Tehran University Medical Journal

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Background: Opiate-induced addiction is a main social problem in Iran. As treatment of this problem is a health priority among the medical community, studies on this topic are very crucial. The exact mechanism of dependence on opiates and their withdrawal syndrome remain unclear. It seems that dopaminergic system and locus coeruleus (LC) have an important role in the expression of somatic signs during opioids withdrawal. The LC has been shown to contain significant levels of dopamine (DA). In the present study, the effects of different D2 dopaminergic receptor agonist and antagonist administration in the LC on withdrawal sign expression in morphine dependence is investigated in rats.
Methods: Adult male Wistar rats, weighing 220–280 g were divided into eight groups (n=8). Two cannulae were stereotaxically implanted bilaterally into the LC of each rat. After a one-week recovery, seven groups were rendered dependent on morphine by subcutaneous injection during a seven-day period. Non-dependent control animals received saline according to the same protocol. Animals received bilateral intra-LC injections of saline (1 μg/site) and quinpirole (0.1, 0.3 and 0.5 μg/site, a D2 agonist) 15 min and sulpiride (5, 15 and 30 μg/site, a D2 antagonist) 30 min prior to naloxone injection about 24 hours after the last dose of morphine or saline according to their respective group. To calculate the total withdrawal score, as an index of withdrawal syndrome, 20 different withdrawal signs were assessed and the scores of the intensity of these withdrawal signs were added.
Results: Total withdrawal scores were significantly decreased by quinpirole (0.1µg/site) and sulpiride (15 and 30 µg/site).
Conclusion: The D2 dopaminergic system in the LC may be involved in the morphine-induced dependency in rats. Further studies are needed to define the mechanism of this dependency in order to improve methods for the rehabilitation of addicts.

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Background: Magnesium Sulfate (MgSO4) has been used as a pharmacologic agent in different situations for many years in the treatment of tachyarrhythmias, myocardial ischemia, preeclampsia, and tocolysis among others. The analgesic effect of MgSO4 for postoperative pain has been used since the 1990s. Postoperative pain is one of the most common complications in the perioperative period and can result in serious consequences in different organs if left untreated. Inguinal herniorrhaphy is among the most common surgeries and is almost always accompanied by severe pain. The object of this study is to determine the effect of a pre-induction infusion of MgSO4 on the reduction of postsurgical pain after herniorrhaphy.
Methods: This double-blind, randomized clinical trial included 105 ASA class I and class II herniorrhaphy patients at Shariati Hospital in years 2004 and 2005. For statistical analysis, the 2 and T tests were used. The patients were divided into three groups based on block randomization. Patients in the following groups received: Group A, 200 ml of normal saline infusion (placebo) Group B, 25 mg/kg MgSO4 in 200 ml of normal saline Group C, 50 mg/kg MgSO4 in 200 ml of normal saline. All groups were infused twenty minutes before induction of anesthesia using identical methods and dosage in all three groups. Heart rate and mean arterial pressure (MAP) at pre- and postintubation and so at skin incision time were charted. Visual analog scale (VAS) pain score, nausea, vomiting and the amount of morphine used before recovery room discharge and in six, twelve and twenty-four hours after recovery discharge was recorded.
Results: The average age for the different groups was as follows: Group A: 33.6, Group B: 37.37, Group C: 32.74. Nausea and vomiting between the case and control groups were not statistically different (60% vs. 71.4%, p=0.0499), nor was the amount of Morphine used. On recovery room discharge, the VAS scores were 8.1, 7.2, and 5.5 for the first, second and third groups, respectively (P<0.001). However, no statistical significance was found for the VAS scores six hours after recovery room discharge.
Conclusion: The results in this study show that pre-induction with MgSO4 has no remarkable effect on decreasing postoperative pain or morphine use for inguinal herniorrhaphy.

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Background: Anxiety is a complex phenomenon with important results. In fact anxiety is a biologic process that has repetitive biological and physiological effect on the biological structure of brine. From long time ago anxiety and fear has bean one of the important psychological issues and for the control of anxiety different drugs with different mechanisms have been presented and understanding mechanisms that are involved lead us to newer drugs discovery. In this research the effect of morphine on the anxiety in the adult Male rats in the Ventral Tegmental area (VTA) and Nucleus Accumbens (NAc) was studied.

Methods: The elevated plus maze was used in combination with the percentage of time spent in the open arms of the maze (OAT %) and the percentage of entries into the open arms (OAE %) to measure anxiety. Increases in the OAT% and OAE% indicate an anxiolytic effect (reduction in anxiety), whereas decreases in the OAE% and OAT% indicate an anxiogenic effect. Adult male rats, weighing 200-240 grams, underwent surgery. After five days, the rats were injected with saline and three different doses of morphine (2.5, 5, and 7.5 µl/rat). Experiment one included the injections into the VTA. In the second experiment, these injections were in the NAc. Behavioral tests were conducted between 12 pm and 4 pm and each animal was used once for each experiment.

Results: In the first experiment, although these doses of morphine injected into the TVA had no effect on the OAE%, a dose of 5µl/rat increased the OAT%, showing a decrease in the animals' anxiety. In the second experiment, doses of 2.5µl/rat injected into the NAc induced a significant increase in the OAT% and OAE%, there by displaying decreased anxiety in the animal. However, no significant change in the activity of the animals was observed.

Conclusion: As a Result of these experiments, it seems that different doses of morphine can decrease anxiety, probably through interaction with gabaergic system.

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Background: Learning and memory are the complicated agents of central nervous system that various regions of brain can be involved in these phenomena, especially regions like hippocamp. Various agents like nitric oxide and morphine can influence learning and memory. About the effects of morphine with other components there was not clear reports so in this study the effect of co-administration of L-Arginine (precursor of nitric oxide) and morphine in hippocampal CA3 area on spatial learning and memory in male rats was investigated.
Methods: Male rats were deeply anaesthetized with ketamine and xylazine and cannula were implanted bilaterally in CA3 of hippocampus by using streotaxic technique, Then male rats were used in seven groups that received saline, L-Arginine (0/3M), L-Arginine (3μg/rat), L-NAME (0/3M), morphine (10mg/rat), L-Arginine (3μg/rat) with morphine or L-NAME with morphine for five days that they were trained in morris water maze to evaluate spatial learning and memory. There was a control group too.
Results: Our results showed that L-Arginine (3μg/rat) improved spatial learning and memory. L-NAME (inhibitor of nitric oxide) decreased spatial learning and memory in male rats. Injection of morphine also decreased spatial learning and memory in male rats. Co-administeration of L-NAME and morphine decreased learning more than morphine individually in male rats.
Conclusion: We concluded that precursor of nitric oxide improved learning and memory in male rats and inhibitor of it and morphine impaired this phenomena and coadministration of inhibitor of nitric oxide and morphine also impaired learning in rats.

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Background: It is demonstrated that morphine and tramadol affects seizure but the mode of action of these drugs on seizure has not been compared yet with increasing of age. The aim of this study was to compare the impact of exposure to these drugs on Pentylenetetrazol-induced seizure in immature rat.
Methods: Male neonate rats were randomly chosen and divided into three groups namely Saline (n=21), Morphine (n=12) and Tramadol (n=13). On postnatal days 8-14, Saline group received normal saline and two other groups received morphine and tramadol with additive doses, respectively. On postnatal days 22-28, the saline treated rats divided into three subgroups and received saline (n=8), morphine (n=8) or tramadol (n=5). Morphine treated rats received saline or morphine (each n=6), and tramadol treated rats received saline (n=7) or tramadol (n=6). At postnatal day 29, they were evaluated for PTZ-induced seizure.
Results: Number of tonic-clonic seizure was increased in all groups compared with control and tramadol+saline groups (P<0.05). Duration of tonic-clonic seizure was decreased in tramadol+saline group compared with other tramadol groups (P<0.05). Latency of tonic-clonic seizurewas decreased in tramadol+saline group compared with control rats (P<0.05), But it was increased in saline+tramadol group compared with other groups except to saline group (P<0.05). Latency of myoclonic contractions in saline+morphine and saline+tramadol groups was lower than in control rats (P<0.05).
Conclusion: Similar age-related changes may occur inchronic exposure to morphine and tramadol in the neonatal period which leads to an increase in severity of seizures in rats on postnatal days 22-28. The effect of morphine and tramadol does not show any significant difference.

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Background: Previous studies indicate that morphine dependent and withdrawal from chronic opiates enhanced anxiety-related behaviours in novel and stressful conditions in rats. Recent studies have shown that exposure to a stressor generates a wide variety of adaptive responses, while enhancing abilities to adopt with the stressor. Therefore, the aim of this study was to examine the effect of chronic restraint stress and acute water immersion (WI) stress on the anxiety profile in morphine-dependent rats.
Methods: Thirty two rats were injected with twice daily doses (10 mg/kg, subcutaneous, at 12 hour intervals) of morphine over a period of 10 days in the presence or absence chronic restraint stress (1 hour/day). On day 11, two hour after morphine injection, anxiety-like behaviours were tested in the elevated plus-maze model in the presence or absence acute water immersion stress. Rats were divided into four groups: dependent- No restraint stress (D/NRS), dependent- restraint stress (D/RS), dependent- restraint stress+ water immersion stress (D/RS+WI), dependent- water immersion stress (D/WI).
Results: Finding have shown that D/RS+WI rats exhibited an increase in the elevated plus-maze open arm entries and time as compared with the control groups (P=0.018 and P=0.037, respectively). Also, this measure was significantly lower in the WI rats than the D/RS+WI rats (P=0.049 and P=0.031, respectively).
Conclusion: Our findings indicate that chronic restraint stress followed by acute water immersion stress decreases the severity of the anxiogenic-like behaviours in morphine dependent rats thus it may have a therapeutic application in the treatment of the asso-ciated disorders in addiction.

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Background: Pain is one of the greatest concerns of patients undergoing total knee arthroplasty (TKA) which is severe and intolerable within 72 hours post-surgery. Appropriate pain management is a key factor in patient's early mobilization, launching physiotherapy, less hospital length of stay and more importantly, patient's satisfaction. New studies with the infiltration of combined analgesic agents peri and intra-articularly has shown encouraging results in pain reduction, good clinical outcome and patient's satisfaction. The purpose of this study was to compare the analgesic effect of locally infiltrated analgesia (I) compared with single injection femoral nerve block (F) and its impact on pain relief, patient's satisfaction, morphine consumption and clinical outcome.

Methods: This research was a double-blind randomized clinical trial on 36 consecutive patients undergone TKA divided into group (F) in which the ipsilateral femoral nerve in the inguinal area was blocked by a single injection of 20 ml ropivacaine (10 mg/ml) and group (I) which a combination of ketorolac, ropivacaine and epinephrine was injected peri and intra-articularly on the knee during TKA. Pain intensity measured by visual analog scale (VAS), clinical outcome (based on range of motion), morphine consumption and patient's satisfaction of pain management after TKA were compared between the two groups.

Results: Pain intensity score (VAS) and Morphine consumption were statistically less in group I than group F during the first 6 hours and 24 hours post surgery respectively (P< 0.05) however, group F had 12-hour VAS score of 5 which was less than group (I) by 1 grade in pain scale (VAS) (P< 0.05). Other parameters were not statistically different in the two groups and patients' response to our pain management protocols proved to be satisfactory in both groups.

Conclusion: Lower level of pain and morphine consumption in group (I) during the first 24 hours post-surgery in contrast to group (F) and its ease of use by a surgeon intra-operatively, introduce local infiltration analgesia as an effective method to decrease the patient's pain and improve patient's satisfaction in early post-surgery period after total knee arthroplasty.

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Background: This study aimed to evaluate the effect of intravenous Ibuprofen Apotel analgesia in comparison with intravenous Morphine alone regimen in patients undergoing lubmar disc surgery.
Methods: This study was a double-blind clinical trial that was performed on patients with moderate to severe lumbar disc pain (VAS score or Visual analog scale more than 4) in August 2019 at Shohada Tajrish hospital. Patients in the Ibuprofen-Apotel group (group A) recieved intravenous Ibuprofen (800 mg) in 100 cc Normal saline in the first 30 minutes of Recovery, then 400 mg in 100 cc Normal saline every 6 hours (48 hours after surgery), plus 30 mg Apotel for each kilogram in100 cc Normal saline in 15 minutes every 8 hours. In group B, Morphine has injected with 70 µg/kg bolus and then 20µg/kg/h infused with a PCA pump with a Maximum Rate of 1mg/hr. Then 60 minutes after surgery, patients' pain was measured using an analog scale.
The primary outcome was defined as a reduction in pain intensity of 3 or more VAS units (which was considered as therapeutic success) and the incidence of side effects was considered as secondary outcomes.
Results: Based on the results of this study, the mean age of the subjects was 33.28±12.48 years. Also, the mean age in the group of Ibuprofen-Apotel and Morphine alone were 35.4±13.6 and 31.16±11.75 years. So, there is not a significant difference between the groups. 77.14% of the subjects (54 people) were male and 22.86% (16 people) were women. In comparing the frequency distribution of individuals in terms of gender and the method of creating analgesia, no significant difference was observed between the groups studied.
According to the results, after the intervention, the highest pain intensity in both groups was significantly decreased. However, no significant difference was observed between the two groups.
Conclusion: The study indicated that Ibuprofen can be effective in controlling postoperative pain.