London SW3 6LX 1 L-NG-nitro arginine methyl ester (L-NAME, 1-75mgkg-1) administered intraperitoneally (i.p.) elicits dose-related antinociception in the mouse assessed by the formalin-induced paw licking procedure. Antinociceptive activity is still present 24 h after injection. L-NAME (75 mg kg 1, i.p.) is also antinociceptive in the acetic acid-induced abdominal constriction and hot plate procedures. 2 L-NAME additionally produces a dose-related inhibition of formalin-induced paw licking following intracerebroventricular (i.c.v., 0.1-I00jig per mouse) and oral (p.o., 75-lSOmgkg -) administration.3 L-Arginine (600mg kg-, i.p.) but not D-arginine (600mg kg 1) or naloxone (5 mgkg ')reverses the antinociceptive effect of L-NAME in the formalin test. 4 High doses of L-NAME (37.5-600mgkg-1) but not D-NAME (75mgkg-1) administered i.p. produce dose-related increases in blood pressure of the urethane-anaesthetized mouse whilst i.c.v. injected L-NAME (0.1 and lOO1pg per mouse) is inactive.5 L-NAME (75 mgkg-1, i.p.) did not inhibit oedema formation in the formalin-injected mouse hindpaw. 6 L-NAME (75mgkg-1) did not produce any overt behavioural changes in treated mice and failed to influence locomotor activity or the incidence of dipping, crossing, rearing or circling behaviour assessed by a modified 'head-dipping' board procedure. A high dose of L-NAME (600mgkg-1) reduced dipping behaviour and locomotor activity suggesting a possible sedative effect. D-NAME (600mgkg 1) was inactive. 7 These results suggest that L-NAME produces an opioid-independent and long-lasting antinociception in the mouse most probably by a direct effect within the central nervous system.
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.
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