effect of α-adrenergic blockers on naloxone-binding in braiN (original) (raw)
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Increased antagonist potency of naloxone caused by morphine pretreatment in mice
European Journal of Pharmacology, 1978
antagonist potency of naloxone caused by morphine pretreatment in mice, European J. Pharmacol. 47 (1978) 415--422. Using the writhing test in mice, it was shown that pretreatment with a single dose of morphine hydrochloride given 3 h previously caused a marked increase in the antagonistic effect of naloxone without any change in the antinociceptive action of morphine itself. It was shown that when mice were pretreated with different doses of either morphine alone, or in combination with naloxone, so that each treatment produced the same antinociceptire effect, the increase in naloxone potency was proportional only to the antinoeiceptive effect of the pretreatment and not to the total dose of morphine present. It was also found that the concurrent administration of naloxone plus morphine prevented the development of "acute dependence" to morphine, as measured by the jumping reaction after challenge with naloxone.
Journal of Neurochemistry, 1981
In isolated bovine adrenal chromaffin cells, p-endorphin, dynorphin, and levorphanol caused a dose-dependent inhibition of catecholamine (CA) secretion elicited by acetylcholine (ACh), with an ID,,, of 50, 1.3, and 4.3 PM, respectively. The inhibition by the opiate compounds was specific for the release evoked by ACh and nicotinic drugs and was noncompetitive with ACh. Stereospecific binding sites for the opiate agonist [3H]etorphine were found in homogenates of bovine adrenal medulla ( K , = 0.59 nM). /3-Endorphin, dynorphin, levorphanol, and naloxone were potent inhibitors of the binding of [SH]etorphine with an ID,, of 12, 0.4, 5.2, and 6.2 nM, respectively. However, [3,5-I2Tyri]-P-endorphin, [3,5-I,Tyri]-dynorphin, and dextrorphan, three opiate compounds with no or little activity in the guinea pig ileum assay, were relatively ineffective in inhibiting the binding of [3H]etorphine (ID,,, of 700,600, and 10,000 nM, respectively). On the other hand, these three compounds were equipotent with p-endorphin, dynorphin, and levorphanol, respectively, in inhibiting the ACh-evoked release of CA from the adrenal chromaffin cells (ID,,, of 10, 1.5, and 6 PM, respectively). Inhibition of CA release was also obtained with naloxone (ID,,, = 14 PM) and naltrexone (IDso > lo-* M), two classical antagonists of opiate receptors, and this effect was additive to that of pendorphin. These data indicate that the opiate modulation of CA release from adrenal chromaffin cells is not related to the stimulation of the high affinity stereospecific opiate binding sites of the adrenal medulla. The physiological function of these sites remains to be determined. Words: Opiate receptors-Catecholamine secretion-Adrenal medulla. Lernaire S. et al. Studies on the inhibitory action of opiate compounds in isolated bovine adrenal chromafin cells: Noninvolvement of stereospecific opiate binding sites. J . Neurochem. 36, 886-892 (1981). Abbreviations used: ACh, acetylcholine; BOC-amino acid, tert-butyloxycarbonyl amino acid; CA, catecholamine; DMPP, Lemaire. l,l-dimethyl-4-phenylpiperazinium iodide; [3,5-IzTyr1]-Pendorphin, [3,5-diiodotyrosine*]-P-endorphin; [3,5-IzTyr1]dynorphin, [3,5-diiodotyrosine1]-dynorphin. Dean, D. M., Lemaire, S. and Livett, B. G . (1980) Effects of enkephalin, morphine and other opiate compounds on catecholamine secretion from monolayer cultures of bovine adrenal chromaffin cells, unpublished. 42 1 -427. 11, 340-351. 1389-1394. USA 73,2515-2519. 209-215.
Journal of Pharmacy and Pharmacology, 2009
alpha(2)-Adrenergic and mu-opioid receptors belong to the rhodopsin family of G-protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with alpha(2)-adrenoceptor-subtypes in mice lacking one individual alpha(2)-adrenoceptor-subtype (alpha(2)-adrenoceptor knockout). Opioid interaction with alpha(2)-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor deficient mice. Displacement of the radiolabelled alpha(2)-adrenoceptor agonist [(125)I]paraiodoclonidine from alpha(2)-adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified. Morphine but not fentanyl or naloxone provoked dose-dependent displacement of [(125)I]paraiodoclonidine from all alpha(2)-adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of alpha(2A)-adrenoceptor knockout mice. Our results indicated that morphine interacted with alpha(2)-adrenoceptors showing higher affinity for the alpha(2B) and alpha(2C) than for the alpha(2A) subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to alpha(2)-adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.
Naltrexone induces down- and upregulation of δ opioid receptors in rat brain regions
Brain Research Bulletin, 1994
induces down-and upregulation of 6 opioid receptors in rat brain regions. BRAIN RBS BULL 35( 1) 69-72, 1994.-Opioid antagonists such as nahrexone, naloxone, and ICI174864 induce a transient down~gulation of 6 opioid receptors prior to up~gulation in NGIOS-15 cells. Here we show that nahrexone can also elicit a transient downregulation of & opioid receptors preceding upregulation in brain. A 1 h treatment of rats with naltrexone (IP, IO mg/kg) resulted in lowered OH-[D-Se~,L-~u']enkephalyl-or B,, vafues in hindbrain, but not in striatum, hippocampus, or cortex. The decrease in hindbrain & receptor density was not accompanied by changes in K* values,
Journal of Neuroscience Research, 1989
Cultures of aggregating fetal rat brain cells express p, 6, and K opioid receptors. The potent and longlasting opioid antagonist naltrexone was used to investigate whether different regulatory mechanisms are involved in the expression of the three receptor subtypes. In cultures treated for seven days, naltrexone increased dose-dependently the binding of 3H-diprenorphine to the three receptor subtypes, with the p sites being affected at a lower concentration than the other two; A Scatchard analysis indicated that this receptor up-regulation was obtained by an increase in the BMax, with no significant change in the affinity of the ligand to the receptors. In contrast to these effects in cultures treated for 7 days, it was surprising to find that a 48 hr treatment with naltrexone had an apparent converse and subtypespecific influence; the antagonist decreased significantly the binding of 3H-diprenorphine to both p and 6 receptors but had no effect on K sites. Two other opioid antagonists, naloxone and levallorphan, had a similar effect. Further analysis of naltrexone's mode of action was obtained by studying its effect on the adenylate cyclase activity. Of several inducers of this enzyme, the P-adrenergic inducer isoproterenol gave the highest increase in cyclic AMP. Naltrexone had no significant effect on the basal adenylate cyclase activity but it altered the pattern of cyclic AMP formation in isoproterenol-stimulated cultures. Overall, the results indicate that in addition to its classic antagonistic activity, naltrexone exhibits in fetal brain aggregates some properties associated with opiate agonists.
Regional saturation studies of [3H]naloxone binding in the naive, dependent and withdrawal states
Brain Research, 1985
We have examined the saturation features (K d and Bronx) of [3H]naloxone binding in rat brain regions in cytoarchitectonically intact tissues of naive, morphine dependent and precipitated withdrawal states using quantitative film autoradiography. Sixty-one saturation experiments in 13 regions of naive rat brains yielded monophasic Eadie-Hofstee plots with a mean (+ S,D.) K a of 1.87 + 0.87 nM and a mean Bma x (+ S.D.) of 101 + 66 fmol/mg. The 61 K d values in naive rats described a normal distribution of regional binding affinities that may reflect the biological variation of a single high affinity binding site. Similar studies in the morphine dependent and prec~p, itated withdrawal states showed no apparent changes in either the K d or Bm~ of regional [aH]naloxone binding. The possibility that in vitro preincubation of tissue sections masked potential alterations in [aH]naloxone binding was examined in competition studies of both morphine and naloxone for 2.0 nM [3H]naloxone binding to striatal sections. Preincubation had no effect on the ability of either opiate agonist or antagonist to compete for [3H]naloxone binding in the naive, morphine dependent or precipitated withdrawal states. The regional data comparing K d and Bma x for [3H]naloxone binding in naive, morphine dependent and precipitated withdrawal states eliminated the possibility that previous efforts to demonstrate alterations in opiate binding were confounded by homogenization and/or limitations of gross dissection. Our data suggest that either potential changes in antagonist binding in dependent and withdrawal states can only be demonstrated under strict in VlVO conditions or that post-binding transduction mechanisms are the sites of adaptive changes in naloxone sensitivity in the states of opiate dependence and withdrawal. * Preliminary reports of these data were given at the 13th Society for Neuroscience Meeting (1983) and the Wenner-Gren Symposium, Stockholm, Sweden (May, 1984).