Background & Objectives: Reports suggest that co-administration of Matricaria Chamomilla (MC) extract with morphine greatly attenuates the dependence on morphine and its injection prior to naloxan inhibits the withdrawal syndrome. Locus Ceruleus (LC) and paragigantocellularis (PGi) nuclei play a key role in appearance of withdrawal syndrome. Thus, this study was conducted to determine the effects of MC extract injection into pGi nucleus on morphine withdrawal in rats.
Materials & Methods: 30 rats (Weighing 250-300gr) were divided into two groups of control (receiving saline) and morphine- treated. Following surgical implantation of cannula, morphine- treated group received morphine twice daily for 7 days. This group was classified into 4 sub-groups. The first sub-group received only morphine while the three remaining sub-groups were administed with Matricaria Chamomilla on day 7, five minutes prior to 1 microliter naloxan injection, with 10, 25, and 50 microgr/lit, respectively. In all groups 5 mg/kg naloxan was injected 3 hours after the final injection of morphine and withdrawal behavior (jumping and climbing) was investigated for 30 minutes.
Results: The results showed that injection of all three high doses of MC extract particulary 25 microgr/microlit into PGi nuclens could significantly decline the symptoms of withdrawal syndrome.
Conclusion: It seems that injection of MC extract into PGi nucleus could be beneficial to the treatrnent of morphine withdrawal syndrome in rats.

Background & objective: With regard to increasing use of opioids and their potential role in infertility research centers around the world are in search of pharmacologic compounds which could neutralize effects of opioids and overcome infertility through administration of GnRH and its analogues which also do not have considerable side effects.
Materials & Methods: In this study male wistar rats weighing 200-250 gr were used. At different intervals (5-10-15 days) 5mg/kg morphine was injected intraperitonneally into the male rats. Then they were divided in 5 groups of 8. The first group contained intact rats, while saline, morphine, naloxone, and fertagyl were injected into the second third, fourth and fifth groups respectively. Then the rats were anesthetized and their bloods were taken for further tests.
Results: The results showed that morphine induces loss of testis weight and diameter, loss of weight in rats, and nutritional and behavior changes. Furthermore, a significant changes in the amounts of LH and testosterone hormones was observed in all groups (p<0.05) while no significant change in the amount of FSH was observed.
Conclusion: Since the experimental groups into which naloxone and GnRH were injected showed no significant difference, we suggest that naloxone and GnRH be administrated as opioid antagonist to slove the problem of morphine-induced infertility.

Background and Objective: Locus coeruleus (LC) has been hypothesized to play an important role in a variety of behaviors and opiate withdrawal. This study was designed to determine the effects of reversible inactivation of LC on self-administration of morphine and morphine- withdrawal syndrome signs (MWS). 

Materials and Methods: 24 male rats (250-300gr) were surgically implanted bilaterally with cannula in LC then implanted with catheters in the right jugular vein. The rats were tested in 2 groups:Control(saline) and morphine. Morphine group was divided into 3 subgroups: control, sham-operated and LC-inactivated group where they received 1µL 2% Lidocaine 5 minutes prior to testing. Animals were allowed to self-administer morphine (1mg/infusion) during 10 consecutive days for 2 hours. The number of lever pressing was recorded. At the end of the training day all groups received naloxone (2mg/kg I.P) and MWS were studied for 30 minutes. 

Results: LC inactivation prevents the development of tolerance and dependence on morphine and greatly attenuates morphine-withdrawal syndrome.

Conclusion: LC inactivation not only attenuates morphine withdrawal syndrome but also prevents morphine tolerance and dependence in rats.

Background and Objective: Increased level of dopamine in accumbens nucleus has a key role in the rewarding effects or positive reinforcement of abused drugs, whereas serotonin facilitates dopamine release in brain .The aim of this study was to investigate the effect of concurrent use of amantadine and paroxetine on reinforcing effect of morphine in conditioned place preference model in mice.
Materials and Methods: In this experimental study male NMRI mice (20-30 g) were used within 6 consecutive days including preconditioning ,conditioning and postconditioning phases. On the first day, after removal of the partitions, time spent in every 3 compartments was measured for 10 minutes. After determination of low and high preferred side, animals received morphine sulfate (5 mg/kg ) intraperitoneally on the 2nd  and 4th days in the least preferred side, but on  the 3rd and 5th days of the test, animals received saline (10ml/kg) in high preferred side. On the test day or postconditioning phase, animals received amantadine, and paroxetine alone or their concurrent does, instead of morphine. Control group received saline in both sides (n = 8).
Results: Our results show that morphine significantly and dose dependently ( 2.5, 5,10 mg/kg) induced CPP (P<0.001). Amantadine, only in doses of 5 and 10 mg /kg (P<0.01, P<0.001, respectively) induced CPP. Paroxetine induced CPP in all doses. Concurrent use of amantadine(10mg/kg) and paroxetine (10mg/kg) significantly enhances morphine - like CPP ( P <0.001).
Conclusion: Concurrent use of drugs, releases dopamine and inhibit reuptake of serotonin, and may potentiate morphine-like CPP and could be useful in decreasing some opioid withdrawal signs.

Background and Objective: A number of β-carboline alkaloids such as harmane are naturally present in the human food chain. In the present study the involvement of dopaminergic system on harmane induced-amnesia was investigated. Materials and Methods: One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Results: Intraperitoneal (i.p.) administration of harmane (5 and 10 mg/kg) immediately after training, dose-dependently decreased memory formation. Administration of D1/D2 receptors agonist, apomorphine (0.5 and 1 mg/kg, i.p.) before testing by itself could not alter memory retrieval. On the other hand, in the animals in which memory formation was impaired due to harmane post-training administration, pre-test administration of apomorphine (0.5 and 1 mg/kg, i.p.) 24 hr after training in day’s test restored memory. Furthermore, administration of SCH23390 (0.025, 0.05 and 0.1 mg/kg, i.p.) or sulpiride (12.5, 25 and 50 mg/kg, i.p.) before testing by itself could not alter memory retrieval, respectively. On the other hand in the animals in which memory formation was impaired due to harmane post-training injection, pre-test administration of SCH23390 (0.05 and 0.1 mg/kg) or sulpiride (25, 50 mg/kg, i.p.) 24 hr after training in day’s test decreased hamane-induced amnesia. Conclusion: These findings indicat the involvement of D1/D2 receptors in harmane induced-amnesia through different mechanism(s).

Background and Objective: Previous studies indicated that morphine consumption during pregnancy could inhibit embryos development. Present study further evaluated the effects of oral morphine consumption on the placenta lacunas development in ten day pregnant Wistar rats. Material and Methods: Female Wistar rats (W: 170-200 gr) were used in the present study. Experimental group were received morphine (0.05 mg/ml of tap water) after one night coupling with male rats for mating. On the day 10th of pregnancy, the pregnant animals were killed with chloroform and the placentas and uterus were removed surgically and fixed in 10% formalin for twenty days. The fixed placentas were processed and stained by H & E method and evaluated for their development. Thickness of layers, surface area of lacuna, as well as the number of cells in both maternal and fetal parts of the placentas was assessed by light microscopy. Results: Our results indicated that the layer thickness of fetal portion and surface area of lacuna of the fetal and maternal portion of placenta reduced in experimental group. In addition, maternal portion layer thickness and cell number of the fetal and maternal portion of placenta increased in the experimental group. Conclusion: Our results showed that oral morphine consumption could inhibit natural function of placenta lacuna and fetal cell development.

Background and Objective: Opiates have complex effects on seizure activity. They have both anti- and proconvulsive effects depending on experimental conditions.
The aim of this study was to determine the effects of different doses of morphine and naloxon on spontaneous seizure activity in mouse brain hippocampal slices.
Materials and Methods: Spontaneous epileptic activity in the brain hippocampal slices of mouse was induced by continuous perfusion of low magnesium artificial cerebrospinal fluid (low -Mg²⁺ ACSF). Extra cellular recordings were performed in the hippocampal CA1 pyramidal cell layer to account for the effects of the drugs on amplitude, duration and number of the ictal events as well as number of interictal spikes. 
Results: Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 µM), morphine decreased seizure activity. Higher morphine concentrations (30 & 100 µM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist, blocked the proconvulsant action of morphine.
Conclusion: The results of this study showed that the effect of morphine on seizure in mouse is dose dependent. In other words, low systemic doses of morphine have anticonvulsant effects while high doses are proconvulsant.

Background and Objective: Post operative pain is one of the important factors affecting recovery from surgery and anesthesia. Gabapentin is used as an anticonvulsant drug that acts through voltage-dependent calcium channels. In some recent studies, oral gabapentin has been reported to reduce post operative pain and morphin consumption following mastectomy and hysterectomy. The aim of the present study was to determine the effect of gabapentin on postoperative pain after abdominal hysterectomy. Material and Methods: In a double-blinded clinical trial design, 50 women aged 35- 50 years old, whom were candidate for hysterectomy referred to Shabih Khani Hospital in 1389, were signed up for the study. Patients received randomly either oral gabapentin 1200 or placebo 1 hr prior to the surgery. Pain was assessed on a visual analogue scale (VAS) at 2, 6, 12, and 24 hr intervals after the operation. Morphine consumption and drug-induced complications such as nausea and vomiting were recorded and compared between the two groups. Results: Factors including age, mean operative time, mean anesthesia time, and BMI were not significantly different between the test and control groups. However, the mean pain scores at 2, 6, 12, and 24 hr after operation were significantly lower in the gabapentin group in comparison to the controls (P<0.0001). The morphin consumption was also significantly lower in the gabapentin group (P<0.0001). Furthermore, the average time before the first to walk following the operation was significantly shorter in the gabapentin group (P=0.002). Conclusion: Preoperative oral gabapentin decreases the pain scores in the postoperative period and lowers the morphine consumption in patients following abdominal hysterectomy.

Background and Objective: Previous studies have shown that morphine consumption during pregnancy may delay the embryo development and/or cause abnormal nervous system function. The present study focused on the effects of maternal morphine consumption on the brain vesicles Prosencephslon and Rhombencephal development in Wistar rat embryos. Material and Methods: A total of 12 female Wistar rats (170-200g) were used in this study. After pregnancy, each rat in the experimental group (n= 6) received 0.05 mg/ml of morphine by tap water, while the animals in the control group only received water only. On the 10th day of pregnancy, the pregnant animals were anesthetized by chloroform and the embryos were removed surgically. The embryos were then fixed in 10%formalin for one week, followed by tissue processing, sectioning, and staining with hematoxylin and eosin (H&E) for each embryo. The sections were examined for primary brain Rhombencephal and Prosencephslon vesicles, and the brain layer development or thickness was examined by light microscopy and MOTIC software. Results: A severe reduction of the area for Rhombencephal and Prosencephslon was observed in the experimental group compared with the control group. Furthermore, the increase in the brain layer thickness was significantly more apparent in the experimental groups in comparison to the control group (P<0.05). Conclusion: Our results show that oral morphine consumption causes a decrease in the primary brain vesicles. This defect may be the cause of abnormal central neuron system function and development observed in the fetuses born from opioid addicted women.

Background and Objective: Development of effective ways to impede drug-induced synaptic changes can play a vital role in the treatment and prevention of relapse as a clinical problem. Previous studies suggest that exercise decreases the sensitivity to the rewarding effects of morphine in rats. This study was designed to investigate the effects of regular swimming exercises on naloxone-precipitated morphine withdrawal signs in rats. Materials and Methods: In this study, 16 rats were divided into the control and experimental groups. The rats were injected with bi-daily doses (10 mg/kg, at 12 hr intervals) of morphine over a period of 14 days during swimming exercises. Exercised rats were submitted to swimming sessions (45 min/d, five days per a week, for 14 days). On day 15, after an acute injection of naloxone (2 mg/kg, IP) 2 h after receiving morphine injection according to a modified version of the Gellert–Holtzman scale, morphine dependent intensity was measured in both groups (swimmer and none swimmer). Results: The results showed that withdrawal signs including abdominal contractions (P= 0.000), wet dog shakes (P= 0.005), weight loss (24h) (P= 0.001), jumps (P= 0.002) and overall Gellert–Holtzman score (P= 0.000) were significantly lower in the swimmer morphine treated rats as compared with non-swimmer control ones (P= 0.0001). Among the evaluated signs, the number of rats per group with erection and genital grooming (62.5%, P=0.05), diarrhea (40%, P=0.025) and writhing (50%, P=0.025) displayed a decrease in swimmer morphine treated rats compared to non-swimmer rats. Conclusion: Our findings indicate that regular swimming exercises can minimize severity of dependency upon morphine in rats.

Background and Objective: It has been shown that the opioidergic system exerts widespread effects on cognitive functions. Interactions between opioid and serotonin receptors have been reported in some brain structures such as the dorsal hippocampus, thus a functional interaction between opioids and serotonin seems possible concerning memory control. The purpose of this study was to assess the effects of CA1 5-HT3 receptor agonist on memory acquisition deficit induced by morphine.
Materials and Methods: In this study, we used 96NMRI mice. These mice were divided into twelve equal groups that received different doses of 5-HT3recepto ragonist, different doses of morphine and a combination of morphine and serotonin 5-HT3 receptor agonist. Morphine was injected into the peritoneum, while 5-HT3 receptor agonist M-Chlorophenylbiguanide (M-chl) was administered via intra-hippocampal injection. A step-down passive avoidance test was used for the evaluation of memory.
Results: Pre-training intra-peritoneal administration of morphine (5 mg/kg) induced amnesia. Moreover, pre-training intra-CA1 administration of 5-HT3 receptor agonist (M-Chl) (0.5 ng/mouse) impaired memory acquisition. Furthermore, intra-CA1 injection of M-Chl (0.005ng/mouse) reversed impairment of memory acquisition induced by morphine (5 mg/kg).
Conclusion: The results demonstrated the existence of a synergistic effect between hippocampal 5-HT3 receptor agonists and opioidergic receptors.

Background and Objective: Datura stramonium L. is a medicinal herb from the family of Solanaceae. It has been used in herbal remedies for promoting health and treating several diseases. The current study was set up to compare the effects of Datura stramonium L. extract on the naloxone-precipitated opiate-withdrawal in mice.
Materials and Methods: Male BALB/c mice (30–35 g, n = 40) were arbitrarily separated into 4 groups. The control group received morphine and normal saline and other groups received three doses of D. stramonium extract (10, 20, or 30 mg/kg, intraperitoneally, i.p.). Physically dependent was made by the administration of morphine in increasing doses (50-75 mg/kg, i.p.). The withdrawal signs were elicited by intraperitoneal injections of naloxone (5 mg/kg) 2 h after the last injection of morphine.
Results: Administration of D. stramonium extract in doses of 20 and 30 mg/kg markedly diminished the jumping numbers compared to the control group (P<0.05). All three doses of D. stramonium extract could significantly suppress the increase in climbing (P<0.05, P<0.001, and P<0.001, respectively) and diarrhea (P<0.001). D. stramonium in higher doses (20 or 30 mg/kg) significantly decreased rearing and itching (P<0.001).
Conclusion: The study findings suggest that D. stramonium extract is effective in alleviating the signs of morphine withdrawal. Additional research is needed to determine the exact mechanisms underlying D. stramonium for inhibiting morphine withdrawal syndrome.