Ca. Parada et al., The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception, NEUROSCIENC, 102(4), 2001, pp. 937-944
Formalin injected subcutaneously into the paw is a widely used model of pai
n. This procedure evokes a short lasting period of flinching (phase 1) and
a long-lasting period of intense flinching (phase 2) following a very short
period of quiescence. Phase 2 has been extensively used to support the inv
olvement of central (spinal cord) sensitization in inflammatory hyperalgesi
a. The present study evaluated the contribution of stimulation of periphera
l nociceptors by the release of endogenous mediators at the sits of Lesion.
The participation of histamine and 5-hydroxytryptamine was demonstrated by
the treatment of the rat hindpaws with selective histamine H1 (pyrilamine
and meclizine) and histamine H2 (cimetidine) receptor antagonists or select
ive 5-hydroxyrrypraminel(1A) (WAY100,135) and 5-hydroxytryptamine(4/3) (tro
pisetron) receptor antagonists. The co-administration of pyrilamine or mecl
izine with formalin (1%) significantly reduced phases 1 and 2. while cimeti
dine had no effect. Pyrilamine administration during the period of quiescen
ce (10 min after formalin administration) caused strong dose-related inhibi
tion of phase 2. The co-administration of tropisetron with formalin caused
a blockade of both phases, while with WAY100.135 caused only inhibition of
the phase 2. In contrast. tropisetron administrated during the period of qu
iescence did not cause antinociception. Histamine and 5-hydroxytryptamine r
eceptors could be strongly activated in naive animals by administration of
a mixture of both agonists or compound 48/80 (2 mug/paw) which is known to
release both mediators from mast cells. Pretreatment of the paws with a mas
t cell stabilizer, sodium cromoglycate, significantly reduced the secund ph
ase of the formalin injection model.
From these results we suggest that phases 1 and 7- of the formalin test are
dependent upon the ongoing afferent input. Furthermore, while histamine H1
participates in both phases, 5-hydroxytryptamine(4/3), participates in pha
se 1 and 5-hydroxytryptamine(1A) in phase 2. (C) 2001 IBRO. Published by El
sevier Science Ltd. All rights reserved.