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Pharmacological Research, Vol . 25, Supplement 1, 1992

EFFECTS OF INDOMETHACIN AND DICLOFENAC ON SUBSTANCE P INDUCED CHEMOTAXIS OF HUMAN MONOCYTES AND POLYMORPHONUCLEAR CELLS . L .LOCATELLI, P .SACERDOTE and A .E . PANERAI DEPT . PHARMACOLOGY, SCHOOL OF MEDICINE, UNIVERSITY OF MILANO, MILANO, ITALY .

It has been known for several years that substance P is involved in the symptomatic effects of arthritic diseases, mainly in the modulation of pain . The growing body of knowledge on the interactions between the nervous and immune systems lead to the hypothesis that substance P could be involved also in the immunological aspects of arthritic diseases (1) . It soon appeared clear that substance P can induce the chemotaxis of polymorphonuclear cells (PMN) and monocytes and the synthesis of cytokines (2) .Moreover, substance P is positively present in the synovial fluid of arthritic patients, where it could be delivered by free nerve terminals in the synovial tissue or by immune cells or bothways(3) .Since chemotaxis of PMN and monocytes is a crucial step of the development and maintainance of the arthritic disease, we thought it worthwhile to investigate the effect of non steroidal anti inflammatory drugs (NSAIDs) on the chemotactic effect of substance P on PMN and monocytes.We evaluated the effects of two NSAIDs : indomethacin and diclofenac, at the concentrations of 10-4 ,

10-6 , and 10 -8 M on the chemotactic effect of two concentrations of

substance p (10 -8 and 10-9 M) that are well whithin those reached by the neuropeptide in rheumatoid arthritis synovial fluid (Sacerdote et al . in preparation) . Figure 1 shows that both indomethacin and diclofenac inhibit the chemotactic response of PMN at the dose of 10 -4 M, while only diclofenac is effective at lower doses . In contrast, the chemotactic effect of monocytes toward substance P is blocked only by the highest dose of the two NSAIDs . The data we present suggest that the effect of NSAIDs (at concentrations that these drugs can reach in the synovial fluid) on the development and progress of arthritic diseases could involve their capacity of blocking the chemotactic activity of substance P .This mechanism may contribute to interrupt the pathological loop of SP-induced stimulation of leucocytes to produce cytokines,that themselves induce pain and the release of substance P from synovial free nerve terminals . It remains to be determined if this effect is shared by NSAIDs of different classes and whether the effect is mediated by the block of

1043-6618/92/2510097-02/$03 .00/0

© 1992 The Italian Pharmacological Society

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Upper panels : inhibitory effect of diclofenac (A) and indomethacin (B) on the PMN chemotaxis induced by 10 -8 ----and 10 -9 SP . Lower panels : effect of diclofenac (C) and indomethacin (D) on monocyte chemotaxis induced by SP (see upper panels for SP concentrations) . References 1)Mc Gillis, Mitsuhashi M .,Payan DG . Immunomodulation by tachikinin neuropeptides . In O'Dorisio MS,Panerai AE Neuropeptides and Immunopeptides, Annals NY Academy-Science,1990 . Vol 594 :8594 2)Kimball E .S, Persico FS, Waught JL .Substance P,neurokinin A,neurokinin B induce generation of IL-1 activity in P388D1 cells . J .Immunology 1988 .141 : 3564-69 3)Lotz M ., Carson DA, Vaughan JH,Substance P activation of rheumatoid synoviocytes :neural pathway in pathogenesis of arthritis . Science . 1985 : 235 :893-95

Effects of indomethacin and diclofenac on substance P induced chemotaxis of human monocytes and polymorphonuclear cells.

97 Pharmacological Research, Vol . 25, Supplement 1, 1992 EFFECTS OF INDOMETHACIN AND DICLOFENAC ON SUBSTANCE P INDUCED CHEMOTAXIS OF HUMAN MONOCYTE...
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