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Involvement of substance P in the anti‐inflammatory effects of the peripherally selective κ‐opioid asimadoline and the NK 1 antagonist GR205171
Author(s) -
Binder Waltraud,
Scott Caroline,
Walker Judith S.
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00625.x
Subject(s) - antagonist , pharmacology , opioid antagonist , opioid , nk1 receptor antagonist , substance p , medicine , (+) naloxone , receptor , neuropeptide
We have previously shown that kappa‐opioids have antiarthritic properties. In this study, using two differently acting drugs (the peripherally selective κ‐agonist, asimadoline, and the NK 1 ‐antagonist, GR205171), we have examined possible roles of the neuropeptide substance P (SP) in the pathogenesis and maintenance of experimental arthritis in rats. The anti‐inflammatory actions and the time dependence of these drugs were compared, and concentrations of SP determined in joint tissue. In untreated animals, SP levels in ankle joint tissue increased late in the disease (by day 21) but substantially lagged behind development of clinical disease. Prolonged (days 1–21 or days 12–18) but not early, short‐term (days 1–3) treatment with the NK 1 ‐antagonist GR205171 (1 mg/kg/day i.p.) significantly attenuated joint damage; SP levels showed multiphasic dose dependence over the 21‐day treatment. The data suggest that GR205171 antagonizes the action of SP by presynaptic as well as postsynaptic mechanisms. Treatment with asimadoline (5 mg/kg/day i.p.) produced marked (and sustained) attenuation of the disease with all three time regimes. The effect of asimadoline on SP levels was time dependent: reduction of SP content after 3 days but an increase after 12 or 21 days treatment, paradoxically with clinical improvement in each case. Drug‐induced changes in SP content could follow from changed release or synthesis from either neural or immune cells. The results suggest that both drugs have potential therapeutic value at different stages of inflammatory joint disease.