NOS inhibitors exhibit antinociceptive properties in the rat formalin test

Abstract

P Pu ur rp po os se e: : To assess the systemic and nociceptive effects of nitric oxide synthase (NOS) inhibitors in the modulation of acute pain in rats subjected to the formalin test.M Me et th ho od ds s: : Formalin 5% was injected in the hind paw in the presence and absence of NOS inhibitors (e.g., 7-nitro indazole, Nnitro-L-arginine and aminoguanidine). Catheters were chronically implanted to continuously record mean arterial blood pressure (MAP) and heart rate (HR). MAP, HR and paw lifting time were recorded at control and every five minutes for 35 min following formalin and NOS inhibitors.R Re es su ul lt ts s: : Formalin injected into the rat hind paw induced a biphasic nociceptive behaviour: an initial acute phase (phase 1: during zero to five minutes after the formalin injection) followed by a prolonged tonic response (phase 2: beginning about ten minutes after the formalin injection). Aminoguanidine, an inhibitor of the inducible NOS and 7-nitro indazole, an inhibitor of the neuronal NOS, did not affect phase 1, whereas N-nitro-L-arginine, a non-selective NOS inhibitor decreased it (49%). All three NOS inhibitors diminished nociceptive behaviours during phase 2. L-arginine reversed antinociceptive effects of N-nitro-L-arginine in phase 1 and in phase 2. Pressor effects induced by formalin in phase 1 were abolished following all three NOS inhibitors. During phase 2, formalininduced pressor effects remained unaffected by N-nitro-L-arginine and aminoguanidine but were inhibited by 7-nitro indazole.C Co on nc cl lu us si io on n: : Our data demonstrate that NO is predominantly generated by vascular endothelial NOS in phase 1 and phase 2, whereas the neuronal NOS and the inducible NOS exhibit antinociceptive effects through a non-NO related pathway in phases 1 and 2 in rats subjected to the formalin test. Objectif : Évaluer les effets généraux et nociceptifs des inhibiteurs de la nitric oxide synthase (NOS) dans la modulation de la douleur aiguë chez des rats soumis au test de formaline. Méthode : De la formaline à 5 % a été injectée dans la patte arrière de rats en présence ou non d'inhibiteurs de NOS (par ex., 7-nitro indazole, N-nitro-L-arginine et aminoguanidine). Des cathéters ont été implantés à demeure pour permettre l'enregistrement continu de la tension artérielle moyenne (TAM) et de la fréquence cardiaque (FC). La TAM, la FC et le temps d'élévation de la patte ont été notés au temps témoin et aux cinq minutes pendant 35 min après l'administration de formaline et d'inhibiteurs de NOS. Résultats : La formaline injectée dans la patte arrière des rats a induit un comportement nociceptif biphasique : une phase aiguë initiale (phase 1 : de zéro à cinq minutes après l'injection de formaline) suivie d'une réponse tonique prolongée (phase 2 : débutant environ dix minutes après l'injection de formaline). L'aminoguanidine, un inhibiteur de la NOS inductible et le 7-nitro indazole, un inhibiteur de la NOS neuronale, n'ont pas modifié la phase 1, tandis que la N-nitro-L-arginine, un inhibiteur de NOS non sél...

Synergistic interaction between meloxicam and aminoguanidine in formalin‐induced nociception in mice

“…Previously, it has been demonstrated that nitric oxide is responsible for nociceptive behaviour in second phase of formalin‐induced nociception in mice (Moore et al, 1993). The second phase is inhibited by both COX‐2 inhibitor meloxicam and iNOS inhibitor aminoguanidine and the present results substantiate earlier observations (Doursout et al, 2003; Dudhgaonkar et al, 2004).…”

Endothelial Nitric Oxide Synthase in Dorsal Root Ganglia during Chronic Inflammatory Nociception

“…The compensatory effect of the different NOS isoforms was suggested by other studies [Boettger et al, 2007]. These findings agree with other works that underline the role of eNOS in nociception; some studies performed on knockout mice as well as studies using different selective and nonselective NOS inhibitors point to a possible role for the eNOS isoform in pain processing [Doursout et al, 2003;Boettger et al, 2007]. Indeed, Doursout et al [2003] stated that eNOS plays a crucial role in inflammatory phases in response to formalin injection.…”

Nitric Oxide is Negatively Correlated to Pain during Acute Inflammation

“…In the present study, the three NOS isoforms were expressed in the gingival mucosa, following tissue injury. While both nNOS [16,17,27] and iNOS [27,28] are frequently suggested to play an important pronociceptive role in several pain models, eNOS is not often studied. However, it was reported that eNOS was the only isoform involved in both phases of the rat formalin test [17] and eNOS -/- mice showed a more rapid recovery from thermal hyperalgesia compared to wild type mice after intraplantar injection of complete Freund's adjuvant [16].…”

“…While both nNOS [16,17,27] and iNOS [27,28] are frequently suggested to play an important pronociceptive role in several pain models, eNOS is not often studied. However, it was reported that eNOS was the only isoform involved in both phases of the rat formalin test [17] and eNOS -/- mice showed a more rapid recovery from thermal hyperalgesia compared to wild type mice after intraplantar injection of complete Freund's adjuvant [16]. Interpretation of findings in NOS -/- mice is compromised by the compensation of other isoforms for the deficient isoform [16,29,30], at least at the spinal level.…”