A NONPEPTIDE NK1-RECEPTOR ANTAGONIST, RP-67580, INHIBITS NEUROGENIC INFLAMMATION POSTSYNAPTICALLY

1 The non-peptide neurokinin NK1-receptor antagonist, RP 67580 (3aR, 7 aR), a perhydroisoindolone derivative, powerfully reduced plasma extra vasation in rat hind paw skin induced by local application of xylene ( ID50 = 0.03 mg kg-1, i.v.) or capsaicin (ID50 = 0.06 mg kg-1, i.v.), o r by i.v. injection of exogenous substance P (SP) or septide ([pGlu6,P ro9]SP(6-11)) (ID50 = 0.04-0.05 mg kg-1, i.v.). RP 67580 (I mg kg-1, i .v.) also abolished capsaicin-induced nasal fluid hypersecretion (by 8 2 +/- 5%). These effects were found to be stereospecific, the enantiom er, RP 68651 (3aS, 7aS), being inactive at 1 mg kg-1, i.v. 2 In rats n eonatally treated with capsaicin (50 mg kg-1, s.c.), plasma extravasat ion induced by SP was significantly increased (by 43 +/- 7%). RP 67580 (I mg kg-1, i.v.) completely inhibited the SP-induced plasma extravas ation in capsaicin neonatally treated-animals, as it did in control an imals. This result suggests that RP 67580 acts at the postsynaptic lev el for the inhibition of plasma extravasation. 3 Opioid receptor agoni sts, mu-(morphine) and kappa-(PD-117302) at 10 mg kg-1, s.c., in contr ast to NK1-receptor antagonists, did not inhibit plasma extravasation induced by exogenous SP. They were, however, partially effective again st plasma extravasation induced by electrical nerve stimulation (74 +/ - 4% and 48 +/- 9% inhibition at 10 mg kg-1, s.c. of morphine and PD-1 17302, respectively, compared to 90 +/- 3% inhibition obtained with R P 67580, 3 mg kg-1, s.c.). These results indicate the presynaptic acti on of opioid receptor agonists, in contrast to the postsynaptic action of NK1-receptor antagonists for the inhibition of plasma extravasatio n. 4 Ligature of the saphenous nerve distal to the point of electrical stimulation, local application of lignocaine to the saphenous nerve, neonatal capsaicin pretreatment, and colchicine at very low doses (120 mug kg-1 day-1 given for 3 days) were found to prevent plasma extrava sation elicited by electrical nerve stimulation. 5 The foregoing resul ts demonstrate that the non-peptide NK1-receptor antagonist, RP67580, is a potent inhibitor of plasma extravasation induced in skin by NK1-r eceptor agonists, by local application of chemical irritants (capsaici n or xylene) or by electrical nerve stimulation. Moreover, opioid rece ptor agonists and colchicine inhibit plasma extravasation induced by e lectrical nerve stimulation but not that elicited by exogenous SP. The refore, it is possible to inhibit neurogenic inflammation either at th e presynaptic level with opioid receptor agonists and colchicine, or a t the postsynaptic level with NK1-receptor antagonists, and that the n ew non-peptide NK1-receptor antagonists may have a great potential for alleviation of inflammation in various pathological syndromes in man.