Raymond M. Quock

Influence of narcotic antagonist drugs upon nitrous oxide analgesia in mice

Nitrous oxide produced a concentration-related suppression of phenylquinone-induced abdominal constriction in mice. This analgesic effect was significantly reduced (but not abolished) by systemic pretreatment with (-)-naloxone or naltrexone but not (+)-naloxone. Systemic pretreatment with methylnaltrexone failed to appreciably influence nitrous oxide analgesia; however, methylnatrexone, administered centrally, significantly attenuated the drug effect. Furthermore, nitrous oxide analgesia was significantly reduced by MR-2266 (which is relatively selective for kappa-opioid receptors) but not by beta-funaltrexamine (which is selective for mu-opioid receptors) at the doses employed in this study. These findings suggest that nitrous oxide analgesia might involve an activation of kappa-opioid receptors in the central nervous system; however, a possible involvement of mu-opioid receptors is not absolutely precluded by this study.

Comparison of nitrous oxide morphine and diazepam effects in the mouse staircase test

Mice were exposed for 10–20 min to room air, 100% oxygen (O2) or increasing concentrations of nitrous oxide (N2O) in O2, then tested for 3 min in a staircase inside a glovebag. N2O produced a concentration-dependent increase in the number of steps ascended (NSA) but no change in the number of rears (NR). Pretreatment with naloxone reversed the increase in NSA and also unmasked N2O reduction in NR. By comparison, increasing doses of the narcotic standard morphine reduced NSA and NR; these changes in NSA and NR were sensitive to antagonism by naloxone. The benzodiazepine standard diazepam produced a dose-related reduction in NR while reducing NSA only at higher doses. These data indicate that N2O influences on NSA and NR resemble neither morphine nor diazepam. In addition, it appears that the opioid activity of N2O might mask its antianxiety activity in this particular paradigm.

Interaction between nitrous oxide and diazepam in the mouse staircase test.

The interaction between nitrous oxide and diazepam was assessed in the mouse staircase test. In this paradigm, the numbers of rears (NR) (simultaneous standing on hindlegs and sniffing the air) and steps ascended (NSA) reflect anxiety and locomotor activity, respectively. Antianxiety drugs characteristically reduce NR but not NSA, while sedative drugs reduce both NR and NSA in generally parallel fashion. In this study, increasing concentrations of nitrous oxide alone produced progressively greater and statistically significant increases in NSA. Nitrous oxide alone had no significant effect on NR until, at a concentration of 75%, it decreased NR. Diazepam alone decreased NR equally and significantly at all doses. With certain combinations of concentration and dose, nitrous oxide enhanced the effect of diazepam on NR without altering NSA. These findings suggest that nitrous oxide can increase the antianxiety effect of diazepam without increasing its sedative effect in the mouse staircase paradigm.

Effects of benzodiazepine agonist, inverse agonist and antagonist drugs in the mouse staircase test

This study examined the effects of the benzodiazepine agonist midazolam and inverse agonist noreleagnine independently and in conjunction with the antagonist flumazenil in the mouse staircase test. According to this paradigm, the numbers of steps ascended (NSA) and rears (NR) reflect locomotor activity and anxiety, respectively. Midazolam reduced NR at doses that did not affect NSA; this NR-lowering effect was blocked by flumazenil. Noreleagnine increased NR at doses that did not affect NSA; this NR-elevating effect was also blocked by flumazenil. Effective antagonist doses of flumazenil alone had no effect on NR or NSA. The exactly opposite effects of midazolam and noreleagnine on NR and their antagonism by flumazenil are consistent with the postulated activities of these drugs at benzodiazepine receptors.

Influence of chronic naloxone treatment on development of hypertension in the spontaneously hypertensive rat

SummaryChronic administration of naloxone by means of miniosmotic pumps retarded the development of hypertension in young spontaneously hypertensive rats (SHRs) in a dose-related manner. Abrupt termination of naloxone treatment resulted in acceleration in the rate of the blood pressure increase, while increasing the naloxone concentration further slowed the development of hypertension in SHRs. The heart rates of SHRs undergoing chronic naloxone treatment were generally lower than those of control SHRs. Naloxone had no influence upon the mean systeolic blood pressures or heart rates of normotensive Wistar-Kyoto control rats. These findings indicate that chronic naloxone treatment can alter the development of hypertension in the SHR.

Sex and strain differences in morphine-induced temperature effects in WKYs and SHRs.

Male and female normotensive Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) all responded to morphine treatment with biphasic dose-response curves, exhibiting hyperthermia at low doses and hypothermia at higher doses. However the direction and magnitude of temperature changes induced by different doses of morphine varied significantly depending upon the sex and strain (WKY vs. SHR) of the test animals. Both WKY and SHR males responded with little change in temperature at 1.0 mg/kg and hyperthermia at 5.0 mg/kg. Hypothermia appeared in SHR males at 10 mg/kg, while hypothermia in WKY males was not seen until 20 mg/kg was administered. Both WKY and SHR females demonstrated a greater sensitivity than their male counterparts to the thermotropic effects of morphine, exhibiting hyperthermia at 1.0 mg/kg, which was greater than the hyperthermia exhibited by male rats, and progressively greater hypothermia at 2.0, 5.0 and 10 mg/kg. SHR females demonstrated hypothermia at lower doses of morphine than did WKY females but were otherwise not different. These findings indicate that (1) morphine-induced temperature effects in SHRs and WKYs are dependent upon dose; (2) SHRs seem more sensitive than WKYs to the hypothermic effects of morphine; and (3) female rats seem more sensitive than male rats to the thermotropic effects of morphine in general.

Strain-dependent differences in responsiveness of mice to nitrous oxide (N2O) antinociception

N2O antinociception was assessed in eight inbred and two outbred mouse strains. Results indicated the following order of responsiveness among the 10 strains: A/J (most sensitive), C57BL/6ByJ, C57BL/6J, BALB/cByJ, C3H/HeJ, Swiss-Webster, CXBK/ByJ, ICR, CBA/J and DBA/2J (least sensitive). These results demonstrate significant strain-dependent differences in antinociceptive responsiveness to N2O. The weak antinociceptive response to N2O in the DBA/2J strain, which is sensitive to morphine and U-50, 488H, indicates some underlying neurobiological difference in the DBA/2J mouse that imparts resistance to N2O. The responsiveness of CXBK/ByJ mice to N2O indicates that mu-opioid receptors may not play an important role in N2O antinociception in mice.

Potentiation of apomorphine-induced stereotypies by naloxone and L-prolyl-L-leucyl-glycinamide

We compared the influences of pretreatment with the narcotic antagonist drug naloxone and the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) upon apomorphine-induced stereotypic climbing activity in mice and apomorphine-induced contralateral rotational behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. Naloxone produced dose-related potentiation in the mouse climbing model, while PLG was without effect. On the other hand, PLG produced dose-related potentiation in the rat rotational paradigm, while naloxone was without appreciable influence. These findings show an asymmetrical potentiation of apomorphine by naloxone and PLG in these two standard experimental models of striatal dopaminergic activity.

Enhancement of apomorphine-induced climbing in mice by reversible and irreversible narcotic antagonist drugs

Abstract Apomorphine produced a characteristic climbing syndrome in mice. Pretreatment of mice with increasing doses of the reversible narcotic antagonist naloxone resulted in a dose-related enhancement of this activity. Central microinjection of mice with the irreversible narcotic antagonist drug chlornaltrexamine also resulted in significant potentiation of apomorphine-induced climbing for up to fourteen days following pretreatment. These data indicate that narcotic antagonist drugs of both reversible and irreversible types are capable of enhancing this dopaminergic drug effect in mice.

Nitrous oxide-induced hypothermia in the rat

Exposure of rats to high levels of nitrous oxide (N2O) in oxygen (O2) reduced body temperature in a concentration-related manner. The hypothermia was partly reversed by pretreatment with naloxone but not naltrexone. But in rats rendered tolerant to morphine by pellet implantation, exposure to 75% N2O/25% O2 evoked a marked hypothermia similar to that observed in morphine-naive animals. In another experiment, the hypothermic effect of chloral hydrate was also sensitive to antagonism by pretreatment with naloxone but not naltrexone. These observations lead us to suspect that N2O-induced hypothermia in rats is possibly not mediated by opiate receptors. The thermotropic activity of N2O may result from some non-opioid action of N2O. Its selective antagonism by naloxone (but not naltrexone) may be due to a unique non-opioid analeptic action of naloxone.