The inflammatory reaction induced by formalin in the rat paw

The involvement of bradykinin and some other inflammatory mediators in form alin-induced oedema and plasma extravasation was examined. Formalin was inj ected in rat paws at two doses, 1.75% or 5%. The lower dose induced the dev elopment of an immediate oedema associated with a progressive accumulation of I-125-labelled albumin in the paws. These changes were suppressed by pre treatment with capsaicin or xylocaine. They were abolished by RP675801 a NK , receptor antagonist, and increased by phosphoramidon or diprotin A. They were not affected by HOE140, a bradykinin B-2 antagonist, captopril, methys ergide, mepyramine, indomethacin, ketoprofen or L-N-G-nitroarginine. The hi gher dose of formalin induced a swelling of the paws which took place in tw o phases associated with two periods of increase in vascular permeability. This oedema was reduced by pretreatment with capsaicin but not with xylocai ne. It was reduced by RP67580 injected before or 30 min after formalin. It was inhibited by mepyramine, methysergide, indomethacin and NS-398, a cyclo oxygenase-2 inhibitor. It was not modified by HOE140. Its development was s imilar in normal and kininogen-deficient rats. We concluded that formalin administered at a low dose induces an oedema whi ch mainly results from a neurogenic inflammation mediated by neuropeptides such as substance P. At higher doses, formalin induces an oedema which main ly depends on the release of substance P, prostanoids, 5-hydroxytryptamine and histamine. Bradykinin plays no significant role in the vascular changes whereas this peptide has been reported to participate in the stimulation o f nociceptive afferent neurons. This discrepancy could be explained by a di fference in the threshold of stimulation of the nociceptive neurons and tha t of the cells of the vascular walls, or by a formation of kinins in close contact of the neurons.