The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception

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.