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Central versus peripheral site of action of the tachykinin NK 1 ‐antagonist RP 67580 in inhibiting chemonociception
Author(s) -
HolzerPetsche Ulrike,
RordorfNikolić Tamara
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16359.x
Subject(s) - capsaicin , substance p , nociception , reflex , tachykinin receptor , nk1 receptor antagonist , antagonist , medicine , endocrinology , prostaglandin , sensitization , chemistry , receptor , anesthesia , pharmacology , neuropeptide , immunology
1 Many studies indicate an involvement of substance P in the transmission of nociceptive stimuli, without, however, presenting any conclusive evidence as to its exact site and mode of action. The present experiments tested the involvement of substance P in the mediation of chemical nociception using the non‐peptidic specific tachykinin NK 1 ‐receptor antagonist, RP 67580 (2‐[1‐imino‐2‐(2‐methoxyphenyl‐ethyl]‐7, 7diphenyl‐4‐perhydroisoindolone (3a R , 7a R )). 2 Mean arterial pressure (MAP) and intragastric pressure (IGP) were measured in anaesthetized rats. The reflex changes of these parameters in response to i.p. or s.c. injections of hydrochloric acid or capsaicin were taken to indicate nociception. 3 Intravenous administration of RP 67580 up to 5 mg kg −1 had little influence on the reflex changes in MAP or IGP in response to hydrochloric acid or capsaicin. In contrast, the sensitization of rats to i.p. capsaicin by preinjection of prostaglandin E 2 was significantly reduced by 1 mg kg −1 RP 67580. 4 Intrathecal injection of 5 μg RP 67580 inhibited the reflex changes of MAP and IGP in response to i.p. or s.c. capsaicin whereas the inactive enantiomer RP 68651 was ineffective. 5 The results indicate that spinal NK 1 ‐receptors are involved in the acute transmission of chemically induced pain, while such receptors in the periphery take part in the sensitization by prostaglandin E 2 . The rather minor ability of i.v. RP 67580 to inhibit the acute nociceptive reflex is attributed to an insufficient penetration of the blood‐brain‐barrier.