Haloperidol pretreatment unmasks the kappa opioid effects of U-50, 488H on cortical EEG and EEG power spectra in rats.

Adult female Sprague-Dawley rats were implanted with chronic cortical EEG electrodes and intravenous cannulae. U-50, 488H injection (5.0 mg/kg) produced initial EEG desynchrony and EEG spectral power that was mainly distributed over the zero to 10 Hz range, including a relatively small spectral peak in the 4-6 Hz band. In contrast, following haloperidol pretreatment (0.1 mg/kg), U-50, 488H injection produced high-voltage EEG bursts and a predominant EEG spectral peak in the 4-6 Hz band. These effects of U-50, 488H after haloperidol pretreatment were identical to those previously demonstrated with the benzomorphan kappa agonist ethylketocyclazocine. Thus, haloperidol pretreatment unmasked the kappa opioid effects of U-50, 488H.

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.

Dissociation of the opioid and nonopioid effects of cyclazocine.

Lower IV doses of (dl)- and (l)-cyclazocine (0.05 and 0.50 mg/kg) in the rat produced opioid EEG and behavioral effects that were antagonized by naltrexone pretreatment. Higher IV doses of (dl)- and (l)-cyclazocine (1.00 and 2.00 mg/kg) produced initial "psychotomimetic-like" behavioral effects that were naltrexone-resistant, followed by the delayed emergence of opioid EEG and behavioral effects that were naltrexone-sensitive, (d)-Cyclazocine produced only "psychotomimetic-like" behavioral effects that were naltrexone-resistant. (dl)-Cyclazocine antagonized morphine-induced EEG and behavioral effects in naive rats. (l)-Cyclazocine precipitated withdrawal symptoms in morphine-dependent rats. In contrast, (d)-cyclazocine produced "psychotomimetic-like" effects, but no withdrawal symptoms. Thus, (dl)- and (l)-cyclazocine produced dose- and time-related opioid and nonopioid "psychotomimetic-like" effects, while (d)-cyclazocine produced only nonopioid "psychotomimetic-like" effects.

Opioid self-administration in rats: pharmacodynamics and pharmacokinetics.

This article provides comparative data obtained during opioid self-administration in rats, using our EEG-EMG rat model of addiction. This model allows continuous recording of EEG and EMG activities and programming of intravenous drug injections. Comparative data on opioid self-administration patterns are presented. These studies on the association between EEG and behavioral correlates of opioid self-administration have contributed to the delineation of similarities and differences in pharmacodynamic and pharmacokinetic characteristics of opioids.

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.

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.

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.

Differential protracted effects of morphine and ethylketocyclazocine challenges on EEG and behavior in the rat.

One group of six adult female Sprague-Dawley rats was given a series of automatically administered i.v. morphine injections over eight days. Similarly, a second group of six rats was given ethylketocyclazocine (EKC). Control rats received chronic i.v. saline injections. Tolerance to EEG and behavioral effects of morphine and EKC was demonstrated. At 15 days morphine post-withdrawal, morphine challenges produced EEG and behavioral stupor for a mean of 5 min, followed by EEG and behavioral arousal for a mean of 131 min. In contrast, morphine challenges in saline control rats produced a biphasic EEG and behavioral response consisting of a mean of 85 min of stupor, followed by a mean of 88 min of arousal. However, at 15 days EKC post-withdrawal, EKC challenges produced a biphasic EEG and behavioral response consisting of a mean of 57 min of depression followed by a mean of 55 min of arousal; control saline rats demonstrated similar responses to EKC challenges. Similar results were obtained at one month post-withdrawal for all groups. Thus, protracted effects on EEG and behavior were evident in rats chronically treated with morphine, but not in rats chronically treated with EKC.

Tremor at rest episodes in unilaterally 6-OHDA-induced substantia nigra lesioned rats: EEG-EMG and behavior.

Twenty male adult Wistar rats were unilaterally lesioned in the substantia nigra (SN) with 6-hydroxydopamine (6-OHDA), and prepared with chronic cortical (ECoG) and neck muscle (EMG) electrodes. Longitudinal study over a period of up to 18 months demonstrated the emergence, in about two-thirds of the rats, of spontaneous repetitive episodes of head and neck tremor during awake at rest, of up to 20 seconds duration each, that were associated with spike and wave-like ECoG activities. These episodes of tremor at rest disappeared during sleep and REM sleep episodes, and also following the i.p. administration of L-DOPA. It is assumed that these tremor at rest episodes are analogous to those reported to occur in primates after experimentally induced dysfunction of the nigro-striatal, extrapyramidal system.

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.

Comparison of abstinence syndromes following chronic administration of mu and kappa opioid agonists in the rat.

Abstinent states were compared following chronic administration of mu and kappa opioid agonists, morphine and ethylketocyclazocine, respectively. Rats were prepared with chronic EEG and EMG electrodes and indwelling IV cannulae. One group of rats was chronically administered IV morphine, while a second group received chronic injections of IV ethylketocyclazocine. Morphine abstinence was associated with suppression of REM sleep occurrences, increases in number of wet-dog shakes, and a decline in EEG spectral power during slow-wave sleep episodes. In contrast, the ethylketocyclazocine abstinence syndrome included minor abstinence signs. Differences in abstinent states between morphine and ethylketocyclazocine indicate the involvement of separate receptor populations in the process of dependence on morphine and ethylketocyclazocine.

Sigma opioid receptors; 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.

Differential neuropharmacological effects of mu, kappa and sigma opioid agonists on cortical EEG power spectra in the rat. Stereospecificity and naloxone antagonism.

The study was designed to determine and compare the acute effects of the enantiomers of mu, kappa and sigma opioid agonists on the cortical EEG with the spectral analysis technique. The relative ability of naloxone to antagonize such effects was also assessed. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG and temporalis muscle EMG recording electrodes, and with permanent indwelling external jugular cannulae. (-)-Methadone(mu agonist) produced increases in spectral power over the zero to 10Hz range, while (-)-ketocyclazocine (kappa agonist) produced increases in the 5-8 Hz band as a predominant peak. The(+) enantiomers of methadone and ketocyclazocine were inactive. The drug (+)-SK-10,047 (sigma agonist), produced a predominant spectral peak in the 7-9 HZ band that was associated with behavior that suggested psychotomimetic effects. The effects of morphine (mu agonist) on EEG and EEG power spectra were more sensitive to antagonism by naloxone than those produced by ketocyclazocine. The effects of (+/-)-SKF-10,047 and (+)-SKF-10,047 were not antagonized by 10 mg/kg of naloxone, while the effects of (-)-SKF-10,047 were partially antagonized by 10 mg/kg of naloxone. These findings further delineate the specificity of the differential effects of mu, kappa and sigma opioid agonists on the EEG and EEg power spectra in the rat.

Sigma receptors mediated 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.

Differential tolerance and cross-tolerance to repeated daily injections of mu and kappa opioid agonists in the rat.

This study was designed to compare the development of tolerance to the effects of morphine and ethylketocyclazocine ( EKC ) on EEG, EEG power spectra and behavior and to assess any cross-tolerance. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG and temporalis muscle EMG recording electrodes and with permanent cannulae in the external jugular vein. In non-tolerant rats, 10 mg/kg (i.v.) injections of morphine and of ethylketocyclazocine produced biphasic EEG and behavioral profiles lasting for 3 and 2 hr , respectively. In both cases, a stuporous phase, associated with high-voltage cortical EEG bursts, was followed by a hyperactive phase, associated with low-voltage desynchronized EEG. However, power spectra derived from epochs of EEG bursting produced by morphine and ethylketocyclazocine were qualitatively different. One group of rats was then given a series of automatic, intravenous injections of morphine, while a second group received ethylketocyclazocine. Following chronic treatment, the duration of the biphasic EEG and behavioral profiles induced by morphine and ethylketocyclazocine were both significantly reduced. In both cases, the intensity of EEG bursting was also reduced as reflected by significant quantitative reductions in EEG power spectral densities. In assessments of cross-tolerance, ethylketocyclazocine tolerant rats were found to be cross-tolerant to the effects of morphine. However, no cross-tolerance to the effects of ethylketocyclazocine in morphine-tolerant rats was observed. These data contribute to a further understanding of the relative heterogeneity of mu and kappa receptor populations and to the differential pharmacodynamics of morphine and ethylketocyclazocine.

Self-administration of ketocyclazocine and ethylketocyclazocine by the rat.

The purpose of the study was to assess possible substitution of either ketocyclazocine or ethylketocyclazocine for morphine in rats maintaining their own dependence by self-administration. Rats were prepared with indwelling IV cannulae, made tolerant to and physically dependent on morphine, then trained to lever press for morphine self-injections on a fixed ratio (FR) schedule of reinforcement. When either ketocyclazocine or ethylketocyclazocine was substituted for morphine, rats self-administered single injections of these kappa opioid agonists at relatively evenly spaced intervals over a 24-hr period. These self-injection patterns continued for up to at least 15 consecutive days. Substitution of saline for the kappa opioid agonists did not result in the emergence of a morphine-like abstinence syndrome. Differences in extent and intensity of withdrawal between morphine and these kappa opioid agonists indicate the involvement of separate receptor populations in the process of dependence on morphine and these kappa opioid agonists.

Electromyographic power spectral changes associated with the sleep-awake cycle and with diazepam treatment in the rat.

Power spectral analysis was used to study temporalis muscle EMG activities during the sleep-awake cycle in the rat. EMG spectra derived from EMG during the states of slow-wave sleep. REM sleep and wakefulness demonstrated qualitative and quantitative differences. Diazepam treatment produced reductions in EMG spectral power during wakefulness. Thus, our experimental model allows qualitative and quantitative delineation of EMG activity associated with behavioral changes or drug treatments.