---

Most cancer patients complain from pain in final part of their disease. One of the aims of health center, in the country is how to relieve pain from such patients. Therefore we tried to carry on a semi-experimental research to find out the effectiveness of Morphine by either continuous infusion or intermittence injection in such patients. We used non-random sampling, the total number of samples were 11 female and 9 male. These patients were on their final phase of disease. The process that we collected the information was based on the check-list which consist of two sections, in first part the demographic characterization of patients was recorded, using observation and interview with patients and in second part of these check-list the level of pain was assessed using visual analogue scale, which marked every two hours and finally the average of this scale in 24 hours is evaluated using as index in our study. Our results indicate that continuous infusion is more effective in relieving pain than intermittence injection (P<0.03). The results of this investigation showed that, age, sex and different type of cancer has got no meaningful variation in changing the main findings of this semi-experimental research.

---

Background&Objective: Morphine is an opioid analgesic and has known effects on different organs. This study was done to determine the histopatological changes of liver due to morphine adminstration in adult mice. Materials&Methods: In this experimental study, 20 male Blab/c mice divided experiment and control groups. In experiment and control group, animals recived 15mg/kg/day morphine and salin normal interperitoneally, for 21 days respectively. Day 22 the livers were dissected under anaesthesiology. Specimens were processed for histological study and stanied with H&E. Results: In experimental group, small sites of necrosis with poly morphic inflammatory infiltration and debris formation of necrotized nucleus in death area, so hepatitis was suggested. Also accumulation of micro droplets of lipid inside the hepatocyte cytoplasm withont nucleus displacement (fatty damages with small vacuoles) observed in cases. In addition, microvesicular steatosis and mouth teeth necrosis in liver parenchyma with inflammation in the vein and portal space were seen in cases. Any changes was not seen in control group. Conclusion: The interperitoneal adminstration of morphine can cause histopatological changes in mice liver.

---

Background&Objective: Post operative pain is a common phenomenon that it is one of the important problems in surgery. Different methods have been used to control post operative pain. Morphine and Buprenorphine are classified as narcotics, and their effect on post operative pain relief has been evaluated in this study. Materials&Methods: This randomized clinical trial (RCT) was done on 40 patients with lumbar disk herniation that randomly classified in morphine and buprenorphine group. During induction of anaesthesia 0.2 mg/kg morphine and 4.5/kg buprenorphine were injected intravenously to the corresponding groups, respectively. At the end of anaesthesia, heart rate, systolic and diastolic blood pressure were evaluated as well as severity of pain. Then, collected achieved data were analysed. Results: The severity of pain in buprenorphine group was less than morphine at all the times except the time of discharge from recovery (p<0.05). With respect to sedation there was a meaningful difference between the two groups at the time of entering recovery and 15 minutes later. The sedation was more in buprenorphine group, (p<0.05) There was no meaningful statistical difference in relation to heart rate between the two groups. Systolic blood pressure, between two groups was significant except at the time of entering recovery. Also, systolic blood pressure was not significant between two groups. Conclusion: This study showed the bupernorphine has long anaesthesia and sedation.

---

Background&Objective: Ascorbic acid, an antioxidant vitamin, is found throughout the mammalian central nervous system. Although, the centeral role of ascorbic acid is unclear, but there is good evidence that ascorbic acid modulates opiate withdrawal syndrome. This study was done to determine the effect of ascorbic acid (A.A.) on naloxone-induced withdrawal signs in morphine-dependent guinea-pigs. Materials&Methods: In this experimental study, male guinea-pigs (300-400 g 8-10 animals/group) were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulfate 3 times a day for 3 days, and withdrawal signs were induced by intraperitoneal (i.p.) administration of naloxone (15 mg/kg) 2 h after the tenth injection of morphine sulfate on day 4 then animals were placed individually into a cylindrical glass (25 cm in diameter, 180 cm height) and the withdrawal signs were recorded over a 60-min period. Results: Chronic pretreatment of guinea-pigs with A.A., 200 mg/kg, s.c. 3 times daily for 3 days, reduced withdrawal jumping, digging, writhing, rearing, face- washing, head and body shakes, penile licking and diarrhea. The mixed dopamine D1/D2 receptor agonist apomorphine (0.5 mg/kg, s.c.) markedly antagonized the inhibitory effect of A.A. on the withdrawal signs. The effect of apomorphine was blocked by the dopamine D1 receptor antagonist SCH23390 (0.5 and 1 mg/kg, i.p.) but not by the dopamine D2 receptor antagonist sulpiride (50 mg/kg, s.c.) nor the peripheral dopamine receptor antagonist domperidone (1 mg/kg, s.c.). Conclusion: It is concluded that chronic administration of ascorbic acid inhibits opiate withdrawal, via a central dopamine D1 receptor mechanism.

---

Background & Objective: Addiction to opiates such as morphine is one of major public health problems. It has been shown that in addicted animals, administration of antioxidant agents such as vitamin C can reduce the withdrawal symptoms (WDS). The aim of this study was to evaluate the preventional effect of grapefruit juice (Citrus Paradisi Macf.) on withdrawal symptoms in rats. Materials & Methods: In this experimental study, Sixteen male Wistar rats (250-300g) randomly divided into two groups (n=8). All animals were addicted by intraperitoneal (i.p) injection of morphine (the 1-3 days: 10 mg/kg, the 4-6 days: 20 mg/kg and the 7-9 days 40 mg/kg daily) for 9 days. The first group received 2 ml Citrus Paradisi Macf. orally 1 hour before morphine administration. The sham group received 2 ml of normal saline. Naloxone (10mg/kg, s.c) was administrated 45 minutes after of an additional dose of morphine (40 mg/kg) in the tenth day for withdrawal symptoms inducing. Then withdrawal symptoms such as frequency of wet-dog shaking, teeth chattering, defecation and penis licking were evaluated for 30 minutes. Results: All withdrawal symptoms including frequency of wet-dog shaking, teeth chattering, defecation and penis licking were reduced in the Citrus Paradisi Macf. group in comparison with the sham group significantly (p<0.05). Conclusion: Our results showed that presumably antioxidant activity of Citrus Paradisi Macf. can reduce withdrawal symptoms. Although the exact mechanisms of its effect in brain need to be elucidate.

---

Background & Objective: The effects of acute and chronic exposures to opiate drugs on anxiety process are controversial. Acute morphine injection showed the beneficial effects on anxiety. Morphine withdrawal induced severe anxiety response in morphine dependence rats. Whereas, the effects of chronic administrations of morphine on anxiety process are less studied. Furthermore, this study was designed to assess the role of morphine dependence on the level of anxiety in Rat. Materials & Methods: In this experimental study, Twenty male Wistar rats (250-300 gr) were made dependent by chronic administration of morphine in drinking water that lasted at least 21 days. Control groups received only sucrose in their water. This study utilized the elevated plus- maze model to evaluate anxiogenic-like behavior in rats. Four fundamental behavior patterns were recorded for 5 minutes: the time spent on open arms, the number of entries into open arms, stretched-attend posture and defecation. Immediately after test, the locomotor activity of each animal was tested by using an automated activity monitor system. The data were analyzed by independent t-test and two-way analysis of variance (ANOVA). Results: Finding indicated that the time spent on open arms and the numbers of entries into open arms were significantly shorter in morphine dependence group than control group (P<0.05). Also, the numbers of stretched-attend posture and defecation were significantly higher in morphine group (P<0.05). Whereas, there were no significant differences between groups in locomotor activity. Conclusion: This study showed that dependent rats may rapidly predispose anxiogenic- like effects in stressful conditions and without the effect on motor activity.

---

Background and Objective: Morphological alterations of hippocampus and dentate gyrus due to opium were reported in humans and animals. Also other evidences have shown that astrocytes actively participate in synaptic plasticity. This study was done to determine the conditioning place preference (CPP) on astrocytes number of Rat dentate gyrus by immunohistochemical technique.

Materials and Methods: In this experimental study, 48 male Wistar Rat weighted average 220-250 g were used. For behavioural tests, Rats divided into eight experimental groups. The Rats were received morphine at different doses (2.5, 5, 7.5 mg/kg) for three days by subcutaneous injection and sham groups, received saline dose (1 mg/kg) and then CPP test in them were investigated. 48 hours after behavioural testing animals were decapitated under chloroform anesthesia and their brains fixed and after tissue processing, slices stained with immunohistochemistery techniques. For morphometric study PTAH staining of astrocytes was used.

Results: The most dose responses of morphine was observed in 7.5mg/kg. The number of astrocytes in the controls (20.627±6.129) was similar to control-saline group (17.339±4.71). This difference was not significant, while the difference in the number of astrocytes in control group with morphine-treated experimental groups was significant (P<0.05).

Conclusion: We concluded that the phenomenon of conditioned place preference induced by morphine can cause a significant increase in the number of astrocytes of sham and experimental groups compared to controls.

---

Background and Objective: Exposure to a stressor generates a wide variety of adaptive responses and alters the pharmacological effects of opioids. Common neural pathways are activated by morphine and stress. This study was done to determine the effect of chronic restraint stress and acute water immersion stress on the severity of naloxone precipitated morphine withdrawal manifestation in morphine-dependent rats. Methods: In this experimental study, 32 adult male Wistar rats were allocated into four groups equally including: morphine-dependent - no chronic restraint stress (D/NS) (Control), morphine-dependent with chronic restraint stress (D/R), morphine-dependent with acute water immersion stress (D/WI) and morphine-dependent with chronic restraint stress under acute water immersion stress (D/R+WI). Rats were injected with bi-daily doses (10 mg/kg/bw, sc, at 12h intervals) of morphine over a period of 10 days in the presence or absence of restraint stress (1 h/day). On day 11, immediately after naloxone hydrochloride injection (2mg/kg/bw, ip), withdrawal manifestation were recorded. Water immersion stress was performed prior to naloxone injection in D/WI and D/R+WI groups. Results: The overall score of morphine withdrawal was significantly lower in D/RS and D/RS+WI rats in compared to controls (P<0.05). Among the graded signs, the mean number of abdominal contractions and jumps was reduced in D/RS+WI and D/RS rats in compared to control groups (P<0.05). Among the checked signs, the number of rats per group with erection and genital grooming were reduced in restraint rats by 25% than control group (P<0.05). Conclusion: Chronic restraint stress with or no acute water immersion stress diminished severity of dependency on morphine. Thus, restraint stress may be applied as a method to ameliorate some of the withdrawal behavioural consequences of morphine.

---

Background and Objective: Chronic use of opioids leads to analgesic tolerance. Protein kinase C (PKC), adenylyl cyclase (AC), nitric oxide (NO) and glycogen synthase kinase 3 beta (GSK-3β) are involved in morphine tolerance. Lithium activates the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway that inhibits GSK-3β and reduces morphine-induced tolerance. This study was performed to evaluate the effects of lithium on morphine dependence symptoms and tolerance of its analgesic effects in Swiss mice by GSK-3β signaling.
Methods: This experimental study was performed on 56 Swiss male albino mice that were randomly allocated into 8 groups (each containing 7 mice). The intraperitoneal injection of morphine at different concentrations (50, 50 and 75 mg/kg) and different hours (08:00, 11:00 and 16:00, respectively) was performed for 4 days, and a single dose 50 mg/kg was administered on the 5th day. The effects of three doses of lithium (1, 5 and 10 mg/kg) given orally, 45 min before morphine injections on morphine-induced analgesic tolerance were evaluated. To evaluate analgesia latency on day 1, 3 and 5, tail flick and hot plate tests were done. The brain of each animal was removed to measure nitrite levels, and histological evaluation and immunohistochemistry for p-glycogen synthase (p-GSSer640) were performed on the last day of the study.
Results: Co-administration of lithium significantly increased the latency of analgesia in comparison with the morphine group on the 3rd and 5th day (P<0.05). Lithium reduced the morphine-induced increase of nitrite levels and also reduced brain damage. In addition, immunohistochemistry assay of p-GSSer640 indicated a significant reduction of the morphine-induced phosphorylation of GS at S640 by GSK in the lithium-treated mice.
Conclusion: Lithium administration can reduce morphine tolerance in adult male Swiss mice.