NOC-9, a selective nitric oxide donor, induces flight reactions in the dorsolateral periaqueductal gray of rats by activating soluble guanylate cyclase.
Previous studies have showed that SIN-1, a nitric oxide (NO) donor, injected into the dorsolateral column of the periaqueductal gray (dlPAG) induces flight reactions. This drug, however, can also produce peroxynitrite, which may interfere in this effect. In addition, it is also unknown if this effect is mediated by local activation of soluble guanylate cyclase (sGC). The aims of this study, therefore, were (1) to investigate if NOC-9 (6-(2-Hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine), a NO donor that does not produce peroxynitrite, would produce flight reactions after intra-dlPAG administration similar to those induced by SIN-1; (2) to verify if these responses could be prevented by local injection of a selective guanylate cyclase inhibitor (ODQ). Male Wistar rats (n=5-12) with cannulae aimed at the dlPAG received injections of TRIS (pH 10.0, 0.5 microl), NOC-9 (75 and 150 nmol), saline or SIN-1 (200 nmol) and were placed in an open arena for 10 min. In a subsequent experiment animals (n=7-8) were pretreated with ODQ (1 nmol/0.5 microl) before receiving NOC-9 150 nmol. NOC-9 induced a significant dose-dependent increase in flight reactions in the first minute after injection (% of animals displaying flight: vehicle=0%, NOC 75=67%, NOC 150=75%). SIN-1 had a similar effect (100% of animals showing flight) but the effects lasted longer (10 min) than those of NOC-9. The effect of NOC-9 (150 nmol) was prevented by pretreatment with ODQ (% of animals displaying flight: vehicle+NOC 150=71%, ODQ+NOC 150=37%). The results suggest that NO donors injected into the dlPAG induce defensive responses that are not mediated by secondary peroxynitrite production. Moreover, they also indicate that these defensive responses depend on activation of local sGC. The data strengthen the proposal that NO can modulate defensive reactions in the dlPAG.
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP 14049900, Brazil.
Andréa Arantes
AA
Braga
Daniele Cristina
DC
Aguiar
Francisco Silveira
FS
Guimarães
D000818:Animals; D002404:Catheterization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004924:Escape Reaction / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D008981:Molsidomine / Q000008:administration & dosage / Q000031:analogs & derivatives; D009043:Motor Activity / Q000187:drug effects; D015999:Multivariate Analysis; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010069:Oxadiazoles / Q000008:administration & dosage; D010487:Periaqueductal Gray / Q000187:drug effects*; D011810:Quinoxalines / Q000008:administration & dosage; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014226:Triazenes / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D014226:Triazenes; C099612:NOC 9; C002385:linsidomine; D008981:Molsidomine; D006162:Guanylate Cyclase