Chronic exposure to morphine and naltrexone induces changes in catecholaminergic neurotransmission in rat brain without altering μ-opioid receptor sensitivity

doi:10.1016/0024-3205(93)90476-J

Life Sciences

Volume 52, Issue 21, 1993, Pages 1685-1693

https://doi.org/10.1016/0024-3205(93)90476-J Get rights and content

Abstract

In order to investigate the role of μ-opioid receptor regulation in catecholaminergic neurotransmission during morphine tolerance/dependence and supersensitivity, we measured changes in number and functional properties of two distinct types of μ receptors in the brain of rats chronically treated with morphine and naltrexone. In membranes of striatum and cortex of morphine treated rats the binding of μ ligand [³H]DAMGO was unaltered, whereas an increase in μ binding sites was found in these brain regions of naltrexone treated rats. The ability of the μ agonist DAMGO to inhibit the dopamine D-1 receptor stimulated cAMP production in striatal slices and the electrically evoked release of [³H]noradrenaline from cortical slices was unaffected in both experimental groups. The major changes found were an increased D-1 receptor stimulated cAMP production and an enhanced release of nonadrenaline in morphine treated rats and a decreased D-1 receptor stimulated cAMP production in naltrexone treated rats. These data support the hypothesis that tolerance and supersensitivity to morphine and other μ-opioids may be caused by up- and down-regulated neuronal second messenger systems linked to μ-opioid receptors, rather than by changes in the sensitivity of the μ-opioid receptor itself.

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The utility of morphine for the treatment of chronic pain is hindered by the development of tolerance to the analgesic effects of the drug. Morphine is unique among opiates in its ability to activate the mu opioid receptor (MOR) without promoting its desensitization and endocytosis. Here we demonstrate that [D-Ala²-MePhe⁴-Gly⁵-ol] enkephalin (DAMGO) can facilitate the ability of morphine to stimulate MOR endocytosis. As a consequence, rats treated chronically with both drugs show reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrate that endocytosis of the MOR can reduce the development of tolerance, and hence suggest an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain.
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It has previously been demonstrated that stimulation of opiate receptors within the nucleus accumbens results in marked hyperphagia, perhaps reflecting enhancement of taste palatability. Rats that have received multiple morphine treatments also increase feeding in response to environmental stimuli that have been associated with the morphine injections. The present investigation further examined this phenomenon. In Experiment 1, it was shown that induction of conditioned feeding was dose-dependent; significant conditioned feeding was obtained with repeated (n = 5) intra-accumbens injections of 5 or 10 μg/μl morphine but not with saline or 1 μg. The conditioned feeding response was blocked by systemic naltrexone (5 mg/kg). In the second experiment, co-treatment with either a D-1 (SCH 23390, 0.1 mg/kg) or D-2 (haloperidol, 0.25 mg/kg) antagonist did not block the development of conditioned feeding, nor did these drugs block morphine-induced feeding. In Experiment 3, it was found that systemic naltrexone blocked the expression of conditioned feeding (confirming Experiment 1), as did SCH-23390, whereas haloperidol did not affect expression of conditioned feeding. In the fourth experiment, we observed that significant conditioned feeding was induced with repeated treatment with the selective mu agonist D-Ala2, NMe-phe4, Glyol5-enkephalin (DAMGO, 2.5 μg), but not with the delta agonist D-Pen2,5-enkephalin (DPEN, 3.1 μg). The final experiment tested the diurnal variability of the expression of conditioned feeding, and it was found that the magnitude of the effect depended on time of day. In summary, the development of opioid-induced conditioned feeding depends on mu opiate receptor stimulation, but not dopamine receptor stimulation. Its expression, however, involves both opiate and D-1 receptor activation. These findings are considered in terms of putative neural mechanisms governing conditioned meal initiation, and implications for compulsive eating and bulimia are also discussed.
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Previous report from our laboratory showed that morphine produces a stimulatory effect of hypothalamic noradrenaline (NA) turnover concurrently with enhanced pituitary-adrenal response after its acute injection and during withdrawal. In the present work we have studied the effects of acute and chronic administration of the kappa agonist U-50,488H as well as the influence of U-50,488H withdrawal on the activity of hypothalamic NA and dopamine (DA) neurons and on the activity of hypothalamic-pituitary-adrenal (HPA) axis. A single dose of U-50,488H (15 mg/kg i.p.) significantly increased hypothalamic NA and decreased DA turnover at the time of an enhanced corticosterone release. Rats rendered tolerant to the kappa agonist by administration of U-50,488H twice a day for 4 days showed no changes in corticosterone secretion. Additionally, a decrease in both hypothalamic MHPG (the cerebral NA metabolite) production and NA turnover was observed, whereas DOPAC concentration and DA turnover were enhanced, which indicate the development of tolerance towards the neuronal and endocrine actions of U-50,488H. After naloxone (3 mg/kg s.c.) administration to U-50,488H-tolerant rats, we found neither behavioural signs of physical dependence nor changes in hypothalamic catecholaminergic neurotransmission. In addition, corticosterone secretion was not altered in U-50,488H withdrawn rats. Present data clearly indicate that tolerance develops towards the NA turnover accelerating and DA turnover decreasing effect of U-50,488H. Importantly and by contrast to mu agonists, present results demonstrate that U-50,488H withdrawal produce no changes in hypothalamic catecholamines turnover or in corticosterone release (an index of the hypothalamus-pituitary-adrenal activity), which indicate the absence of neuroendocrine dependence on the kappa agonist. As has been proposed, this would suggest that the mu and the kappa receptor be regulated through different cellular mechanisms, as kappa agonists have a lower proclivity to induce dependence.
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Chronic exposure to morphine and naltrexone induces changes in catecholaminergic neurotransmission in rat brain without altering μ-opioid receptor sensitivity

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Biochem. Pharmacol.

Biochem. Pharmacol.

Eur. J. Pharmacol. Mol. Pharmacol.

Eur. J. Pharmacol. Mol. Pharmacol.

Biochem. Pharmacol.

Life Sci.

Pharmacol. Biochem. Behav.

Life Sci.

Life Sci.

Eur. J. Pharmacol.

Dev. Brain Res.

Anal. Biochem.

Eur. J. Pharmacol.

Brain Research

Dev. Brain Res.

Eur. J. Pharmacol. Mol. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Nature