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We have examined the role of benzodiazepine receptors in nitrous oxide-induced neuronal depression in rats. The changes in neuronal excitability induced by nitrous oxide and the benzodiazepine inverse agonist, Ro15-4513, were monitored by measurement of visual evoked potentials (VEP). Administration of Ro15-4513 10 mg kg-1 i.p., in rats breathing air, did not affect the amplitude or latency of VEP. However, the same concentrations of Ro15-4513 antagonized nitrous oxide-induced depression of VEP amplitudes. We conclude that antagonism of nitrous oxide-induced depression by Ro15-4513 indicates that at least part of the decreased neuronal excitability caused by nitrous oxide could be ascribed to interactions with the GABAA receptor complex.

Electrophysiological and biochemical effects of deprenyl and beta-phenylethylamine were studied in rats. d,1-Deprenyl, 1-deprenyl (4-6 mg/kg) and beta-phenylethylamine (75 mg/kg) induced a desynchronization of ECOG after i.p. administration of drugs. The effects lasted several hours. The biochemical analysis indicate that d,1-deprenyl (4 mg/kg) nearly doubled the concentration of brain dopamine (DA) while the concentration of noradrenaline was not altered. The maximal increase was reached at 60 min and the enhanced concentration of DA stayed at this level up till 180 min after administration of drug. Treatment of rats with alpha-methyl-p-tyrosine (200 mg/kg) did not antagonize a deprenyl induced desynchronization of ECOG. However, even low dose of haloperidol (0.1 mg/kg) abolished the arousal effect of d,1-deprenyl and beta-phenylethylamine. It is suggested that desynchronization of EEG induced by deprenyl is more likely due to increased endogenous beta-phenylethylamine than to increased concentration of endogenous DA in the brain.

By using electroencephalographic (EEG) and electromyographic recordings in anaesthetized and free-moving rats, two opioid peptides, known as selective agonists forμ andδ opiate receptors, respectively, were examined for their epileptogenic properties.

SUMMARY 1. The relationship between the effects of GABA-ergic drugs and D-ala2 -met-enkephalinamide (DALA)-induced myoclonic contractions of inframandibular muscles has been studied in the rat. 2. GABA-ergic drugs altered enkephalin-induced myoclonic contractions in the following manner: (a) The GABA-mimetic drugs, muscimol, gabaculine and baclofen, decreased DALA-induced myoclonic contractions. (b)The GABA antagonist, bicuculline and the anticonvulsant substance, sodium valproate (dipropylacetic acid, DPA) potentiated DALA-induced myoclonic contractions. The potentiating effect of DPA is probably due to its opiate-like activity, since naloxone abolished this effect. 3. The modulatory effect of the GABA-mimetic drug on enkephalin-induced myoclonic contractions may give grounds for further study to test the possible use of other GABA-mimetic drugs and possibly opiate antagonists for the treatment of myoclonic syndromes.

Ibogaine, an indole alkaloid, administered intracerebroventricularly 4-16 micrograms, attenuated a naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. It appears that ibogaine has a more consistent effect on certain selective withdrawal signs related to the locomotion. This might explain an attenuating effect of ibogaine on some withdrawal signs. However, due to complex interaction of ibogaine with serotonin and other neurotransmitter systems, the mechanism of ibogaine antiwithdrawal effect remains unknown and requires further elucidation.

Several studies have demonstrated analgesic effects of cholinesterase inhibitors and of 4-aminopyridine (Fastier and McDowall, 1958a and b; Saxena 1968; Harris et al. 1969; Harris and Dewey 1972; Weinstock et al. 1980; Lipman and Spencer 1980). Mechanisms by which colinergic agents exert antinociceptive activity have so far remained unresolved. However, Aiello-Malmberg and others (1979) proposed that physostigmine does not act exclusively as a cholinergic agent and may be producing its analgesic effects by increasing the brain levels of 5-hydroxytryptamine. Ireson (1979) found that atropine reversed the analgesic activity of physostigmine which indicates that the muscarinic synaptic site is of essential importance for this action of physostigmine. The possibility of antinociceptive activity of cholinesterease inhibitors through an activation of opiate receptors in the central nervous system has been examined but with contradictory results. Harris and others (1969), reported that naloxone reversed the analgesic effect of physostigmine and oxotremorine. This finding was not confirmed by later studies (Pleuvry and Tobias 1971; Lipman and Spencer 1980).

Antinociceptive effects of physostigmine and 4-aminopyridine after i.p. administration were studied in rats according to the Randall-Selitto nociception method. The antinociceptive action of physostigmine was not significantly influenced by atropine, naloxone or alpha-methyl-p-tyrosine. The antinociceptive action of 4-aminopyridine was also unaffected by simultaneous administration of atropine, naloxone or pretreatment by DL-p-chlorophenylalanine. However, 4-aminopyridine was without antinociceptive effect in rats pretreated with alpha-methyl-p-tyrosine. It is suggested that the antinociceptive action of 4-aminopyridine is mediated by a noradrenergic system.

By using electroencephalographic (EEG) and electromyographic recordings in anaesthetized and free-moving rats, two opioid peptides, known as selective agonists for mu and delta opiate receptors, respectively, were examined for their epileptogenic properties. The delta receptor peptide (DSTLE, 4.6-18.6 nmol, intraventricularly, ivt), a putative delta opiate agonist, produced a dose-related increase of myoclonic contractions (MC) with epileptic discharges in anaesthetized rats and severe wet dog shakes, with occasionally falling down, in free-moving animals. Morphiceptin, a specific mu opiate agonist, used in equimolar doses and under the same experimental conditions, had a significantly less pronounced effect on the number of MC and epileptiform EEG phenomena. Similarly, DSTLE (18.6 nmol) injected in the CA2 area of the hippocampus, a region with a nearly equal distribution of mu and delta opiate receptors, induced epileptic discharges in anaesthetized and free-moving rats, while an equimolar dose of morphiceptin had no significant effect. It is suggested that the epileptiform activity of opioid peptides is mainly due to an activation of delta opiate receptors in the central nervous system.

Myoclonic twitches (MT) in the submandibular muscles induced by intraventricular administration of D-ala2-met-enkephalinamide (DALA) were studied electromyographically in the rat. Measurement of MT activity was selected since it permits parallel study of the effect of enkephalin on both dopaminergic and serotonergic transmitter systems. The twitches induced by enkephalin were blocked by naloxone, gamma-hydroxybutyrate, and ergometrine, but potentiated by haloperidol. Methysergide did not alter the stimulatory effect of DALA. These results were interpreted as a possibility for a specific enkephalin-induced activation of the so-called inhibition-mediating dopaminergic system, which is sensitive to the blocking action of ergometrine, but resistant to the blocking action of haloperidol.

Enkephalinase inhibitors phosphoramidon, thiorphan or phelorphan suppressed naloxone-precipitated withdrawal symptoms in acute and chronic morphine dependent mice and rats. It is suggested that decreased biotransformation of the endogenous opioid peptides might compensate the relative shortage of exogenous opiates during withdrawal in opiate dependent subjects and could be a new and promising way to attenuate the severity of abstinential syndrome.

In order to elucidate the relationship between REM sleep and the enkephalinergic system, the effects of REM sleep deprivation (REMSD), stress and the enkephalinase inhibitor phosphoramidon on handling-induced convulsions were studied in mice. REMSD, stress and phosphoramidon (25-500 micrograms icv) increased the frequency of handling-induced convulsions (HIC) in normal mice. However, only in the last two groups were HIC antagonized by naloxone (1 mg/kg IP). In REMSD mice, phosphoramidon decreased the frequency of HIC, this effect being abolished by naloxone. The increase of neuronal excitability during REMSD is suggested to be associated with an insufficiency of the enkephalinergic system.

Resident peritoneal macrophages from morphine-addicted rats (4 days) released more prostaglandin (PG) E2 and thromboxane (Tx) B2, but not 6-keto-PGF1a, than cells from control animals. This effect, which was due to an enhancement of endogenous AA turnover, was not related to any changes in cAMP synthesis or lysososomal enzyme secretion. [D-Ala2]-Met-enkephalin had no effect on eicosanoid release in vitro. Both morphine and PGE2 have been shown to depress macrophage functions. We suggest that morphine-stimulated macrophage PGE2 synthesis, and the consequent inhibition of phagocytosis, could contribute to the decreased resistance to infections associated with opiate addiction.

The effect of the enkephalinase inhibitor phosphoramidon on the withdrawal syndrome following acute and chronic morphine-induced physical dependence in mice, was investigated. Phosphoramidon administered intracerebroventricularly (50-200 micrograms) suppressed significantly the naloxone-precipitated withdrawal jumping and wet dog shakes while forelimb shakes were potentiated in both acute and chronic morphine-dependent mice. It is suggested that increased saturation of the opioid receptors by endogenous opioid peptides following enkephalinase inhibition, might suppress the severity of the withdrawal syndrome.