Effect Of Chronic Morphine Treatment Research Articles

Distribution of Substance P and Methionine-Enkephalin in Salivary Glands and Effect of Chronic Morphine Treatment on Levels of These Peptides

Substance P-like immunereactivity (SPLI) and methionine-enkephalinlike immunoreactivity (MELI) were determined in salivary glands from rats by radioimmunoassay. In all salivary glands investigated (submandibular gland, sublingual gland and parotid gland). SPLI and MELI were detected. The amount of both peptides is comparable to or relatively higher than those found in any other peripheral tissue. The level of SPLI showed a tendency to increase following chronic treatment with morphine; the enhancement in the submandibular gland and the sublingual gland was especially remarkable. The level of MELI was decreased, particularly in the submandibular gland.

Effect of chronic morphine treatment on the adrenaline biosynthesis in adrenals and brain regions of the rat

Phenylethanolamine- N-methyltransferase (PNMT) activity and tissue catecholamine content were examined after 13 days morphine treatment. Prolonged morphine treatment did not alter the PNMT activity in brain regions (A1/C1 and A2/C2 cell groups, medial basal hypothalamus, median eminence). However, the enzyme activity and the adrenaline content were increased in the adrenal medulla of male rats. In parallel, morphine treatment induced adrenal hypertrophy. In female or hypophysectomized male animals the chronic morphine treatment had no effect on adrenal weight but evoked the increase of PNMT activity. It is concluded that the morphine-induced increased adrenaline biosynthesis in the adrenal gland is not fully dependent on the intact pituitary-adrenal axis and may be mediated partly by a neural mechanism (increased splanchnic nerve activity) or by a direct effect of morphine.

Immunosuppressive effects of chronic morphine treatment in mice

In this report we describe the immunomodulatory effects of subcutaneous morphine pellets in mice, a model commonly used in the study of opiate tolerance and dependence. Mice given a single 75 mg morphine pellet displayed marked atrophy and reduced cellularity of the spleen and thymus, and an attenuated lymphocyte proliferative response to T- and B-cell mitogens (concanavalin A and bacterial lipopolysaccharide, respectively). These immunosuppressive effects were observed 72 hr following implantation of the pellet, a time point by which the mice also had developed tolerance to the antinociceptive effect of the pellet. Splenic and thymic atrophy with reduced mitogen-induced lymphocyte proliferative responses and opiate tolerance were also apparent in mice subjected to a multiple pellet implantation schedule. However, implantation of a pellet containing 37.5 mg morphine did not suppress mitogen-stimulated lymphocyte proliferation, which was slightly elevated in this group. These findings concur with other observations suggesting immunosuppression with morphine tolerance. Furthermore, we suggest that chronic morphine treatment acts as a pharmacologic stressor that mimics behavioral stress.

Gastric acid secretory responses to cholinergic and histaminergic stimulation in chronic morphine-treated rats

The effects of chronic morphine administration on cholinergic and histaminergic activities were evaluated in rats by observing their gastric acid secretory responses to secretagogues. The responses of in-vivo perfused stomachs to 2-deoxy-D-glucose or pentagastrin, and of the isolated gastric mucosa to histamine or bechanechol, were not significantly different between naive and chronic morphine-created animals. It is suggested chat the chronic morphine-created rats exhibit normal cholinergic and histaminergic activities as well as receptor sensitivities to acetylcholine and histamine. Many investigations have demonstrated chat chronic administration of morphine leads not only to the development of tolerance and physical dependence, but also to some physiological alterations. However, the chronic effects of the narcotic on cholinergic activity appear to be complex (Crossland and Slater, 1968; Bhargana and Hay, 1972; Jhamandas and Sutak, 1974; Mohanakumar and Sood, 1983). It also remains unclear whether chronic administration of the opiate will cause changes in the activity of the histamine-containing cells or in receptor sensitivity to histamine. The present study examines the effects of chronic morphine treatment on cholinergic and histaminergic activities in rats by observing the gastric acid secretory responses of in-vivo perfused stomachs and isolated mucosal preparations Co secretagogues.

Effects of chronic morphine treatment on opioid-induced inhibition and facilitation of acetylcholine release in guinea-pig thalamic slices

The effect of chronic morphine treatment on acetylcholine (ACh) release from guinea-pig thalamic slices and on [ 3H]-dihydro-morphine binding to the brain of normal, tolerant and abstinent guinea-pigs was studied. Morphine (30 μM) inhibited the electrically-evoked ACh release to the same extent in normal and tolerant slices. This effect was antagonized by naloxone. Morphine (30 μM) in the presence of naloxone (10 μM) facilitated electrically-evoked release of ACh. This effect displayed tachyphylaxis in normal slices and was absent in the brain taken from tolerant animals. The reduction of [Ca ++] in the medium increased the facilitatory response in normal slices and the inhibitory response in normal and tolerant tissue. The high and low affinity binding sites to [ 3H]-dihydro-morphine were the same in the thalami, caudate nuclei and cortices of normal, tolerant and abstinent animals. It is concluded that the cholinergic structures of the guinea-pig thalamus are unlikely to be involved in morphine tolerance. In fact, the facilitation appears to be an ancillary phenomenon which quicklydis plays tachyphylaxis in normal tissue while the inhibition of ACh release remains unchanged.

The effects of chronic morphine treatment on neurotensin-induced antinociception.

Previous studies have shown that the opioid antagonist naloxone does not alter neurotensin (NT)-induced antinociception. In the present studies, tolerance to morphine in mice significantly attenuated NT-induced antinociception, but not NT-induced hypothermia. In addition, centrally administered NT inhibited naloxone-precipitated jumping in morphine-dependent mice. These results indicate complex interactions between NT-induced antinociception and opioid systems.

Effect of chronic morphine treatment on β-endorphine biosynthesis by the rat neurointermediate lobe

The effect of chronic morphine treatment on the in vitro biosynthesis of β-endorphin by rat pars intermedia was investigated. Tolerance and physical dependence were induced in 200 g rats by the subcutaneous implantation of 75 mg morphine pellets for either 3 days or 15 days. Immediately following sacrifice of the animals the neurointermediate lobes were removed and incubated with [3H]phenylalanine. The protein extracts of the lobes were analyzed for the incorporation of the labelled amino acid into total protein, pro-opiomelanocortin, β-lipotropin (β-LPH) and β-endorphin. The biosynthesized products were purified by immunoprecipitaion with an anti-serum to β-endorphin. The identity and purity of β-endorphin were verified by polyacrylamide disc gel electroporesis with sodium dodecyl sulfate, and microsequencing. The identity of pro-opiofmelanocortin (POMC) was verified by peptide mapping of its tryptic digestion products. The results showed that morphine treatment induced a decreased in the incorporation of the radioactive amino acid into total protein, pro-opiomelanocortin, β-LPH and β-endorphin. The decrease was more pronounced for the incorporation into β-LPH and β-endorphin than into pro-opiomelanocortin and total proteins, suggesting an effect of morphine treatment on the processing of the pro-opiomelanocotrin to its final maturation products.

Effect of chronic morphine treatment on the interaction between the periaqueductal grey and the nucleus raphe magnus of the rat

The analgesic action of morphine is, in part, mediated through activation of a descending pathway. Major components of this pathway include the periaqueductal grey (PAG) and the nucleus raphe magnus (NRM). Injection of glutamate into the PAG increased the firing rate of its cells, led to an increase in the firing rate of NRM cells, and produced analgesia. The experiments reported here were designed to determine the effect of morphine tolerance on the interactions between the PAG and the NRM. Rats were made tolerant to morphine by implanting them with morphine pellets. The response of single cells in the NRM to the injection of glutamate into the PAG was recorded before and after iontophoretic application of naloxone into the NRM. It was shown that in morphine-tolerant animals, the response of NRM cells to microinjection of glutamate into the PAG was reduced significantly. However, when naloxone was iontophoresed into the NRM, there was a small increase in the spontaneous firing rate, and the injection of glutamate into the PAG produced a significant increase in the firing rate of the cells in the NRM. It is concluded that chronic morphine treatment decreased the effectiveness of excitation of cells in the PAG in activating NRM cells, and this process may play a part in the tolerance developed to the analgesic effect of morphine.

Partial purification of nuclear protein kinase from small dense nuclei of mouse brain and the effect of chronic morphine treatment.

Abstract: To deduce whether or not the nuclear protein kinase activity may be responsible for the change in phosphorylation of chromatin proteins during morphine tolerance‐dependence, the nuclear protein kinases from small dense nuclei of mouse brain have been partially purified by ammonium sulfate fractionation and phosphocellulose column chromatography. Two peaks of cyclic AMP‐independent nuclear protein kinase activity are eluted from the phosphocellulose column by a linear NaCl gradient. During morphine tolerance‐dependence, the specific activity of peak I, but not of peak 11, is increased significantly relative to placebo controls. This increase in nuclear protein kinase activity may partially account for the elevated chromatin protein phosphorylation in small dense nuclei of mouse brain seen during morphine tolerance‐dependence.

The effect of chronic morphine treatment of excitatory junction potentials in the mouse vas deferens.

1 Intracellular recordings were made from smooth muscle cells of vasa deferentia in vitro. Vasa from two groups of mice were studied; the first were naive and the second had been chronically pretreated with morphine for 3 days. The vasa from morphine-pretreated mice were maintained in Krebs solution containing normorphine (300 nM). 2 The resting membrane potentials of the smooth muscle cells were the same in both groups of mice. 3 The excitatory junction potentials (e.j.ps) evoked by stimulation of the intramural nerves were depressed by normorphine in both groups of mice. The EC50 for this action of normorphine was 560 nM for the naive group and 6.6 microM for the morphine-pretreated group. 4 The EC50 for adenosine in depressing e.j.p. amplitude was the same in the two groups. 5 Naloxone did not change the resting membrane potential in cells from either group of mice. In morphine-pretreated mice, naloxone caused a marked increase in the amplitude of the evoked e.j.p. 6 The EC50 for noradrenaline in causing a contractile response of the isolated vas deferens was the same in both groups of mice. 7 The results indicate that changes in postsynaptic sensitivity to transmitter do not occur following morphine pretreatment.

Effects of chronic morphine treatment on dopamine-mediated turning behaviour in rats and mice with 6-hydroxydopamineinduced unilateral nigro-striatal lesions

Subcutaneous implantation of morphine tablets in rats with a unilateral 6-hydroxydopamine lesion of nigro-striatal dopamine neurones caused a reduction, after 4 days, in the rates of contralateral/ ipsilateral circling produced by apomorphine and d-amphetamine. Naloxone-precipitated morphine withdrawal on day 5 led to faster d-amphetamine-induced circling together with, in the majority of rats, a corresponding increase in the apomorphine-induced circling rate. A minority of the naloxone-withdrawn rats failed to circle when given apomorphine and they remained unresponsive for 2 weeks after morphine withdrawal. The findings, although consistent with the hypothesis that chronic morphine treatment induces a degree of supersensitivity in dopamine receptors, suggest that other changes take place in the striatum. No change in the d-amphetamine-induced circling rate of 6-hydroxydopaminelesioned mice was recorded after 4 days of morphine treatment. Naloxone-precipitated morphine withdrawal revealed a subsensitivity to d-amphetamine which subsequently changed to an increased sensitivity and then returned to normal 14 days after morphine withdrawal. The results emphasize that chronic morphine administration does not have the same effect in the striatum of rats and mice.

The effects of chronic morphine treatment on histamine concentration and histidine decarboxylase activity in rat brain

1. 1. We reported previously ( Henwood and Mazurkiewicz-Kwilecki, 1975) that chronic morphine (Mo) administration or Mo withdrawal from Mo dependent rats resulted in a significant decrease in the endogenous histamine (HA) concentration in different brain regions of the rat. 2. 2. Present studies indicated a significant increase in histidine decarboxylase (HD) activity in the hypothalamus and in the cortex of Mo dependent rats. The latter observation is consistent with an increased HA synthesis in these brain regions. 3. 3. Significant increase in HD activity was also noted after Mo withdrawal. 4. 4. Present data produce evidence that HA, the new putative neurotransmitter in the brain, is involved in the mechanism of Mo dependence and Mo withdrawal.

Effect of chronic morphine treatment on brain chromatin template activities in mice

Chromatins have been isolated from both placebo- and chronic morphine-treated mice. The specific activity of chromatin-directed UTP incorporation was measured. Evidence is presented to show that the chromatin template activity isolated from tolerant animals is increased. The increase may be due to the alteration of non-histone protein in chromatin. This is a narcotic-specific phenomenon, since the morphine-induced increase can be blocked by naloxone.