morphine

It has been found that morphine may affect proliferation of cancer cells in addition to the effect of analgesia. In this study, the effects of morphine, naloxone, cannabinoid receptor type 1 inhibitor (Am251), phospholipase C inhibitor (U73122) and pregabalin were evaluated on YM1 esophageal cancer cell line viability. Esophageal cancer cell line YM1 cells were propagated in RPMI-1640 medium containing 10% FBS. Then the cells were treated with different doses of drugs for 24 hours and the cell viability was determined by the MTT method. The results were analyzed by one-way ANOVA and LSD post hoc test. The investigation showed that morphine in all three doses (87, 175 and 350 μM) significantly reduced the viability of cells (p < 0.05). The addition of 60 μM naloxone to the culture medium could not change the survival rate of esophageal cancer cells. But naloxone along with 350 μM morphine significantly decreased the survival rate compared to the control group (p < 0.001) and the naloxone group (p < 0.02). Phospholipase C inhibitor (U23177, 1mM) alone (P < 0.001) or together with 350 µM morphine decreased cell viability (p < 0.001). Also, AM251 140 μM alone (p < 0.05) or together with morphine decreased cell viability (p < 0.001). Pergabalin with a concentration of 6 μM with 6 mM alone (p < 0.05) or together with morphine decreased cell viability compared to the control group (p < 0.001) and the ratio of the 350 μM morphine group (p < 0.01). Also, cell viability in the group that was exposed to all three compounds was greatly reduced (p < 0.001). The results showed that morphine and the drugs investigated in this study can be used as potential options to reduce cell growth in patients with advanced esophageal cancer.

Behavioral sensitivity in response to morphine injection is a suitable model for studying the neuronal substrates of behavioral plasticity that is associated with reward and opioid abuse. The lateral septum (SL) plays a vital role in the reward and learning processes. The LS nucleus contains GABAergic neurons, and the outputs of this region into the ventral tegmentum (VTA) precisely regulate the amount of released dopamine. In the present study, we investigated the effects of injection of GABAB receptor agonists and antagonists on behavioral sensitivity to morphine in the conditioned place preference (CPP) model. In this experimental study, male Wistar rats were divided into 17 groups. Doses of 0.5, 1, 2.5, 5, 7.5, 10, 12.5, and 15 mg/kg of morphine were injected subcutaneously (S.C) into animals to determine effective and ineffective doses of morphine. An adequate amount of morphine was injected for 3 days to induce sensitization; after 5 days, CPP was performed with an ineffective dose of morphine. Doses of 1.5, 6, and 12 / µg/rat of agonist (baclofen) and antagonist (CGP35348) were injected into LS in the first 3 days of sensitization, 10 minutes before morphine injection. Baclofen at 6 µg/rat (p<0.05) and CGP35348 at 12 µg/rat (p<0.01) significantly reduced morphine sensitivity. GABAB receptors in the LS region can be an important target in the treatment of drug abuse.

Social isolation in the weeks after lactation can change the behavior of mature animals including yawning, a phylogenetic and contagious behavior. This study was conducted with the aim of determining the effect of social isolation stress on yawning behaviors in adult male rats treated with morphine and naloxone. A sample of 32 rats (21-day after weaning) was selected and the rats were put in separate cages with black plastic buffers for 6 weeks. Eight rats were put in a group (control group) and the other rest were put in individual cages: one male rat in each cage; and we grouped them as follows: in group 1 or the control group (social), each cage had 8 rats receiving (saline) at a dose 1 mg/kg and their yawning behavior was recorded for 60 minutes after 6 weeks. Group 2 (social isolation) received no treatment with opioid agonist and antagonist kept in separate cages with one rat in each cage. Their yawning behavior was recorded for 60 minutes after 6 weeks. Group 3 (social isolation) received treatment with opioid agonists (morphine) at a dose 5 mg/kg for 6 weeks and their yawning behavior was recorded for a 60-minute period starting 30 minutes after injection. Group 4 (social isolation) received treatment with opioid antagonists morphine (naloxone)at a dose 1 mg/kg for 6 weeks and their yawning behavior was recorded for a 60-minute period starting 30 minutes after injection. The graph shows that the number of yawning in the group receiving morphine (n=8, p ≤0.05) was not significantly different from the control group in the social isolation condition (n=8, p ≤ 0.05). Moreover, there was an increase in the number of yawning in the groups receiving naloxone (n=8, p ≤0.001). In social isolation group, morphine injection did not change the number of yawning in male rats, while naloxone, a mu-opioid receptor antagonist, increased the number of yawning in social isolation conditions.

Previous studies have shown that ghrelin inhibits the activity of Hypothalamus-Pituitary-Thyroid (H-P-T) axis. It is also proved that ghrelin increases the appetite via Agouti Related Protein and neuropeptide Y Pathway, decreases T3 and T4 secretion. Also morphine by effect on Pituitary hormones like TSH decreases T3 and T4 concentrations. Thus, the goal of this study was to determine the influence of the interaction between ghrelin and morphine on thyroid hormones concentration. Twenty one male Wistar rats weighing 200-250 g were randomly divided into 3 groups. The groups received 5 nmol ghrelin, 1µg morphine or 5 nmol ghrelin together with 1µg morphine in third cerebral ventricle in volumes of 3 μl .The blood samples were collected every day. Starting one day before and up to one day after injections. Brain slices were taken to ensure that the place of the canulae was right. The plasma was analysed by Radioimmunoassay technique to determine T3 and T4 concentrations. The results showed that the i.c.v injection of ghrelin and morphine significantly decreased the mean plasma concentrations of thyroid hormones (P<0.05). Co-administration of these two substances in some of groups showed that decrease mean plasma concentrations of thyroid hormones (P<0.05). This study showed that ghrelin and morphine significantly decreased mean plasma concentration of T3 and T4. Co-administration of two substances in some of groups showed that decrease mean plasma concentration of thyroid hormones (p<0.05).

Morphine has adverse effects on the female reproductive system. The aim of this study was to investigate the interference effects of MgSO4 (intra ventromedial hypothalamus (VMH) and naloxone in the rat with polycystic ovaries induced by morphine.

80 female rats (200-250 g) kept under standard conditions were surgically coordinated (Anterior- Posterior: -1/92, Ventral: 9, Lateral: 0.5) using a stereotactic device. After recovery they were microinjected morphine (0.1-0.4 µg/rat, intra-VMH) and pre-injected naloxone hydrochloride (0.1-0.4 µg/rat, intra-VMH) and also MgSO4 (1-5 µg/rat) prior to the naloxone. The control group received physiological saline (1 µL/rat, intra-VMH). 3 days after the experiment, uterus, ovary and brain samples were collected and studied histopathologically using hematoxylin & eosin.

The ovaries in group in which morphine was injected showed polycystic features as compared to the control group. This effect was reversed by the naloxone pre-injection, but, prior treatment with MgSO4 returned the aspect. However, this substance alone did not have a significant effect on the ovaries. In addition, the inflammatory effect of morphine on the ovary and the uterus was reversed with pre-injection of naloxone, but it was also returned by the MgSO4. These materials did not have significant effect on neurons of VMH.

These results indicate that the effect of morphine is mediated by mu opioid receptor which is dependent to the calcium ion signalling mechanism.

Septohippocampal system plays an important role in regulating fear and anxiety behaviors. In this study, the effects of histamine injected into the dorsal hippocampus and opioidergic agents into medial septum on the anxiety-like behaviors in rats were analyzed, using the Elevated Plus-Maze (EPM) test. Injection of 1 and 5 μg/rat histamine into dorsal hippocampus had no effect on anxiety-like behavior, while injection of 10 μg/rat histamine increased the percentage of open arm time (%OAT) and open arm entry (%OAE), which indicated the anxiolytic effects of histamine. Microinjection of morphine, μ-opioid receptor agonist, into the medial septum (1μg/rat) increased the (%OAT) and (%OAE). Doses of 0.25, 0.5 μg/rat morphine had no effect on anxiety. Co-administration of histamine ineffective dose (1μg/rat) to the dorsal hippocampus and ineffective dose of morphine (0.25µg/rat) to the medial septum increased the (%OAT) and (%OAE). Subsequently, injection of different doses of naloxone (1, 2, 4 µg/rat), as an opioid receptor antagonist, into the medial septum in the presence and absence of an effective dose of histamine (10 µg/rat) in the dorsal hippocampus, was studied. Injection of naloxone (4 µg/rat) into medial septum decreased the (%OAT) and (%OAE), but did not alter the locomotor activity, which indicated the anxiogenic effects of naloxone. Simultaneous injection of histamine (10 µg/rat) into dorsal hippocampus with doses of naloxone (1, 2, 4 µg/rat) into the medial septum, indicate anxiolytic effects and increased %OAT and %OAE in Elevated Plus Maze, although when the dose of naloxone was 4μg/rat, this effect was less observed. The results indicate that hippocampus histaminergic system interact with medial septum opioidergic system and the interaction of these systems modulates anxiety behavior.

Ghrelin increases food intakes and body weight while weight loss and fasting is accompanied by increased levels of cortisol. The goal of this study was to determine the effects of cortisol and morphine on ghrelin concentration in ewes with different levels of energy requirements.Ten Zandi ewes were randomly divided in to two groups. The groups were fed either by 50% or 100% of energy content in diet for 10 days. After a week animals in both groups received cortisol(60 μg/kg), morphine(0. 15 mg/kg) or simultaneous injection of cortisol and morphine respectively. Blood samples were collected 2 hours after infusions.Ghrelin concentration significantly increased in the 7th day of experiment compared to first day in the %50 group. While in the group by 100% energy level, significant changes wasn’t observed in ghrelin concentration. After injection of cortisol ghrelin reduction in the both groups. Morphine increased ghrelin in both groups. After simultaneous injection of cortisol and morphine there was no significant increasing and decreasing changes in both groups.

Studies have revealed the effect of morphine and nicotine on different types of memory and learning. These drugs produce more of their effects via the mesolimbic dopaminergic pathway. The aim of the present study was to investigate the effects of intra nucleus accumbens (intra-NAc) injection of the dopamine D2 receptor antagonist (sulpirid) in nicotine’s effect on morphine-induced amnesia. This experimental study was performed on 185 male rats. Rats were anesthetized with intra-peritoneal injection of ketamine hydrochloride، plus xylazine and then placed in a stereotaxic apparatus. Two stainless-steel cannuale were placed in the nucleus accumbens shell. The behavioral testing was started in inhibitory avoidance task، and the step-through latency for entering into the dark compartment was measured for the assessment of memory retention. The amnesia induced by post-training morphine restores with pre-test injection of morphine، nicotine or nicotine plus ineffective dose of morphine. In contrast، pre-test intra-NAc injection of the dopamine D2 receptor antagonist (sulpiride) which had no effect on memory alone prevented the nicotine reversal effect on morphine memory impairment. These results suggest that the dopamine D2 receptor of the nucleus accumbens may play an important role in the improving effect of nicotine on the morphine-induced amnesia.

Morphine for years as an analgesic drug is used, but given that the repeated administration of morphine is associated with dependence and tolerance, recent studies try is to administration of aqueous extract of fennel, along with its analgesic effect of morphine and the strengthening of reduce its consumption.This experimental study performed on 80 male mice (28±3g). Animals were grouped randomly in to control, positive control and receivers of Foeniculum vulgareextract. Control group and positive control group received normal saline 0.9% and indomethacin (5mg/kg, i.p.), respectively. Treatments groups were injected with doses, (100 mg/kg, i.p.), (200 mg/kg, i.p.) and (400 mg/kg, i.p.) of aqeous extract of Foeniculum vulgare. Animals were injected with acetic acid 0.6% (10ml/kg) for iducing of visceral pain, 30 minutes after of each intraperitoneal administration. Antinociceptive effect was recorded by counting the number of writhes immediately after injection of acetic acid during 30 minutes. In following treatments interaction of morphine in the antinociceptive effects of Foeniculum vulgare extract were studied with treatment ofmorphine (2mg/kg, i.p.) 15 minute after the administration of the extract in writhing test.this study showed that aqueous extract of F. vulgareat 100, 200 and 400 mg/kg and indomethacin (5mg/kg) induced a significant reduction in pain response compared to the control group (p<0.001). morphine (2mg/kg, i.p.) also coused antinociception and the concurrent use of F. vulgareand morphine produced more remarkable antinociception compared to their individual usages (p<0.001).Foeniculum vulgare andmorphine also showed synergistic drug interaction for antinociception in the writhing test.

Adrenergic neurotransmission plays important role in opiate withdrawal. In this study the effect of alpha-2 agonist (clonidine) on opiate withdrawal were studied because there are opposite reports about its actions. Animals divided to 4 groups: Control and three groups that they received clonidine in three doses (0.02 mg /kg, 0.2 mg/kg and 2 mg/kg). Animals were addicted by injection of morphine and withdrawal syndrome was induced with injection of 20mg/kg (i.p.) naloxone. Withdrawal signs were evaluated for 30 min.Clonidine had not affected grooming, paw tremor and ejaculation and other sign such as body tremor in doses. 0.02 mg/kg (P≤0.02), 0.2 mg/kg)P≤0.04(and 2 mg/kg) P≤0.002), defecating in doses 0.02 mg/kg (P≤0.015), 0.2 mg/kg) P≤0.039(and 2 mg/kg)P≤0.015), chewing in doses 0.02 mg/kg (P≤0.0001), 0.2 mg/kg)P≤0.001(and 2 mg/kg)P≤0.001), teeth chattering in doses 0.0 2mg/kg (P≤0.02), 0.2 mg/kg)P≤0.01(and 2 mg/kgP≤0.02) and wet dog shakes in doses. 0.02 mg/kg (P≤0.026), 0.2 mg/kg)P≤0.011(and 2 mg/kg)P≤0.034) decreased significantly. This drug increased standing on feet (P≤0.02(and jumping (P≤0.005) in 2 mg/kg dose. It seems that clonidine decreased signs by induce endogenous opiate release or affects alpha-2 receptors and inhibit noradrenalin release Enhancement of signs may be related to clonidine action on the other receptors such as α1-adrenoceptors or imidazoline receptors.

In present study, the effects of intra-dorsal hippocampal (intra-CA1) injection of cannabinoid receptor agents on memory formation have been investigated in 3-days morphine-treated rats. Passive avoidance task of memory has been used to examine for retrieval of memory formation, 24 h after training. morphine was injected subcutaneously (S.C.), once daily for 3-days followed by 5 days free of the morphine before training. Post-training intra–CA1 administration of cannabinoid receptor agonist, WIN55, 212-2 (0.25 and 0.5 µg/rat) and CB1 receptor antagonist, AM251 (25 and 50 ng/rat, intra–CA1) decreased memory retrieval. Administration of AM251 (25, 50 and 100 ng/rat, intra – CA1), 2 min before injection of effective dose of WIN55, 212-2 (0.5 µg/rat) decreased the response induced by WIN55, 212-2. Repeated administration of different doses of morphine (2.5, 5 and 10 mg /kg) for 3-days incraesed memory retrieval. However, repeated administration of different doses of morphine (2.5, 5 and 10 mg /kg) for 3-days reversed amnesia induced by WIN55, 212-2. The results suggest that cannabinoidergic and opioidegic system have a close interaction on memory retrieval and WIN55,212-2 influence on memory formation and subchronic morphine pre-treatment may restore memory through a possible opioidergic receptor sensitization.