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  • 1
    ISSN: 1432-1912
    Keywords: Key words Hypothalamic noradrenaline turnover ; Pituitary-adrenal axis ; Corticosterone ; Morphine dependence ; Calcium channels ; Nimodipine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of the L-type calcium channel antagonist nimodipine on both the activity of noradrenergic neurons projecting to the hypothalamus and the pituitary-adrenal response during morphine tolerance and withdrawal was analysed. Tissue concentration of hypothalamic noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxy-phenylethylen-glycol (MHPG) were determined by high-pressure liquid chromatography. Plasma corticosterone concentration (a marker of pituitary-adrenal activity) was measured by radioimmunoassay. Rats rendered tolerant to morphine decreased hypothalamic MHPG concentration, and reduced hypothalamic NA turnover. Chronic infusion of nimodipine concurrently with morphine prevented the decrease in NA turnover during tolerance. After naloxone administration to tolerant rats we found a striking parallelism between an increased activity of the hypothalamic-pituitary-adrenal axis and an enhanced activity of noradrenergic neurons projecting to the hypothalamus. However, hypothalamic NA turnover and MHPG concentration, both elevated during withdrawal, returned to control levels in rats infused chronically with nimodipine, concomitantly with a reduction of the secretion of corticosterone. Taken together, these data indicate that increased noradrenergic neuronal activity in the hypothalamic nerve terminals is associated with the neuroendocrine morphine withdrawal syndrome and suggest that an up-regulated calcium system might contribute to the activation of these neurons.
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  • 2
    ISSN: 1432-1912
    Keywords: Key words Opioids ; Tolerance ; Guinea-pig ileum ; Calcium channels ; Nimodipine ; BAY K 8644
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The influence of the L-type Ca2+ channel modulators nimodipine (a Ca2+ blocker) and BAY K 8644 (a Ca2+ activator) on the expression of tolerance to the inhibitory effects of κ- and μ-opioid agonists in the guinea-pig ileum from guinea-pigs rendered tolerant to the κ-opioid receptor agonist U-50,488H was investigated. Tolerance to U-50,488H was induced by its administration (15 mg/kg twice a day) for 4 days. Control groups received saline at the same time schedule. Chronic infusion of guinea-pigs with nimodipine (2 μg/μl/h for 7 days) or BAY K 8644 (0.5 μg/μl/h for 7 days), did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) preparation from naïve guinea-pigs. The Ca2+ antagonist nimodipine increases the potency of U-50,488H (selective κ agonist) to reduce the amplitude of neurogenic contractions of the MPLM strip in naïve animals, whereas the Ca2+ activator BAY K 8644 induced the opposite effect. However, the effect of DAMGO (selective μ agonist) was not modified in guinea-pigs infused with nimodipine or BAY K 8644. Tolerance to the inhibitory effects of both U-50,488H and DAMGO was observed following administration of U-50,488H for 4 days and was revealed as a rightward shift of the concentration-response curves for the two agonists. Chronic infusion of guinea-pigs with nimodipine concurrently with chronic U-50,488H, markedly attenuated the expression of selective tolerance to U-50,488H as well as the cross-tolerance between U-50,488H and DAMGO. By the contrary, the magnitude of tolerance to U-50,488H and to DAMGO was enhanced by concomitant infusion of BAY K 8644. The results suggest that, in the GPI, κ-opioid receptor may be functionally linked to the dihydropyridine sensitive Ca2+ channel: The blockade of the channel increased whereas its activation reduced the potency of U-50,488H. In chronic experiments, nimodipine prevented the expression of tolerance to U-50,488H and the cross-tolerance between U-50,488H and DAMGO, whereas BAY K 8644 produced the opposite effect. These results suggest that, in the GPI, selective tolerance to κ-agonist as well as cross-tolerance between κ- and μ-opioid agonists would involve activation of L-type Ca2+ channels, which could indicate that intracellular Ca2+ may be the final common pathway through which myenteric neurons adapt to the chronic opioid exposure.
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  • 3
    ISSN: 1432-1912
    Keywords: Tolerance ; Guinea-pig ileum ; Calcium channels ; Nimodipine ; BAY K 8644
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of the L-type Ca2+ channel modulators nimodipine (a Ca2+ blocker) and BAY K 8644 (a Ca2+ activator) on the expression of tolerance to the inhibitory effects of κ- and µ-opioid agonists in the guinea-pig ileum from guinea-pigs rendered tolerant to the κ-opioid receptor agonist U-50,488H was investigated. Tolerance to U-50,488H was induced by its administration (15 mg/kg twice a day) for 4 days. Control groups received saline at the same time schedule. Chronic infusion of guinea-pigs with nimodipine (2 μ/μl/h for 7 days) or BAY K 8644 (0.5 μ/μl/h for 7 days), did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) preparation from naive guinea-pigs. The Ca2+ antagonist nimodipine increases the potency of U-50,488H (selective κ agonist) to reduce the amplitude of neurogenic contractions of the MPLM strip in naïve animals, whereas the Ca2+ activator BAY K 8644 induced the opposite effect. However, the effect of DAMGO (selective µ agonist) was not modified in guinea-pigs infused with nimodipine or BAY K 8644. Tolerance to the inhibitory effects of both U-50,488H and DAMGO was observed following administration of U-50,488H for 4 days and was revealed as a rightward shift of the concentration-response curves for the two agonists. Chronic infusion of guinea-pigs with nimodipine concurrently with chronic U-50,488H, markedly attenuated the expression of selective tolerance to U-50,488H as well as the cross-tolerance between U-50,488H and DAMGO. By the contrary, the magnitude of tolerance to U-50,488H and to DAMGO was enhanced by concomitant infusion of BAY K 8644. The results suggest that, in the GPI, κ-opioid receptor may be functionally linked to the dihydropyridine-sensitive Ca2+ channel: The blockade of the channel increased whereas its activation reduced the potency of U-50,488H. In chronic experiments, nimodipine prevented the expression of tolerance to U-50,488H and the cross-tolerance between U-50,488H and DAMGO, whereas BAY K 8644 produced the opposite effect. These results suggest that, in the GPI, selective tolerance to κ-agonist as well as cross-tolerance between κ- and µ-opioid agonists would involve activation of L-type Ca2+ channels, which could indicate that intracellular Ca2+ may be the final common pathway through which myenteric neurons adapt to the chronic opioid exposure.
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  • 4
    ISSN: 1432-1912
    Keywords: Key words Morphine ; Tolerance ; Hypothalamus ; CRF ; AVP ; pituitary-adrenal axis ; Noradrenergic activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The changes in the content of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in discrete brain nuclei during chronic opioids administration have not been well established. We evaluated the effects of acute and chronic morphine administration on the content of CRF and AVP in different hypothalamic and extrahypothalamic (bed nucleus of the stria terminalis, BNST) nuclei in rats. Concomitantly, changes in hypothalamic noradrenaline (NA) turnover [estimated by the 3-methoxy-4-hydroxyphenylethyleneglycol MHPG/ NA ratio] and in plasma corticosterone release (as a marker of the activity of the hypothalamus-pituitary-adrenal axis) were determined. Male rats were implanted with placebo (naïve) or morphine (tolerant) pellets for 7 days. On day 8, groups of rats received an acute injection of either saline i.p. or morphine (30mg/kg i.p.) and were sacrificed 30min later. Acute morphine injection to naïve rats increased both the release of corticosterone and the hypothalamic NA turnover. CRF and AVP showed no modifications in the paraventricular nucleus (PVN) or in the median eminence (ME). CRF content decreased in the ventromedian nucleus (VMN) and increased in the BNST, but did not change in the arcuate nucleus (AN). AVP was elevated in the supraoptic nucleus (SON) but not changed in the suprachiasmatic nucleus (SCN). In chronic morphine-treated rats, there was a pronounced decrease in the NA turnover and in the release of corticosterone, which indicates that tolerance develops to the acute effects of morphine. Correspondingly, CRF and AVP were enhanced in the PVN and decreased in the ME, when compared with naïve rats injected with morphine. CRF content was decreased in the AN and in the BNST, but increased in the VMN. The AVP content was decreased in the SON, and no modifications were seen in the SCN. The present study shows that, in addition to the modifications in corticosterone secretion and in hypothalamic NA turnover, chronic morphine administration produces a complex response in the CRF and AVP systems. These modifications might contribute to the behavioral, emotional and neuroendocrine alterations produced during opioid tolerance.
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  • 5
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The content of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) increases during chronic morphine treatment. Because these experiments cannot distinguish between increased synthesis or reduced release, the present study measured changes in CRF and AVP mRNAs in the PVN by in situ hybridization. Concomitantly, changes in noradrenaline turnover in the PVN and changes in plasma corticosterone release were determined. Male rats were implanted with placebo (naive) or morphine pellets for 7 days. On day 7, groups of rats received an acute injection of either saline i.p. or morphine (30 mg/kg, i.p.). Acute morphine injection did not change the total size of the labelled area for CRF mRNA in the PVN of naive or morphine-pelleted rats, indicating that the number of CRF-containing neurones was unchanged. On the other hand, in rats chronically treated with morphine, the intensity of labelling for CRF mRNA was significantly reduced, suggesting a decrease in the synthesis of CRF. In placebo rats, injection of saline or morphine did not affect the surface hybridized for AVP mRNA. By contrast, in the morphine-group injected with saline, there was a significant reduction in the number of labelled neurones, measured by the size of labelled area. Similarly, there was a decrease in intensity of AVP mRNA expression in the parvocellular and magnocellular neurones of the PVN in the morphine-group injected with saline, suggesting a decreased synthesis of AVP in these neurones. In parallel with the decrease in the expression of CRF and AVP mRNAs in the PVN, there was a pronounced decrease in noradrenaline turnover and in the release of corticosterone in the morphine-pelleted rats. In conclusion, present results show that, in addition to modifications in corticosterone secretion and in noradrenaline turnover, chronic morphine administration produces a reduction in the synthesis of CRF and AVP.
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