Nitrous oxide generalizes to a discriminative stimulus produced by ethylketocyclazocine but not morphine.

The discriminative stimulus properties of nitrous oxide, an analgesic and anesthetic gas, were evaluated in rats trained to discriminate the effects of morphine or ethylketocyclazocine. Administration of nitrous oxide in concentrations as high as 80 percent did not produce generalization to the discriminative cue produced by morphine. Nitrous oxide did, however, generalize in a concentration-dependent manner in rats trained to discriminate ethylketocyclazocine, a psychotomimetic opioid. Naltrexone, a potent narcotic antagonist, did not block the generalization of nitrous oxide to ethylketocyclazocine. These results suggest that the subjective effects of nitrous oxide are similar to those produced by psychotomimetic drugs rather than those produced by morphine. These findings are in close agreement with those generated in man. Thus, nitrous oxide exhibits some pharmacological properties similar to those of morphine, for example, naloxone reversible analgesia. Yet, it has other properties such as subjective effects that are dissimilar from morphine.

Evidence that ethanol-induced impairment of roto-rod performance is not mediated by opioid mechanisms.

1. The performance of mice, trained to remain on a roto-rod, was significantly impaired by both morphine and ethanol. The behavioral impairment was dose dependent. 2. Naloxone (10, 30 and 100 mg/kg) was found to antagonize only the morphine-induced impairment of roto-rod performance. 3. Animals made tolerant to morphine did not perform better than non-tolerant animals when challenged with ethanol, but did perform better when challenged with morphine. As such, no cross tolerance developed between ethanol and morphine in this model. 4. These results suggest that the ethanol-induced impairment of roto-rod performance is not mediated via opioid mechanisms.

Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors.

The analgesic effect of morphine in the rat tail jerk assay was enhanced by the serotonin uptake inhibitor, fluoxetine. Tail jerk latency was not affected by fluoxetine alone. Morphine's affinity for opioid receptors labeled in vitro with 3H-naloxone or 3H-D-Ala2-D-Leu5-enkephalin was not altered by fluoxetine, which has no affinity for these sites at concentrations as high as 1000 nM. In rats trained to discriminate morphine from saline, fluoxetine at doses of 5 or 10 mg/kg were recognized as saline. Increasing the fluoxetine dose to 20 mg/kg did not result in generalization to either saline or morphine. The dose response curve for morphine generalization was not significantly altered by fluoxetine doses of 5 or 10 mg/kg. Those rats treated with the combination of morphine and 20 mg/kg of fluoxetine did not exhibit saline or morphine appropriate responding. Fluoxetine potentiates the analgesic properties of morphine without enhancing its affinity for opioid receptors or its discriminative stimulus properties.

Chronic ethanol alters the receptor binding characteristics of the delta opioid receptor ligand, D-Ala2-D-Leu5 enkephalin in mouse brain.

The binding characteristics of the delta opioid receptor ligand, 3H-D-Ala2-D-Leu5 enkephalin, were markedly altered in brains obtained from mice fed an ethanol-containing diet for five days. Control mice exhibited both a high and low affinity site for 3H-D-Ala2-D-Leu5 enkephalin, whereas those consuming the ethanol diet were found to possess only one binding site. This singular site has an intermediate KD value with an increase in receptor number when compared to the high and low affinity sites observed in control mice. The in vitro addition of ethanol to a brain membrane preparation obtained from untreated mice, at a concentration equivalent to that found in the blood of the ethanol-treated mice, did not markedly affect D-Ala2-D-Leu5 enkephalin binding characteristics. No alteration in the binding characteristics of 3H-naloxone, a mu receptor ligand, was noted following five days of ethanol consumption. Mice maintained on the ethanol-containing diet were tolerant to the activity-stimulating effects of acute ethanol administration. These results suggest that mice consuming an ethanol diet in sufficient quantities to render them tolerant exhibit a specific loss of a 3H-D-Ala2-D-Leu5 enkephalin binding site, while the binding of 3H-naloxone was unchanged.

Differential effects of selected dopaminergic agents on locomotor activity in normotensive and spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) exhibit a significantly higher level of spontaneous locomotor activity than age-matched normotensive controls (WKY). The direct-acting dopamine agonists, apomorphine and pergolide, produced a biphasic effect on locomotor activity levels in normotensive controls. Low doses of these agonists decreased activity levels, while higher doses of these agonists dramatically stimulated activity. In marked contrast to these results was the effect observed in the SHR, in which these agonists at all doses tested decreased activity. Amphetamine, a dopamine releaser, stimulated activity levels in both the WKY and SHR; however, the magnitude of the increase was somewhat attenuated in the SHR.