• EEG, EEG power spectral and behavioral profiles of two inbred rat strains upon acute and chronic opiate exposure

      Mayo-Michelson, Lieser; Young, Gerald A. (1992)
      Utilizing EEG, EEG power spectra and behavioral parameters, two inbred rat strains, Lewis (LEW) and Fischer 344 (F344) were compared following acute morphine, chronic morphine and acute ethylketocyclazocine (EKC) treatment. Following acute morphine administration, the LEW rats exhibited greater duration of morphine-induced EEG slow-wave bursts and associated behavioral stupor. For both LEW and F344 rats, suppression of onset to slow-wave sleep increased in a dose-related manner. Regarding morphine dose, all spectral parameters differed except peak frequency. For the chronic morphine study, LEW and F344 inbred rat strains were exposed to morphine (iv) over a period of seven days in order to discern differences in tolerance development and physical dependence. Following morphine injection, the LEW group exhibited a greater mean total amount, as well as a greater rate of reduction, of stuporous behavior across the seven days tested. The LEW rats exhibited a positive linear profile of opiate-induced hyperexcitability, while a quadratic profile emerged for the F344 group. Over days, differences in patterns of latency to onset of slow-wave sleep between the two strains were also revealed; the F344 rats exhibited a greater change (as reduction of suppression) across the seven days tested. Naloxone was administered (iv) following the seven days of morphine treatment in order to delineate differences in dependence. The LEW animals reflected a greater amount of withdrawal-type behavioral responses, e.g., wet dog shakes, diarrhea, body stretch, sluggish behavior. However, assessment of power spectral parameters pre- and post-naloxone treatment revealed a greater withdrawal response for the F344 group. Acute administration of EKC also revealed differences between LEW and F344 inbred rat strains. EKC-induced EEG slow-wave bursts and associated behavioral stupor increased in a dose-related manner, and was greater in duration, for the LEW animals; a less robust, quadratic trend over doses was displayed by the F344 group. Separation of the phases revealed rat strain differences; overall, the LEW animals displayed a dose-related EEG response. Except for total power, the F344 group displayed little variation across the three doses tested in the burst phase; the interburst phase reflected dose-related differences for this group but to a lesser extent in comparison to the LEW rats. (Abstract shortened with permission of author.)
    • Interactions between dynorphin A-(1--13) and morphine: In vivo effects on EEG, in vitro effects on tritium-morphine binding, and correlations between them in naive and morphine tolerant rats

      Meng, Yuqing; Young, Gerald A. (1993)
      Utilizing an in vivo EEG functional assay and in vitro receptor binding techniques, the mechanisms of the modulatory effects of dynorphin A-(1-13) on morphine-induced EEG effects and receptor binding in naive vs. morphine-tolerant rats were studied. In naive rats, dynorphin A-(1-13) i.c.v. pretreatment significantly attenuated cumulative i.v. morphine-induced EEG spectral power and the maximal response, although dynorphin A-(1-13) alone produced little or no EEG bursting activity. Dynorphin A-(1-13) also significantly decreased the maximal binding (B{dollar}\sb{lcub}\rm max{rcub}{dollar}) for ({dollar}\sp3{dollar}H) -morphine without altering the affinity constant (K{dollar}\sb{lcub}\rm d{rcub}{dollar}) in rat cortical membranes. A significant linear correlation between in vivo EEG spectral power increases and in vitro receptor binding was found. These data suggest that the regulatory effects of dynorphin A-(1-13) on morphine-induced responses are non-competitive in nature. The linear correlation between in vivo and in vitro data suggests that the antagonism by dynorphin A-(1-13) on morphine-induced EEG changes may occur at the receptor level in naive rats. In morphine-tolerant rats, dynorphin A-(1-13) i.c.v. pretreatment produced opposite effects to those found in naive rats. Instead of antagonizing morphine-induced EEG spectral power, dynorphin A-(1-13) pretreatment significantly increased cumulative i.v. morphine-induced EEG spectral power and the maximal response. The effects of dynorphin A-(1-13) on ({dollar}\sp3{dollar}H) -morphine binding were complex in cortical membrane preparations from morphine-tolerant rats. While dynorphin A-(1-13) inhibited ({dollar}\sp3{dollar}H) -morphine binding at lower morphine concentrations, it was unable to inhibit ({dollar}\sp3{dollar}H) -morphine binding at higher morphine concentrations. Significant logarithmic correlations between in vivo EEG spectral power increases and in vitro receptor binding data were found. These findings suggest that while dynorphin A-(1-13) behaved as a non-competitive antagonist in naive rats, there may be positive cooperativity between morphine and dynorphin A-(1-13) at relatively lower affinity morphine binding sites in morphine-tolerant rats. Dynorphin A-(1-13) was also found to modulate morphine-induced qualitative EEG properties differently in naive vs. morphine-tolerant rats. While dynorphin A-(1-13) pretreatment qualitatively shifted the relative distribution of cumulative i.v. morphine-induced spectral power to predominantly faster frequencies in naive rats, it had no effects on the relative distribution of EEG spectral power in morphine-tolerant rats. These data suggest that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. (Abstract shortened by UMI.)
    • Interactive effects of MK-801 and morphine on EEG, EEG power spectra and behavior in rats: Acute, tolerance and dependence studies

      Haberny, Kathleen Anne Y.; Young, Gerald A. (1993)
      Recent studies investigated an interaction between MK-801 and morphine-induced analgesia which originates in spinal and supraspinal subcortical areas of the CNS, particularly in the periaqueductal gray. Interactive effects between MK-801 and morphine-induced cortical EEG that coincides with behavior generated in mesolimbic areas have not been demonstrated. The present study first investigated an acute interaction between MK-801 and morphine-induced effects on cortical EEG and EEG spectral parameters in rat. Rats were administered one of five doses of MK-801 (0.003-0.3 mg/kg, i.p.) prior to morphine (3 mg/kg, i.v.), or MK-801 (0.1 mg/kg, i.p.) prior to an increasing cumulative morphine dose over a period of 120 minutes (5-120 mg/kg, i.v.). MK-801 pretreatment produced a significant dose-response effect and increased morphine-induced global spectral power (mV{dollar}\sp2{dollar}/Hz), duration of morphine-induced high voltage slow wave EEG bursts and latency to sleep onset. MK-801 significantly decreased morphine-induced mean frequency, mobility, complexity and edge frequency, and shifted the relative distribution of total power as a function of frequency band to lower frequencies, increasing power in the 0-5 Hz range. Significant interaction effects were found for all spectral parameters except peak frequency. Pretreatment with MK-801 shifted the cumulative morphine dose-response curve for total power to the left and for complexity to the right. The results demonstrated that MK-801 potentiates morphine-induced effects on EEG and EEG spectral parameters quantitatively in rat brain and produces qualitative changes in the EEG response to morphine. A potential interaction between MK-801 and morphine tolerance and dependence was further investigated. Rats were treated for seven days with morphine alone or with morphine and MK-801. Control groups received chronic MK-801 alone or saline. On day eight all rats received morphine alone followed by naloxone. An additional group received chronic morphine alone, followed by MK-801 on day eight prior to morphine and naloxone. Co-treatment significantly accelerated the development of tolerance to morphine-induced total power and latency to sleep onset. MK-801 co-treatment decreased, where chronic morphine alone increased, the excitatory response to morphine. Chronic co-administration had no effect on the EEG and behavioral response to naloxone precipitated morphine withdrawal, but acute MK-801 in morphine tolerant animals prevented the behavioral signs of morphine withdrawal. The results support recent reports that chronic morphine treatment produces supersensitivity to glutamate in the rat cortex and alteration in mesolimbic dopamine levels which are modulated by glutaminergic activity. In conclusion, acute co-treatment with MK-801 significantly potentiates morphine-induced EEG, EEG spectral parameters and behavior, and attenuates the behavioral signs of withdrawal from morphine following chronic morphine administration. Chronic co-treatment, furthermore, accelerates the development of tolerance to morphine-induced effects on these parameters.
    • Kappa-opioid induced regulation of mu-opioid mediated effects on EEG power spectra and behavior in rats

      Paquette, Nicole Corinne; Young, Gerald A. (1991)
      The regulatory effects of kappa-opioid ligands on mu-opioid induced changes in EEG power spectra and behavior were evaluated in rats receiving various acute and chronic treatments. Rats were implanted with cortical EEG electrodes and i.c.v. and/or intravenous (i.v.) cannulae. EEG spectral parameters were derived from digitized EEG samples with spectral analysis techniques. Pretreatment with intracerebroventricular (i.c.v.) injection of dynorphin, morphine and dynorphin/morphine resulted in quantitative and qualitative changes in EEG power spectra in rats given i.c.v. morphine 24 hr later. I.c.v. injections of morphine (20 {dollar}\mu{dollar}g/rat) produced high-voltage, slow-wave EEG bursts (1-10 Hz). Injections of i.c.v. morphine in rats pretreated with i.c.v. dynorphin (20 {dollar}\mu{dollar}g/rat), morphine (20 {dollar}\mu{dollar}g/rat) or dynorphin/morphine twenty-four hours earlier, produced quantitative increases in absolute EEG spectral power. Injections of i.c.v. morphine in rats pretreated with i.c.v. dynorphin/morphine 24 hr earlier, also produced qualitatively different EEG power spectra with a predominant peak in the 4-6 Hz band, similar to the EEG power spectra seen after acute administration of kappa opioids. Correlated changes in sensitivity to antagonism of these EEG effects by naloxone were also found. Thus, Dynorphin may act as a possible regulator of certain {dollar}\mu{dollar}-opioid receptor-associated phenomena, such as morphine-induced EEG bursts at a binding site which is nor-BNI insensitive. Chronic administration of morphine, a {dollar}\mu{dollar}-opioid selective agonist, for seven days resulted in tolerance development to EEG bursts and EEG absolute power, but not to latency to onset of slow-wave sleep (SWS). Chronic morphine administration was also associated with increases in the duration of hyperexcitability. Chronic administration of U-50,488H, a selective {dollar}\kappa{dollar}-agonist, was not associated with any changes in the duration of EEG bursts, latency to onset of SWS or duration of sedation. The coadministration of U-50,488H and morphine produced no significant tolerance development to the duration of EEG bursts and latency to onset of sleep, but increased the duration of sedation. Morphine or ethylketocyclazocine (EKC) challenges before and after chronic treatment with either morphine or U-50,488H resulted in greater tolerance development to the duration of EEG bursts and to increases in EEG absolute spectral power compared to the group receiving chronic coadministration. (Abstract shortened with permission of author.)