ANTINOCICEPTIVE PROFILE OF THE PSEUDOPEPTIDE B-2 BRADYKININ RECEPTOR ANTAGONIST NPC-18688 IN MICE

1 The purpose of this study was to investigate the topical and systemi c anti-hyperalgesic effect of the newly-developed pseudopeptide B-2 re ceptor antagonist, NPC 18688, in different models of nociception in mi ce. 2 Given systemically 30 min beforehand, NPC 18688 (10-300 nmol kg( -1), i.p.) caused no agonist effect, but produced a dose-related and s ignificant inhibition of abdominal constrictions caused by intraperito neal injection of acetic acid (0.6%), acetylcholine (ACh, 4.5 mg kg(-1 )) or kaolin (50 mg kg(-1)). The calculated mean ID(50)s and the perce ntages of maximal inhibitions (MI) for these effects were: 77, 34 and >300 nmol kg(-1) and 65+/-6, 70+/-5 and 40+/-3%, respectively. The ant i-hyperalgesic effect of NPC 18688 (100 nmol kg(-1), i.p.) occurred ra pidly (30 min) and lasted for at least 150 min. Hoe 140 (3-30 nmol kg( -1) i.p) given 30 min beforehand also inhibited, in a graded manner, a cetic acid and ACh-induced writhing, with mean ID(50)s and MI of 6 and 9 nmol kg(-1) and 56+/-7 and 62+/-6%, respectively. 3 NPC 18688 (10-3 00 nmol kg(-1), i.p.) caused a graded inhibition of both phases of for malin (2.5%)-induced pain, its effects being more potent in relation t o the second phase of the formalin test. The calculated mean ID(50)s a nd the MI were >300 and 60 nmol kg(-1) and 20+/-3 and 60+/-5% against the first and second phases of formalin-induced nociception, respectiv ely. NPC 18688 at the same doses also inhibited, in a dose-related man ner, formalin-induced paw oedema (MI of 35+/-3%). 4 When injected loca lly in the mouse paw, NPC 18688 (2, 10 and 20 nmol/paw) had no agonist activity. However, when co-injected with formalin NPC 18688 (2-20 nmo l/paw), it produced significant inhibition of both phases of formalin response, with MI of 40+/-3 and 33+/-2%, respectively. NPC 18688 at 10 nmol/paw also significantly inhibited formalin-induced paw oedema (25 +/-2%). 5 Given intraperitoneally, NPC 18688 (30-300 nmol kg(-1)) dete rmined a graded inhibition of the nociceptive response caused by intra plantar injection of capsaicin (1.6 mu g/paw) (40+/-2%). However, NPC 18688 (up to 300 nmol kg(-1), i.p.), given 30 min beforehand, had no s ignificant analgesic effect when analyzed in the tail flick and in the hot plate pain models, nor did it change the performance of animals i n the rota rod test. 6 The action of NPC 18688 was quite selective for the B-2 receptor, and like Hoe 140, (1 to 100 nmol kg(-1), i.p.) it c aused graded inhibition of bradykinin (BK, 3 mol/paw)-induced increase in mouse paw volume, with mean ID(50)s of 61 and 6 nmol kg(-1), respe ctively. In addition, at 100 nmol kg(-1) the dose at which NPC 18688 s ignificantly antagonized BK (3 nmol)-mediated rat paw oedema in naive animals, it had no significant effect on des-Arg(9)-BK (100 nmol/paw)- induced oedema in paws that had been desensitized to BK. NPC 18688 (21 0 nmol kg(-1)), like Hoe 140 (230 nmol kg(-1)) given s.c. 30 min befor ehand, completely abolished BK (28 nmol)-induced hypotension, without affecting the fall of mean arterial blood pressure induced by i.v. inj ection of ACh (2 nmol kg(-1)). Finally, NPC 18688 (1 mu M) did not aff ect ACh-mediated contraction in the guinea-pig ileum or toad rectus ab dominii in vitro. 7 These results demonstrate that the newly-developed and selective pseudopeptide B-2 receptor antagonist, NPC 18688, altho ugh less potent than the available second generation of B-2 peptide BK receptor antagonists, exhibits topical and long-lasting systemic anti -hyperalgesic properties when analysed in several models of nociceptio n in mice, making it a useful tool for investigating the participation of BK and related kinins in physiological and pathological processes. Finally, this new class of selective pseudopeptide B-2 receptor antag onist may constitute a new strategy for developing the third generatio n of potent and long-lasting orally-active non-peptide BK antagonists, which may be useful for the management of clinical disorders involvin g BK and related kinins.