O. Hong

Sigma receptors mediate the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties

Our present findings suggest that SKF-10,047, the prototype sigma agonist, has its opioid entity residing with its (-) isomer, while both its (+) and (-) isomers possess psychotogenic properties similar to those produced by PCP. We found that (-)-SKF-10,047 blocks EEG and behavioral effects of morphine in the naive rat, precipitates withdrawal in morphine-dependent rats, produces physical dependence as evidenced by naloxone-induced withdrawal, and displaces [3H]dihydromorphine from brain homogenates. (+)-SKF-10,047 did not produce dependence upon chronic treatment, and it did not displace [3H]dihydromorphine from brain homogenates. Such pharmacodynamic dissociation with SKF-10,047 suggests an association of sigma receptors with psychogenic, but not opioid effects. The latter are most likely mediated by mu or kappa receptors.

Modulation of morphine-induced EEG and behavioral effects by dynorphin A-(1-13) in non-tolerant and morphine-tolerant rats

The purpose of the present study was to assess effects of dynorphin A-(1-13) on morphine-induced changes in electroencephalographic (EEG) spectral power and morphine-induced suppression of slow-wave sleep in non-tolerant and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG electrodes, electromyographic electrodes in the temporalis muscle and with intracerebroventricular (i.c.v.) cannulae and, in some cases, additional intravenous (i.v.) cannulae. Injections of morphine (i.c.v., 20 micrograms/rat) produced a biphasic EEG and behavioral response, composed of 2-3 hr of slow-wave bursts and increased spectral power (0-4 Hz) in the EEG, associated with behavioral stupor, followed by 2-3 hr of EEG and behavioral arousal. Dynorphin (i.c.v., 20 micrograms/rat), administered 10 min before injections of morphine in non-tolerant rats, antagonized morphine-induced increases in spectral power of the EEG and morphine-induced suppression of slow-wave sleep. In addition, EEG power spectra obtained after intraventricular administration of morphine from rats, treated with dynorphin and morphine intraventricularly 24 hr earlier, were qualitatively similar to those previously found after acute administration of kappa opioid agonists. In morphine-tolerant rats, pretreatment with dynorphin given intraventricularly, 10 min prior to intraventricular administration of morphine, restored morphine-induced increases in EEG spectral power and suppression of slow-wave sleep. The results suggest that dynorphin may modulate the characteristics of opioid receptors.

EEG, EEG Power Spectra, and Behavioral Correlates of Opioids and Other Psychoactive Agents

The discovery of electrical potentials of the brain is thought to have been made by Caton (1875), who presented the results of his research with rabbits and monkeys to the British Medical Association in Edinburgh. Half a century later in Jena, Austria, Hans Berger (1929) discovered human brain waves and, hence, Berger is recognized as the father of electroencephalography, the recording of oscillations in the potential differences between two points in the brain (Berger, 1937).

Intracerebroventricular morphine produces diuresis 24 h after previous dynorphin/morphine treatment

The effect of dynorphin A-(1-13) on morphine-induced urine output was studied in the rat. The previous simultaneous intracerebroventricular (i.c.v.) injection of dynorphin (20 micrograms/rat) and morphine (20 micrograms/rat) altered the response of rat given morphine (20 micrograms/rat) 24 h later, producing a 3-fold increase in urine output. In contrast, previous injection of dynorphin or morphine alone had no effect.

Differential tolerance to repeated daily injections of N-allylnormetazocine and its enantiomers in the rat

This study was designed to compare the development of tolerance to the effects of N-allylnormetazocine (SKF-10,047) and its enantiomers on the EEG and on behavior. Adult female Sprague-Dawley rats were implanted with chronic cortical electroencephalogram (EEG) and electromyogram (EMG) recording electrodes in the temporalis muscle and with permanent cannulae in the external jugular vein. In non-tolerant rats, 10 mg/kg (i.v.) injections of SKF-10,047 racemate produced primarily aroused wakefulness for about 120 min, that was associated with alternation between desynchronized EEG and theta waves in the EEG. After these rats received a series of automatic, intravenous injections of SKF-10,047 racemate, the aroused wakefulness state induced by SKF-10,047 racemate lasted for about 40 min. In non-tolerant rats, 2.5 mg/kg (i.v.) injections of (+)-SKF-10,047 induced a psychotomimetric EEG and behavioral state for about 30 min, which included continuous theta wave activity in the EEG. After chronic treatment with (+)-SKF-10,047, the psychotomimetic state induced by (+)-SKF-10,047 persisted for about 20 min. In non-tolerant rats, 2.5 mg/kg (i.v.) injections of (-)-SKF-10,047 produced an aroused EEG and behavioral wakefulness for about 30 min, which was then followed by slow-wave bursts in the EEG and associated behavioral stupor for about 90 min. After chronic treatment with (-)-SKF-10,047, injection of (-)-SKF-10,047 produced predominantly aroused wakefulness for about 45 min. The data suggest that (+)-SKF-10,047 exerts psychotogenic properties, but not opioid properties. On the other hand, the data suggest that (-)-SKF-10,047 possesses opioid properties.

Sigma opioid receptor; SKF-10,047 update

We found that (-)-SKF-10,047 blocks EEG and behavioral effects of morphine in the naive rat, precipitates withdrawal in morphine-dependent rats, produces physical dependence as evidenced by naloxone-induced withdrawal, and displaces [3H] dihydromorphine from brain homogenates. (+)-SKF-10,047 did not produce dependence upon chronic treatment, and it did not displace [3H] dihydromorphine from brain homogenates. Such pharmacodynamic dissociation of SKF-10,047 effects suggests an association of sigma receptors with psychotogenic, but not opioid characteristics. The latter are most likely mediated by mu or kappa receptors.

Suppression of PCP-induced behavioral arousal in the rat by yohimbine pretreatment.

The ability of yohimbine pretreatment to block PCP-induced increases in general motor behavior and head bobbing was assessed in adult female Sprague-Dawley rats. PCP-induced (5 mg/kg i.p.) increases in motor activity were significantly antagonized by yohimbine (5 mg/kg i.p.). More specific PCP-induced (5 mg/kg i.v.) head bobbing was antagonized in a dose-related manner by yohimbine (2.5 and 5 mg/kg i.p.). These data may lead to a better understanding of the mode of action of PCP.

Bidirectional cross-tolerance between methadone (mu)- and ethylketocyclazocine (kappa)- tolerant rats

Our laboratory previously reported on unidirectional cross-tolerance between morphine and methadone, both mu opioid agonists, and between morphine and ethylketocyclazocine (EKC), the latter being a relatively selective kappa opioid agonist. Morphine-tolerant rats were found to be non-cross-tolerant to methadone and EKC, but methadone- and EKC-tolerant rats were cross tolerant to morphine. In the present study, we characterized the cross-tolerance between methadone and EKC. A group of female adult Sprague-Dawley rats was made tolerant to methadone by a series of automatic i.v. injections ranging from 0.25 mg/kg per 2 h on the first day to 2.0 mg/kg per 1.5 h on the ninth day. Another group of rats was similarly made tolerant to EKC with doses ranging from 0.5 mg/kg per 2 h on the first day to 4 mg/kg per h on the ninth day. Relatively similar degrees of tolerance development to the EEG and behavioral effects of methadone and EKC were reflected by decreases in durations of action and decreases in opioid-induced EEG power spectral changes. Methadone-tolerant rats were found to be cross-tolerant to the EEG and behavioral effects of EKC, and, similarly, EKC-tolerant rats were found to be cross-tolerant to those of methadone. Thus, a bidirectional cross-tolerance between a mu and a kappa agonist was demonstrated. The present results together with those reported earlier indicate that cross-tolerance may not be directly related to the receptor selectivity of the opioids. It is possible that differential physicochemical properties of these opioids may play a more decisive role in the phenomenon of cross-tolerance.