytriptamine 5-HT receptor antagonist, in the formalin test was
examined in rats. Sarpogrelate was administered intraperitoneally, locally subcutaneously at the formalin test site or intrathecally 10 min
before formalin injection. Intraperitoneal 1–100 mgrkg and local 0.01–1 mg administration of sarpogrelate suppressed flinching
Ž.Ž . Ž . Ž.
behavior in both phases 1 0–9 min and 2 10–60 min in a dose-dependent manner. Intraperitoneal 100 mgrkg and local 1 mg
injection 7 min after formalin injection reduced phase 2 flinches to the same degree as with the pre-treatment. Intrathecal administration
1–100 mg showed no antinociceptive action, and facilitated phase 2 flinches at 10 mg. The plasma concentration of sarpogrelate after
local administration of 1 mg was lower than after intraperitoneal administration of 10 mgrkg, although local administration produced
more potent antinociception. The data imply that the antinociceptive effect of sarpogrelate results mainly from an action at peripheral
sites. q2000 Elsevier Science B.V. All rights reserved.
Keywords: Sarpogrelate; 5-HT receptor antagonist; Antinociception; Formalin test; Rat
The 5-hydroxytriptamine 5-HT plays an important
role in nociceptive transmission. Intrathecally administered
5-HT shows antinociceptive effects in acute pain models in
rats Yaksh and Wilson, 1979; Schmauss et al., 1983;
Bardin et al., 1997 . In contrast, peripheral injection of
5-HT facilitates pain responses Hong and Abbott, 1994 .
The 5-HT receptors are divided into several subgroups.
Among these receptor subtypes, the 5-HT receptor is
crucial for pain modulation. This subtype is widely dis-
tributed in peripheral tissues including platelets and is also
present in the central nervous system Hoyer et al., 1994 .
The 5-HT receptor has a localization that subserves noci-
ception and analgesia. Local administration of selective
5-HT receptor antagonists produces antinociception in the
rat formalin test Abbott et al., 1996 , and intradermal
Corresponding author. Tel.: q81-27-220-8453; fax: q81-27-220-
E-mail address: email@example.com H. Obata .
injection of a 5-HT receptor agonist into the rat hindpaw
produces hyperalgesia in the paw Tokunaga et al., 1998 .
In contrast, intrathecal injection of 5-HT receptor agonists
mediates antinociception in rat acute pain models Solomon
and Gebhart, 1988; Danzebrink and Gebhart, 1991 .
Sarpogrelate MCI-9042, or R,S -1- 2- 2- 3-metho-
. x Ž.
xyphenyl ethyl phenoxyl-3- dimethylamino -2-propyl hy-
drogen succinate hydrochloride is a new 5-HT receptor
antagonist that was first introduced as a therapeutic agent
for ischemia associated with thrombosis. In radioligand
binding studies, this drug shows specificity for 5-HT
receptors Maruyama et al., 1991; Nishio et al., 1996 , a
result confirmed by studies using in vitro functional assay
systems Pertz and Elz, 1995 . Kikumoto et al. 1990
proved that the effect of sarpogrelate against platelet ag-
gregation was mediated by its 5-HT receptor-blocking
properties. Furthermore, sarpogrelate inhibits 5-HT release
accompanying collagen-induced platelet aggregation Hara
et al., 1991 . The drug shares both these properties with
the classical 5-HT receptor antagonist, ketanserin De-
Clerck and Xhonneux, 1985 , which also has weak activity
0014-2999r00r$ - see front matter q2000 Elsevier Science B.V. All rights reserved.
PII: S0014-2999 00 00522-7