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PubMed1980

Self-administration of D-Ala2-Met-enkephalinamide at hypothalamic self-stimulation sites.

The relationship between the action of enkephalin and the reinforcing action of electrical stimulation in the posterior lateral hypothalamus of the rat was studied with the self-administration approach. Adult male albino rats implanted with a combination cannula and stimulation electrode in hypothalamus were pretested for the reinforcing effects of electrical stimulation. Only subjects that self-stimulated at moderate to high rates were given self-administration tests. The chamber for the self-administration tests was fitted with one lever at each end of a rectangular plexiglass box. In a session, one lever was 'active', the other not. The active lever, if depressed, yielded 20 nl of CSF (artificial cerebrospinal fluid), or CSF in which one of the test substances was dissolved. Each subject was tested repeatedly for the reinforcing effects first of a control solution (CSF), then of D-Ala2-Met-enkephalin (DALA), a long-acting synthetic analogue of enkephalin, then of morphine, and then of opioids mixed with naltrexone or naloxone. Following these tests, the subjects were once again given self-stimulation tests to ascertain the functional integrity of the 'reward' system after the repeated self-administration tests. The results demonstrate that when the test solution was DALA instead of CSF the subjects pressed the active lever at a higher rate than for CSF, and they exhausted the supply more rapidly than for CSF. The rate on the active lever was also significantly higher than on the inactive lever. DALA at 1 and 5 microgram/microliter concentrations proved more reinforcing than at 0.1 microgram/microliter. Naltrexone did not block the reinforcing effect of DALA, whereas naloxone blocked DALA-induced reinforcement. These data extend the report of ventricular methionine-enkephalin positive reinforcement to DALA injected directly into the lateral hypothalamus.

Animals↗
PubMed1982

Opiate alkaloids antagonize postsynaptic glycine and GABA responses: correlation with convulsant action.

Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amino acid responsiveness were assessed using intracellular recording techniques applied to murine spinal cord neurons in primary dissociated cell culture. Application of opiates was by superfusion and amino acids by iontophoresis. Glycine and GABA but not glutamate responses were antagonized by the opiate alkaloids. Since opiate effects on glycine and GABA responses were not naloxone-reversible, only weakly stereospecific, and not produced by the opioid peptide [D-Ala2]-Met-enkephalinamide, it is unlikely that these effects were mediated by opiate receptors. Opiate depression of glycine inhibition was correlated with the induction of paroxysmal depolarizations in cultured spinal cord neurons, suggesting that antagonism of inhibitory amino acid transmission may underlie the convulsant actions of high concentrations of the opiate alkaloids.

Animals↗
PubMed1984

Simultaneous measurement of cholecystokinin- and vasoactive intestinal polypeptide-like immunoreactivity from cat frontal cortex in vitro: effect of morphine and D-Ala2-D-Leu5-enkephalin.

The two peptides vasoactive intestinal polypeptide (VIP) and cholecystokinin (CCK) have been demonstrated to be discretely distributed in the cerebral cortex. This distribution closely parallels the distribution of mu- and delta-opiate receptors in the frontal cortex. The basal efflux and potassium-stimulated release of VIP- and CCK-immunoreactivity was studied in the presence and absence of morphine and D-Ala2-D-Leu5-enkephalin (DADL), agents with relative affinity for the mu and delta receptors, respectively. The basal efflux of VIP- and CCK-immunoreactivity was not affected by these opiates; however, the potassium-stimulated release of VIP-immunoreactivity was profoundly inhibited in a dose-dependent manner by both morphine (ED50 = 1 X 10(-9) M) and DADL (ED50 = 3.02 X 10(-9) M). The inhibition produced by either morphine or DADL was shown to be reversed by naloxone.

Animals↗
PubMed1994

Dual regulation by opioids of 3H-norepinephrine release in the human neuroblastoma cell-line SK-N-SH.

Depolarization-evoked 3H-norepinephrine release from SK-N-SH cells was found to be regulated by opioid ligands. Opioids exerted either inhibition or augmentation of 3H-norepinephrine release. Both effects were mediated by opioid receptors. In addition, a nonopioid inhibitory effect of opiates on release was observed. The SK-N-SH cell-line provides a suitable model for studying the various mechanisms underlying the opioid regulatory pathways within single cells.

Cell Line↗
PubMed1995

Comparison of the prevalence of the poor metabolizer phenotype for CYP2D6 between 203 Hmong subjects and 280 white subjects residing in Minnesota.

Genetic polymorphism of the P450IID6 (CYP2D6) enzyme system can be an important component of the variability in response to drug therapy. Interpopulation differences in the prevalence of deficiencies of drug-metabolizing enzymes may be clinically important in the selection and dosage of drug therapies for patients. Since 1980, the State of Minnesota has had more than a 1000% increase in population of Hmong refugees from Laos. The Hmong are frequently treated in our institution's international clinic with virtually no systematically acquired knowledge about the ability of this relatively ethnically pure population to metabolize commonly used Western medications. To further our knowledge of drug metabolism in this population, we identified the prevalence of the poor metabolizer phenotype for CYP2D6 in a sample population of Hmong subjects and compared this prevalence to that in a sample population of white subjects. Urine collected after ingestion of dextromethorphan in 237 healthy Hmong and 280 healthy white volunteers was analyzed by HPLC. Based on probit plots of the metabolic ratios (dextro-methorphan/dextrorphan), 8.9% of Hmong subjects and 6.1% of white subjects were assigned the poor metabolizer phenotype (difference not significant). Weak associations were found between body surface area and metabolic ratio for both Hmong and white men and between smoking status and metabolic ratio for white subjects only. We conclude that the prevalence of poor metabolizers for the CYP2D6 enzyme system is similar between Hmong subjects and white subjects residing in Minnesota and that an antimode of 0.3 for metabolic ratio appears to be reasonable for the populations studied.

Adolescent↗
PubMed1978

Morphine: effects on serotonergic neurons and neurons in areas with a serotonergic input.

The hypothesis that morphine acts on the serotonergic system to produce analgesia is based on the previous observations that (1) lesions and stimulation of midbrain raphe nuclei after the threshold to nociceptive stimuli; (2) morphine alters the turnover of serotonin (5-hydroxytryptamine; 5-HT). Microiontophoretic experiments were carried out to determine if morphine affected the firing rate of cells in five areas of the serotonergic system consisting of 5-HT containing neurons in the midbrain raphe nuclei (dorsal raphe and median raphe) or neurons in three areas (amygdala, optic tectum and subiculum) which are thought to receive a 5-HT input from the raphe nuclei. Morphine administered microiontophoretically slowed or inhibited the spontaneous neuronal firing in 34% of the cells studied in both the pre- and post-synaptic areas; systemically administered morphine gave similar results. However, the inhibition of neuronal firing by morphine in the five areas of the serotonergic system studied was not a specific narcotic effect because (1) it was not stereospecific; and (2) it was rarely blocked by naloxone. The inhibitory effect of morphine does not appear to be related to the analgesic effects of morphine because neuronal firing in the midbrain raphe nuclei and three possible postsynaptic areas was rarely altered by a nociceptive stimulus. It is concluded that (1) the analgesic effect of morphine is not related to an effect on neurons in the midbrain raphe nuclei and three areas which receive an identified 5-HT input; and (2) the effect of morphine on neurons in these five areas of the serotonergic system is not a specific narcotic effect.

Animals↗
PubMed1995

Conformational epitopes on CYP2D6 are recognized by liver/kidney microsomal antibodies.

BACKGROUND/AIMS: Four linear antigenic sites have been shown on the CYP2D6 molecule that are recognized by serum positive for liver/kidney microsomal antibody (LKM) type 1. The aim of this study was to search for antibodies against CYP2D6 conformational antigenic sites in LKM-1-positive sera. METHODS: The capacity of four LKM-1-positive sera, before and after absorption with synthetic peptides representing CYP2D6 linear antigenic sites, and rabbit sera against linear antigenic sites between CYP2D6 amino acids 254-271 and 373-389 to inhibit the O-demethylation of dextromethorphan by CYP2D6 was tested in vitro. RESULTS: Inhibition of O-demethylation of dextromethorphan was not modified by absorption of antibodies against linear CYP2D6 antigenic sites. In addition, rabbit sera against two of these sites did not inhibit the reaction. These results strongly suggest that antibodies against CYP2D6 conformational antigenic sites were present in LKM-1-positive sera. CONCLUSIONS: The autoimmune response against CYP2D6 is directed against linear and conformational antigenic sites. These results strengthen the argument that the LKM-1 response is polyclonal and antigen driven.

Animals↗