Role of Nitric-Oxide Synthase Isoforms in Nitrous Oxide Antinociception in Mice

Abstract

Exposure of mice to the anesthetic gas N 2 O evokes a prominent antinociceptive effect that is sensitive to antagonism by nonselective nitric-oxide synthase (NOS) inhibitors. The present study was conducted to identify whether a specific NOS isoform is implicated in N 2 O antinociception in mice. In the abdominal constriction test, exposure of mice to 25, 50, and 70% N 2 O resulted in a concentration-dependent antinociceptive effect that persisted for up to 6 min following removal of the mice from the N 2 O atmosphere into room air. This N 2 O antinociceptive effect was antagonized by pretreatment with S-methyl-Lthiocitrulline (SMTC) and higher doses of L-N 5 -(1-iminoethyl)-ornithine (L-NIO), which reportedly inhibit the neuronal and endothelial isoforms of NOS, respectively. Nevertheless, the N 2 O-induced antinociception was unaffected by pretreatment with low doses of either SMTC or L-NIO or by pretreatment with 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), which selectively inhibits inducible NOS. The s.c. pretreatment with SMTC and L-NIO reduced brain NOS activity in a dose-dependent manner, whereas AMT had no such effect. Moreover, in blood pressure experiments, SMTC increased SBP in doseunrelated fashion, whereas L-NIO showed an appreciably weaker but dose-related increase in SBP. The i.c.v. pretreatment with SMTC also reduced N 2 O antinociception and brain NOS activity without increasing of SBP. These results suggest that it is the neuronal isoform of NOS that is involved in mediation of the antinociceptive effect of N 2 O in the mice.

Differential involvement of various sources of reactive oxygen species in thyroxin-induced hemodynamic changes and contractile dysfunction of the heart and diaphragm muscles

“…Whereas eNOS-derived NO consistently shows a protective role in hypertension [36,37], there are, however, some inconsistencies in the literature regarding the role of nNOS- and iNOS-derived NO in BP regulation. For instance, several reports show decreased BP after nNOS inhibition [36,38,39], whereas others show the opposite [40–42]. Likewise, some studies describe a role for iNOS in the pathogenesis of hypertension [37,43,44] even as other studies show protective effects [45–47].…”

Assessment of heat production, heat loss, and core temperature during nitrous oxide exposure: a new paradigm for studying drug effects and opponent responses

“…The neurochemical mediators through which inhaled N 2 O might increase peripheral blood flow could involve nitric oxide (NO), a potent vasodilator with an important role in blood flow distribution (69). A role for NO in N 2 Oaugmented heat dissipation seems plausible in part because Quock and colleagues (7,26,28) have implicated NO in other N 2 O effects, specifically its antinociceptive and anxiolytic effects. Additionally, because hypoxia-induced hypothermia is attenuated by microinjection of a NO synthesis inhibitor in the preoptic hypothalamus (65), it is possible that central as well as peripheral NO release could participate in mediating the hypothermic effect of N 2 O.…”

Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the midbrain

“…NOS activity is apparently critical to the antinociceptive response to N 2 O since N 2 O-induced antinociception in rats and mice is blocked by pretreatment with any of a variety of NOS-inhibiting arginine analogs (McDonald et al, 1994;Ishikawa and Quock, 2003a) and also by pretreatment with an antisense oligodeoxynucleotide directed against the neuronal NOS enzyme (Li et al, 2004). Moreover, DBA/2 inbred mice that are poorly sensitive to N 2 O-induced antinociception failed to exhibit an increase in NOS enzyme activity during exposure to N 2 O when compared to N 2 O-sensitive C57BL/6 mice (Ishikawa and Quock, 2003b;Henry et al, 2005).…”

“…We have previously reported that the antinociceptive effect of N 2 O is also antagonized by inhibition of nitric oxide (NO) production (McDonald et al, 1994;Ishikawa and Quock, 2003a;Li et al, 2004), implicating an involvement of NO in the drug effect as well. The present study was conducted to ascertain whether the opioid receptors and NO function that are involved in N 2 O-induced antinociception are co-localized in the periaqueductal gray (PAG) of the midbrain, which has been shown to be involved in N 2 O-induced antinociception (Zuniga et al, 1987;Hodges et al, 1994;Fang et al, 1997).…”