1 7-Nitro indazole (7-NI, 10-50mgkg-'), 6-nitro indazole and indazole (25-100mgkg-') administered i.p. in the mouse produce dose-related antinociception in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays. The EDm values (mg kg-') were as follows: 7-NI (27.5 and 22.5), 6-nitro indazole (62.5 and 44.0) and indazole (41.0 and 48.5) in the two assays respectively. 3-Indazolinone, 6 amino indazole and 6-sulphanilimido indazole (all 50 mg kg-') were without effect. With the exception of 5-nitro indazole (50 mg kg-') which produced sedation, none of the other indazole derivates examined caused overt behavioural changes. 2 The antinociceptive effect of 7-NI (25 mg kg-', i.p.) in the late phase of the formalin-induced hindpaw licking assay was partially (46.7 ± 16.2%, n = 18) reversed by pretreatment with L-but not D-arginine (both 50 mg kg', i.p.). 3 The time course of 7-NI induced antinociception in the mouse was correlated with inhibition of brain (cerebellum) nitric oxide synthase (NOS) activity. Maximum antinociceptive activity and NOS inhibition were detected 18-30 min following i.p. administration. In contrast, no antinociceptive effect or inhibition of cerebellar NOS was detected 75 min post-injection. 4 7-NI, 6-nitro indazole, indazole, 3-indazolinone and 6-amino indazole (all 50 mg kg-') failed to influence mean arterial pressure (MAP) over the 45 min after i.p. administration in the anaesthetized mouse. Similarly, 7-NI (25 mg kg-') administered i.v. in the anaesthetized rat did not increase MAP or influence the vasodepressor effect of i.v. injected acetylcholine (ACh) over the same period. 0.06 fLM, n = 6) in phenylephrine-precontracted rabbit aortic rings. 6 These data provide further evidence that antinociception following administration of 7-NI in the mouse results from inhibition of central NOS activity and is not associated with inhibition of in vivo vascular endothelial cells NOS. Accordingly, 7-NI (or a derivative thereof) may provide an alternative approach to the development of novel antinociceptive drugs.

0.47 tiM. Following i.p. administration in mice, 7-NI (10-50 mg kg-') produces dose-related antinociception as evidenced by an inhibition of late phase (15-30 min) but not early phase (0-5 min) hindpaw licking time following subplantar injection of formalin (10 pl, 5% v/v). The ED50 for this effect was 26 mg kg-' (equivalent to 159.5 pmol kg-'). Similar i.p. administration of 7-NI (20 and 80 mg kg-') in urethane-anaesthetized mice failed to increase MAP. Thus, 7-NI is a novel inhibitor of NOS which exhibits selectivity for the brain enzyme. Accordingly, 7-NI may be a useful starting point for the development of selective, centrally acting NOS inhibitors devoid of cardiovascular side effects and as a tool to study the central pharmacological effects of nitric oxide (NO).