Stimulatory Effect Of Morphine Research Articles

Comparative analysis of the effects of opioids in angiogenesis

BackgroundAngiogenesis, the formation of blood vessel from pre-existing ones, plays an important role in many pathophysiological diseases, such as cancer. Opioids are often used in clinic for the management of chronic pain in cancer patients at terminal phases. Here, we investigated and compared the effects and mechanisms of four opioids on angiogenesis.MethodsWe performed angiogenesis assays on human umbilical vein endothelial cells (HUVEC) that represent an in vitro model to assess the toxicity of drugs to endothelium.ResultsMorphine and oxycodone at 0.1 μM to 100 μM dose-dependently increased endothelial cell tube formation and proliferation. We observed the same in endothelial cells exposed to fentanyl at 0.1 μM to 10 μM but there was a gradual loss of stimulation by fentanyl at 100 μM and 1000 μM. Morphine and fentanyl reduced endothelial cell apoptosis-induced by serum withdrawal whereas oxycodone did not display anti-apoptotic effect, via decreasing Bax level. Oxycodone at the same concentrations was less potent than morphine and fentanyl. Different from other three opioids, codeine at all tested concentrations did not affect endothelial cell tube formation, proliferation and survival. Mechanism studies demonstrated that opioids acted on endothelial cells via μ-opioid receptor-independent pathway. Although we observed the increased phosphorylation of mitogen-activated protein kinase (MAPK) in cells exposed to morphine, fentanyl and oxycodone, the rescue studies demonstrated that the stimulatory effects of morphine but not fentanyl nor oxycodone were reversed by a specific MAPK inhibitor.ConclusionOur work demonstrates the differential effects and mechanisms of opioids on angiogenesis.

Morphine enhances LPS-induced macrophage apoptosis through a PPARγ-dependent mechanism.

Morphine has been widely used for the treatment of pain and extensive studies have revealed a regulatory role for morphine in cell apoptosis. However, the molecular mechanisms underlying morphine-mediated apoptosis remain to be fully elucidated. The present study aimed to investigate the effects of morphine on lipopolysaccharide (LPS)-induced bone marrow-derived macrophage (BMDM) apoptosis and to determine the role of the peroxisome proliferator-activated receptor (PPAR)γ signaling pathway in this process. BMDMs were isolated from BALB/c mice and stimulated with LPS. Hoechst 33342 staining and flow cytometric analysis were performed to evaluate the effects of morphine on LPS-induced apoptosis of BMDMs. Caspase activity assays were used to determine the involvement of the apoptosis pathway. The expression levels of caspase-3, caspase-8, caspase-9 and PPARγ were analyzed using western blotting. Finally, GW9662, a specific PPARγ antagonist, was used to determine whether the regulatory effects of morphine on LPS-induced BMDM apoptosis were PPARγ-dependent. The results of the present study revealed that morphine increased the apoptosis of LPS-stimulated BMDMs. Morphine upregulated the expression levels and activity of caspase-3 in LPS-stimulated BMDMs, but downregulated the expression levels and activity of caspase-8. Morphine treatment also upregulated LPS-induced PPARγ expression levels in BMDMs. Finally, the stimulatory effects of morphine on LPS-induced apoptosis and caspase-3/9 activation were markedly reduced by GW9662. In conclusion, the findings of the present study indicated that morphine significantly promoted LPS-induced BMDM apoptosis and caspase-3/9 activation. These results suggested that the intrinsic pathway of apoptosis may be involved in the proapoptotic effects of morphine on LPS-stimulated BMDMs, which may be dependent, at least partially, on PPARγ activation.

Morphine Stimulates Migration and Growth and Alleviates the Effects of Chemo Drugs via AMPK-Dependent Induction of Epithelial-Mesenchymal Transition in Esophageal Carcinoma Cells.

The role of morphine, an opioid analgesic drug, in cancer biology has increasingly garnered attention due to its frequent usage in postoperative period for pain management in cancer patients. In this work, we demonstrated that morphine, at clinically relevant concentrations, stimulated migration and growth, and alleviated chemo drugs' efficacy in esophageal carcinoma cells. Although morphine did not affect survival, it protected esophageal carcinoma cells from chemo drugs-induced apoptosis. Mechanistical studies showed that morphine increased RhoA but not Rac1 activity. In addition, morphine activated AMP-activated protein kinase (AMPK) pathway, induced epithelial-mesenchymal transition (EMT) via upregulating Snail and Slug levels, and increased oxidative stress in esophageal carcinoma cells. Rescue studies further demonstrated that the stimulatory effects of morphine in esophageal carcinoma cells are through activation of AMPK pathway but not RhoA or opioid receptor. In addition, morphine induced EMT in an AMPK-dependent manner whereas increased RhoA activity in an AMPK-independent manner. Our work demonstrates the protective role of morphine on esophageal carcinoma cells via AMPK activation, which may provide a new guide in clinical use of morphine for patients with esophageal carcinoma.

Stimulatory and inhibitory effects of morphine on pentylenetetrazol-induced epileptic activity in rat

Aims The present study attempts to evaluate the effects of different doses of morphine on experimental epileptiform activity caused by pentylenetetrazol (PTZ) in rats. Methods Thirty adult male rats were assigned to saline (n = 5), morphine (2, 5, and 10 mg/kg, n = 15), naloxone (1 mg/kg, n = 5), and pre-treated with naloxone+morphine (1 + 10 mg/kg, n = 5) groups. The animals were anesthetized with ketamine + xylazine (80 + 8 mg/kg), and then a bipolar electrode was implanted into the CA1 (AP: −2.76 mm, ML: −1.4 mm and DV: 3 mm). To evaluate the effects of drugs on spike count and their amplitudes by elab amplifier, after drug administration for 25 min, PTZ (80 mg/kg, i.p.) was injected to induce epileptiform activity. Finally, diazepam (10 mg/kg) was used to suppress epileptic activity. Results The results revealed that morphine at a dose of 2 mg/kg decreased, and at doses of 5 and 10 mg/kg had an increasing effect on seizure-like events (SLEs). Nevertheless, morphine at a dose of 10 mg/kg enhanced SLEs significantly (p < 0.01). Naloxone at a dose of 1 mg/kg had no significant effect on the spike count but increased amplitude of them (p < 0.001). Moreover, being pretreatment with naloxone at a dose of 1 mg/kg, the morphine group showed significantly increased in the spike count (p < 0.05). Conclusions Morphine has biphasic effects on PTZ-induced epileptiform activities that way at a low dose has an inhibitory effect, but if the dose is increased, it will intensify the desired event and that the stimulatory effects of morphine appear not to be via opioid receptors.

Morphine stimulates CCL2 production by human neurons

BackgroundSubstances of abuse, such as opiates, have a variety of immunomodulatory properties that may influence both neuroinflammatory and neurodegenerative disease processes. The chemokine CCL2, which plays a pivotal role in the recruitment of inflammatory cells in the nervous system, is one of only a few chemokines produced by neurons. We hypothesized that morphine may alter expression of CCL2 by human neurons.MethodsPrimary neuronal cell cultures and highly purified astrocyte and microglial cell cultures were prepared from human fetal brain tissue. Cell cultures were treated with morphine, and cells were examined by RNase protection assay for mRNA. Culture supernatants were assayed by ELISA for CCL2 protein. β-funaltrexamine (β-FNA) was used to block μ-opioid receptor (MOR)s.ResultsMorphine upregulated CCL2 mRNA and protein in neuronal cultures in a concentration- and time-dependent fashion, but had no effect on CCL2 production in astrocyte or microglial cell cultures. Immunocytochemical analysis also demonstrated CCL2 production in morphine-stimulated neuronal cultures. The stimulatory effect of morphine was abrogated by β-FNA, indicating an MOR-mediated mechanism.ConclusionMorphine stimulates CCL2 production by human neurons via a MOR-related mechanism. This finding suggests another mechanism whereby opiates could affect neuroinflammatory responses.

Stimulatory effect of morphine on rat pineal melatonin synthesis via a cyclic AMP-dependent transcription pathway

The expression of mRNA of opioid receptors and the existence of opioid binding site in the rat pineal gland have been demonstrated previously. A major finding was that morphine enhanced the activity of the rate-limiting enzyme, N-acetyltransferase (NAT) and increased the level of melatonin in rat pineal gland. An attempt has been made in order to clarify the mechanism of this induction. In the present study, the stimulatory effect of morphine on the expression of NAT mRNA in the rat pineal gland has been demonstrated using semi-quantitative RT-PCR technique. The results showed that both acute and chronic morphine treatments significantly increased NAT mRNA expression in rat pineal gland. In addition, the effect of morphine on the phosphorylation of the transcription factors, cyclic AMP responsive element-binding protein (CREB) was investigated. Western blot analysis showed that morphine significantly increased phosphorylation of CREB. These results indicate that at least one downstream messenger pathway for the activation of opioidergic system on the induction of melatonin synthesis in the rat pineal gland acts via cyclic AMP-dependent cascade and transcription mechanism.

Effects of repeated morphine treatment on metabolism of cerebral dopamine and serotonin in alcohol-preferring AA and alcohol-avoiding ANA rats.

The alcohol-preferring AA (Alko Alcohol) rats are more rapidly sensitized to the locomotor activity-stimulating effects of small doses of morphine than the alcohol-avoiding ANA (Alko Non-Alcohol) rats. To study the involvement of dopaminergic and serotonergic transmission in this behaviour, the effects of acute morphine (1 mg/kg) challenge on the concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT, serotonin) and their metabolites were estimated in three dopaminergic areas in AA and ANA rats on the fourth day after a 3-day morphine or saline treatment. Acute administration of morphine enhanced DA metabolism in the caudate-putamen in the AA, but not in the ANA, rats; in the nucleus accumbens and in the olfactory tubercle the acute effect of morphine was similar in rats of both lines. Morphine pretreatment did not significantly enhance acute morphine's effects on DA metabolites in any of the brain areas studied in rats of either line. Acute administration of morphine enhanced brain 5-HT metabolism in the AA rats but not in the ANA rats, but after repeated treatment it induced no enhancement of 5-HT metabolism. With the methods used, no significant differences were found between the AA and ANA rats in the effects of repeated morphine on cerebral dopaminergic or serotonergic mechanisms which could account for the different behavioural sensitization found previously in rats of these lines. However, both monoamines studied might be involved in the acute locomotor stimulatory effects of morphine.

Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate–putamen in rats sensitized to morphine

In this study, we describe a model of opiate sensitization characterized by a brief schedule of treatment with repeated morphine administrations. In this model, we investigated the changes produced by repeated morphine treatment on dopamine transmission at the level of the two major terminal dopaminergic areas, the dorsolateral caudate–putamen and the nucleus accumbens in its two subdivisions, the shell and the core. Rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with 1 and 5 mg/kg (s.c.) of morphine, and dopamine transmission was monitored by microdialysis. In this model, we show that repeated morphine produces a strong behavioral sensitization accompained by increased stimulation of dopamine transmission in the core of the nucleus accumbens and in the caudate–putamen, and by a decreased stimulation of dopamine transmission in the shell of the nucleus accumbens, as compared to control rats. Moreover, we administered to these animals amphetamine (0.5 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) to assess whether cross-sensitization occurs between opiates and psychostimulants in conditions independent of the context. In the present study, we did not observe either behavioral or biochemical sensitization to amphetamine and to cocaine in rats sensitized to morphine. These results suggest that rats behaviorally sensitized to morphine show opposite changes in the stimulant effect of morphine in the nucleus accumbens shell and core and in the dorsal caudate–putamen. Moreover, this study suggests that sensitization of the dopamine system to a given agent does not necessarily extend to drugs of abuse of different pharmacological classes.

Regulation of motilin release: studies with ex vivo perfused canine jejunum.

The regulatory process of motilin release was studied in segments of canine jejunum isolated and perfused ex vivo. The secretion of motilin in the effluent venous system of the isolated intestine was measured by radioimmunoassay in response to various pharmacological agents injected intra-arterially. Muscarinie agonist and antagonist, respectively, increased and decreased the release of motilin. The stimulatory effect of carbachol was still documented after tetrodotoxin (10(-5) M) was injected in the system to block neural influence on M cells. Bombesin and morphine also increased the release of motilin. The effect of bombesin was still documented in the presence of atropine or tetrodotoxin, but the stimulatory morphine effect was blocked by atropine. Both phenylephrine and octreotide decreased the release of motilin stimulated by carbachol in a jejunal segment pretreated and denervated with tetrodotoxin. Therefore, a revised model for the regulation of motilin release from M cells of intestinal mucosa can now be proposed. Cholinergic and bombesin receptors are present on M cells to encode a stimulatory signal, whereas adrenergic and somatostatin receptors are responsible for inhibitory transmission. The stimulatory effect of morphine is mediated via a muscarinic transmitter.

Cold exposure attenuates effects of secretagogues on serum prolactin and growth hormone levels in male rats.

The stimulatory effect of morphine, dexmedetomidine (an alpha 2-adrenoceptor agonist), 1-(3-chlorophenyl)-piperazine (m-CPP, a 5-HT1B agonist), U-50488H (a kappa-opioid receptor agonist), pimozide (a dopamine antagonist), and restraint stress on prolactin and growth hormone (GH) secretion was compared during cold exposure (4 degrees C) and under basal conditions (30 degrees C) in male rats. Rectal temperature was also measured. The stimulatory effect of morphine, dexmedetomidine, m-CPP, and partially U-50488H on prolactin secretion was attenuated in rats kept at 4 degrees C. Cold exposure did not abolish prolactin release induced by pimozide and restraint stress. Cold exposure also antagonized the effect of morphine and dexmedetomidine on GH secretion. The stimulatory effect of morphine on prolactin and GH secretion was restored in the warm environment despite the sustained hypothermia. Cold exposure blocked the stimulatory effect of morphine on prolactin secretion in rats that were tolerant to the hypothermic effect of morphine. Thus hypothermia caused by morphine, dexmedetomidine, and m-CPP during cold exposure is not the sole factor in the antagonistic effect of cold. We suggest that cold exposure releases some compound(s) modulating hypothalamic neural pathways.

Morphine stimulates phagocytosis of Mycobacterium tuberculosis by human microglial cells: involvement of a G protein-coupled opiate receptor

Opiate-induced immunosuppression has been implicated in the pathogenesis of infections caused by a variety of microorganisms, including human immunodeficiency virus (HIV). Although effects of opiates on lymphocyte function have been studied more extensively, morphine also has been shown to inhibit several functional activities of mononuclear phagocytes (e.g. chemotaxis, respiratory burst activity and phagocytosis). Opiate addiction has been identified as a risk factor for clinical tuberculosis prior to the HIV epidemic, and macrophages are a key cell in the pathogenesis of Mycobacterium tuberculosis. Thus, the hypothesis was tested in the present study that morphine would suppress phagocytosis of M. tuberculosis by human microglial cells, the resident macrophages of the brain. Contrary to this hypothesis, treatment of human fetal microglial cell cultures with morphine (10 −8 m) was found to stimulate phagocytosis of nonopsonized M. tuberculosis H37Rv. The stimulatory effect of morphine was blocked by naloxone and the μ opiate receptor selective antagonist β-funaltrexamine. Also, morphine-induced increase in phagocytic activity was markedly inhibited by pertussis toxin and was unaffected by cholera toxin, suggesting the mechanism of morphine's stimulatory effect on microglial cell phagocytosis involves a G i protein-coupled μ opiate receptor. The results of this in vitro study support the concept that exogenous and endogenous opioids play an immunomodulatory role within the central nervous system through their interaction with G protein-coupled receptors on microglial cells.

Variation in tolerance to the antinociceptive, hormonal and thermal effects of morphine after a 5-day pre-treatment of male rats with increasing doses of morphine.

The manifestation of tolerance to the effects of morphine on nociception and the secretion of anterior pituitary hormones, and the correlation of hormonal effects to changes in body temperature and to hypothalamic monoamines were studied in male rats. Morphine (three times a day in increasing doses) or saline (control) were administered intraperitoneally during a 5-day treatment and either saline or morphine was administered as an acute challenge 92 h later. The influence of the thermal environment on the effect of morphine on the body temperature was also studied. The 5-day morphine regimen was sufficient for the development of tolerance to the antinociceptive effect of morphine. After a 92-h lag-time, the tolerance was still complete. Tolerance to the depressant effect of morphine (10-25 mg/kg) on cold-stimulated TSH secretion was seen at 2 h, but was only barely detectable at 1 h, after the injection of a challenge dose. On the other hand, a tolerance to the stimulatory effect of morphine on prolactin secretion was already seen 1 h after the acute dose of morphine. Tolerance to the hypothermic effect of morphine (25 mg/kg) was evident in rats kept at +4 degrees C after the challenge dose. On the contrary, no tolerance to the hyperthermic effect of morphine (15 or 25 mg/kg) was observed in rats kept at +30 degrees C. However, the hyperthermia was reversed when these rats were moved to +4 degrees C for 30 min, irrespective of whether they were morphine pretreated or not. Thus the removal of the hyperthermic stimulus decreased the core temperature of all rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Individual differences in the psychomotor effects of morphine are predicted by reactivity to novelty and influenced by corticosterone secretion

Clinical observations show that individual vulnerability to the reinforcing properties of drugs plays an important part in the subsequent development of addiction. In animals, individual vulnerability to psychostimulants has been found to be predicted by their locomotor response to novelty as well as their corticosterone response. Rats with a high locomotor response to novelty (High Responders or HR) relative to Low Responders (LR), show a higher sensitivity to both the psychomotor and reinforcing effects of psychostimulants and a longer lasting corticosterone secretion in response to stress. In this study, we addressed two main questions. First, does the locomotor response to novelty also predict the psychomotor effects of morphine? Second, do differences in corticosterone secretion underlie individual differences in the stimulant effects of morphine? We compared the locomotor response to morphine (2 mg/kg s.c.) in: (i) HR and LR rats with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) HR and LR rats in which stress-induced corticosterone secretion was suppressed by adrenalectomy but basal levels of corticosterone were maintained by implantation of subcutaneous corticosterone pellets. In animals with an intact HPA axis, HR rats showed a higher locomotor response than did LRs to morphine. In animals in which corticosterone secretion was suppressed, the enhanced locomotor response of the HRs to morphine fell to that observed in the LRs. In conclusion our data show that, (1) individual reactivity to novelty can predict individual vulnerability to the psychomotor effects of opioids, and (2) stress-induced corticosterone secretion may play a role in determining individual differences in sensitivity to these drugs. These results are comparable to those observed with psychostimulants, and suggest that a common biological mechanism underlies individual vulnerability to the effects of both classes of drugs.

The presence and actions of opioid receptors in bovine pineal gland.

The mammalian pineal gland and its main hormone, melatonin, working in conjunction with the hypothalamic suprachiasmatic nuclei, synchronize circadian rhythm and hence refine numerous physiological and biochemical parameters. An interaction among melatonin, opioids, and analgesia has been suspected for many years, since during nighttime, when the level of melatonin is high, the mammals are less sensitive to pain. In studying this phenomenon further, we have identified a single population of opioid receptors in the bovine pineal gland using [3H]-diprenorphine and other ligands. The receptors have a dissociation equilibrium constant (Kd) of 1.36 +/- 0.31 nM and a density (Bmax) of 17.93 +/- 5.22 fmol/mg protein. In competitive experiments, the concentration of drugs required to inhibit 50% of the [3H]-diprenorphine binding (IC50) in descending order of potency was found to be naltrexone > fentanyl > naloxone > nalbuphine > morphine > nalorphine > DAGO > dynorphin > metenkephalin. In order to delineate the function of the opioid system in the pineal gland, the effects of both opioid receptor agonists and antagonists on the basal activity of N-acetyltransferase were examined in the bovine pineal explants in culture. Morphine, an opioid receptor agonist, increased significantly the activity of N-acetyltransferase in a dose-dependent fashion. In addition, the stimulatory effect of morphine was inhibited by naloxone, an opioid receptor antagonist. The results of these studies indicate the existence of pineal opioid receptors, which play a pivotal role in the synthesis of melatonin and its action in synchronizing pineal events.

MORPHINE INFLUENCE ON ADENYLATE CYCLASE ACTIVITY IN PERIPHERAL BLOOD LYMPHOCYTES OF ALCOHOLIC PATIENTS

The effect of morphine on adenylate cyclase activity in lymphocytes was tested in 20 normal controls, 16 alcoholics in withdrawal and 9 sober alcoholics. Alcoholics in withdrawal were characterized by a significantly increased stimulatory effect of morphine, whereas sober alcoholics showed an inhibitory effect. The morphine effect was abolished by naloxone and correlated with the severity of withdrawal and alcohol intoxication.

Morphine-Induced Transactivation of HIV-1 LTR in Human Neuroblastoma Cells

Infection by human immunodeficiency virus (HIV) is followed in many cases by a clinically quiescent or latent phase that appears to continue as long as host antiviral defense is intact. This has raised the possibility that certain host susceptibility factors (i.e., environmental cofactors) might influence the progression of the disease. In this study we demonstrate that morphine can function to activate HIV/LTR-CAT fusion gene (HIV-long terminal repeat-chloramphenicol acetyltransferase) when transfected into undifferentiated human SH-SY5Y neuroblastoma cells. The stimulatory effect of morphine is amplified in SH-SY5Y cells that have been induced to differentiate first with phorbol 12-myristate 13-acetate (PMA) and is much less in cells differentiated with retinoic acid (RA). Morphine does not appreciably activate HIV/LTR-CAT expression in human MOLT-3 and other T cells. Morphine activation of HIV/LTR-CAT in the SH-SY5Y cells is not reversible by naltrexone and appears to involve a Fos/Jun signaling system. Our results suggest that narcotics such as morphine may lead to activation of latent HIV infection. This may be particularly important in tissues, such as brain, which can host latent HIV infection and which is uniquely damaged in patients with acquired immunodeficiency syndrome (AIDS) as evidenced by neuronal degeneration and dementia. We also predict that these findings may have important implications for the pathogenesis of AIDS, particularly in opiate drug abusers.

Inhibitory and stimulatory effects of morphine on locomotor activity in mice: Biochemical and behavioral studies

A possible interaction between the opposite effect (inhibition and stimulation) of morphine on locomotor activity in mice and monoaminergic systems in the striatum was studied. Ten minutes after systemic administration, morphine at 1.25 mg/kg decreased locomotor activity and the levels of 3-methoxytyramine (3-MT), whereas at 20 mg/kg locomotor activity and 3-MT levels increased. At the same time, no change in the other monoamine metabolite (DOPAC, HVA, MHPG, and 5-HIAA) levels was observed. Sixty minutes after administration, morphine at 1.25 mg/kg did not induce any change in locomotor activity or in all the monoamine metabolite levels measured. On the other hand, morphine at 20 mg/kg maintained an initial increase in locomotor activity and increased not only 3-MT levels, but also other metabolite (DOPAC, HVA, MHPG, and 5-HIAA) levels. These results suggest that, at low dosages, the inhibitory effect of morphine on locomotor activity in mice may be related to a decrease of the presynaptic dopamine release in the striatum and that the stimulatory effect of morphine, at high dosages, may be related to an increase of the presynaptic dopamine release in the striatum.

Role of Alpha-Adrenergic Mechanism in Effects of Morphine on the Hypothalamo-Pituitary-Adrenocortical and Cardiovascular Systems in the Rat

The role of alpha-adrenergic mechanism in the acute effects of morphine in the hypothalamo-pituitary-adrenocortical (HPA) and cardiovascular (CV) systems, and the interrelationship between the HPA and CV responses to alpha-adrenoceptor antagonists and/or morphine were studied by peripheral administration of prazosin, a selective alpha 1-adrenoceptor antagonist, and yohimbine, a selective alpha 2-adrenoceptor antagonist, in conscious, unstressed or ether-stressed rats. The test substances were administered intravenously or intraperitoneally in chronically cannulated or noncannulated rats. In the i.v. experiment, morphine (1 mg/100 g BW) rapidly induced a pronounced bradycardia and a short-lasting fall in blood pressure (BP), followed by a rise in BP, and increased plasma corticosterone concentration. Prazosin (0.5 mg/kg BW) induced a rapid fall in BP and tachycardia, and increased plasma corticosterone concentration. Pretreatment with prazosin did not block the effect of morphine on the CV system, but abolished the morphine-induced increment in plasma corticosterone concentration. Yohimbine (0.5 mg/kg BW) induced a rapid and a subsequent slowly developing rise in BP and tachycardia, and increased plasma corticosterone concentration. Pretreatment with yohimbine did not block the effect of morphine on the CV system nor alter the stimulatory effect of morphine on the secretion of corticosterone. In the intraperitoneal experiment, morphine (2 mg/100 g BW) stimulated the secretion of adrenocorticotropic hormone (ACTH) and corticosterone and prazosin (1 mg/kg BW) stimulated the secretion of corticosterone, but pretreatment with prazosin reduced the morphine-induced increment in plasma corticosterone concentration in unstressed rats. In stressed rats, morphine reduced the stress-induced increment in plasma ACTH and corticosterone concentrations and prazosin also reduced the stress-induced increment in plasma corticosterone concentration. Pretreatment with prazosin did not alter the inhibitory effect of morphine...

Involvement of central histamine receptors in corticosterone secretion induced by intraventricular administration of morphine.

The effect of intracerebroventricular (i.c.v.) administration of morphine on corticosterone secretion was studied in conscious, unstressed rats. A dose-dependent increase in serum corticosterone levels was observed 1 h after morphine injection. The corticosterone response to morphine was antagonized in a dose-dependent manner, and at larger dose almost abolished, by i.c.v. pretreatment of rats with naloxone, an opioid receptor antagonist. Intraventricular pretreatment of rats with mepyramine and cimetidine, the histamine H1- and H2-receptor antagonists, significantly diminished the corticosterone response to morphine. These results suggest that central opioid receptors are involved in the stimulating effect of morphine on the hypothalamo-pituitary-adrenocortical axis. Central histamine H1- and H2-receptors seem to be substantially involved in the stimulatory effect of morphine on corticosterone secretion in conscious, unstressed rats.

Previous treatment with morphine and sensitization to the excitatory actions of opiates: Dose-effect relationship

The stimulatory effect of morphine on locomotor activity has been shown to be largely modified in rats that have been formerly dependent on this drug. In the present study, the relationship between the chronic dose of morphine and the degree of sensitization to the excitatory effect of opiates was investigated. To this end, four groups of rats were treated daily for 30 days with 1.25, 5, 20 and 80 mg/kg of morphine (i.p.) and challenged with morphine (1.25 and 2.5 mg/kg) or fentanyl (40 and 80 μg/Kg) 1–4 months after ceasing the treatment. Drug-induced hypermotility in post-dependent rats appeared to be linearly related to the dose of the preceding chronic treatment after test doses of both morphine and fentanyl. The results are discussed in terms of a persistent dose-related modification of the neuronal mechanism subserving the excitatory component of the action of opiates; such a modification might offer a neurobiological basis for the fact that “relapse tendencies” for opiates persist for a long time after withdrawal.