In the present study, the effects of morphine sensitization on morphine-induced impairment of memory formation and the state-dependent retrieval of a passive avoidance task learned under morphine influence have been investigated in mice. Pre-training administration of morphine (0.5, 2.5 and 5mg/kg) dose dependently suppressed the learning of one-trial passive avoidance task. Pre-test administration of morphine (0.5, 2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under pretrainign morphine influence. The inhibitory effect of morphine (5 mg/kg) on memory formation was significantly antagonized by pretreatment administation of naloxone (0.025, 0.5 and 1 mg/kg) before .the pre-training morphine. The pre-test administration of naloxone dose dependently inhibited the restoration induced by morphine (5 mg/kg). Amnesia induced by pre-training morphine significantly was inhibited in morphine-sensitized mice, which had previously received once daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days. Morphine sensitization did not affect on morphine state-dependent memory of passive avoidance. The inhibition of morphine-induced amnesia in morphine-sensitized mice was suppressed by one daily injections of naloxone (0.5, 1 and 2 mg/kg) 30 min prior to s.c. injections of morphine (20 mg/kg/day × 3 days). These results suggest that morphine sensitization affect the impairment of memory formation, but not the facilitation of retrieval induced by morphine.

Newly developed compound derived from the immune system help combat morphine abuse by destroying the drug soon after it enters the bloodstream. A morphine-6-succinyI-SA (M-6-S-SA) vaccine was designed in an effort to obtain a potent, long - lasting anti-morphine immune response for the treatment of morphine abuse. The analogue incorporated a succinic anhydride linker moiety in place of hydroxy group at c-6 of the morphine framework. Then morphine 6-hemi-succinate was conjugated to serum albumin (SA) in aqueous solution in the presence of tributylamin, isobutylchlorformate and dioxan. M-6-S-SA was synthesized in three chemical steps starting from morphine sulphate and the extent of conjugation was determined by base hydrolysis of the conjugate, extraction and measurement of free morphine or with U. V absorbance. An average of 6.5 molecules of morphine were conjugated to each molecule of protein 1200 morphine addictions from separate areas of Iran vaccinated with suitable doses in 3 steps for each addiction. After vaccination 95% of addictions immunized with three doses of the vaccine, were found to be producing antibody in 60 days later as determined by Electrophoresis method, which measures binding antigen by antibody with western blotting ELISA and TLC over layer. Necrosis, fever, shock, etc in all steps and with whole volunteers. Finally the Morphine Vaccine also recommends for prevention of morphine addiction because we obtained very good results with 100% immune and clinical response. We also found that, there would be no cross- reaction between these antibody and analgesic drugs.

Background and purpose: Morphine vaccine is a product of morphine-6- succinate synthesis and its conjugation with albumin serum. Each dose contains 0.5 mg Aluminum hydroxide, 8 mg sodium chloride, 1.12 mg di- sodium hydrogen phosphate, 1.1 mg sodium di- hydrogen phosphate and 50 mg morphine-6- succinate albumin serum. Humoral safety is achieved in morphine addicts following three successive doses within 0-30- 60-day intervals. Its immunogenicity brings about withdrawal without the risk of abstinence syndrome. This study was conducted to examine the effect morphine vaccine on morphine addicts. Methods and Materials: Based on the Ethics protocol of Pasteur Institute of Iran, this clinical trial was conducted on 102 male volunteer addicts (mean age 25 years). Variables included vaccine dosage and concentration on of antibodies. Volunteers were divided into groups of 30 (experimental) and 4 (placebo).Adjuant was injected to placebo group addicts; the three experimental groups were given 5, 12, 100 and 600 mg within 0- 30-60 days interval through injection to deltoid; all subjects referred for follow-up on the 90th day. Blood samples and antibody evaluation was obtained from all three groups in months 5, 7, 9, 11 and 12.Results: A positive correlation was observed between antibody production and vaccine dosage as well as frequency of injection.Anti-morphine antibody was detected after the first injection of 100mg/ml, 600mg/ml and second injection of 12.5mg/ml doses. Antibody levels reached the peak by three months and did not decline to the baseline after one year Conclusion: the vaccine was well tolerated and lacked the reverse and unfavorable effects, characteristic of vaccines and drugs. On day 90, humoral immunity was created in all patients.

In the present study, the effect of swim stress on morphine-induced tolerance was investigated in mice using formalin test. In this respect, intraperitoneal administration of different doses of morphine (3, 6, and 9 mg/kg) induced a dose-dependent antinociception in both acute and chronic phases of the formalin test. In addition, an exposure to swim stress 2 or 3 times for 3 consecutive days was performed in order to induce tolerance. This exercise decreased morphine-induced antinociception. Meanwhile, morphine administration (25 mg/kg) for 3 days in the presence of swim stress (for two to three times) potentiated tolerance induced by morphine in both phases of the formalin test. Administration of a higher dose of morphine (50 mg/kg) for 3 days in the presence of swim stress did not alter morphine-induced tolerance in both phases of the test. On the other hand, administration of the latter dose of morphine for 3 days in the absence of swim stress decreased morphine-induced antinociception in both phases of the formalin test. It can be concluded that there may be a cross interaction between morphineinduced antinociception and swim stress.

Background: The most effective groups of drugs for the treatment of surgical pain are opioid analgesics. But due to the development of tolerance, chronic use of opioids limits their effectiveness. However, the real need and analgesic response to opioids in postoperative pain has not been determined in addicted patients. Therefore this study was performed, to evaluate the analgesic response to morphine in postoperative pain of ovariohysterectomy in morphine dependent rats, compared with the non dependents.Materials and Methods: The present study was carried out on 36 adult female rats. Animals were divided into four groups (6 in each group): Control- ovariohysterectomy, control - sham, dependent- sham and dependent - ovariohysterectomy groups. Rats became dependent to morphine by taking morphine in their drinking water for 21 days. Rats were anaesthetized with ether, and after incision of the abdomen, uterus and ovaries were removed above the cervix. Latency time was assessed by Tail flick test before and after the operation and after inducing morphine 4 mg/kg (sub cutaneously). Data were expressed as latency time and percent of maximal possible effect [%MPE].Results: The results of present study showed that the mean latency time to noxious stimulus in tail flick test was not significantly different before and after the surgery in the four groups of animals Which indicated. that latency time in morphine dependent rats (9.1±0.4s), was not significantly different from control rats (10.1±1.25s) in tail flick test. Morphine injection increased the latency time in all of the groups significantly. The percent of MPE showed that the maximum analgesic effect of morphine in morphine dependent rats [48.7±11.8s] after ovariohysterectomy was significantly higher than sham - dependent rats (19.6±5s).Conclusion: The present study showed that there was not a significant difference in analgesic response to morphine after ovariohysterectomy in normal and morphine dependent rats.But ovariohysterectomy only increased the analgesic effect of morphine in dependent animals.

Background and aims: Recent studies have demonstrated that subcutaneous rout for opioid administration is a useful way for management of postoperative pain. The aim of this study was to compare the analgesic efficacy and adverse effects of intermittent intramuscular injection and subcutaneous morphine boluses after cesarean section.Methods: Sixty patients, aged 16 to 45, scheduled for caesarian section were randomly assigned to receive analgesia via either intramuscular (intramuscular group, 0.15 mg/kg) or subcutaneous injections of morphine (subcutaneous group, 0.15 mg/kg). Postoperative pain was assessed at rest and walking, using a visual analogue scale (VAS) every 4 hours. A Mini Mental Status examination was used to assess cognitive functions before surgery, at 2, 24 and 48 hours after surgery and at hospital discharge. Side effects were also recorded systematically during the first 48 hours after surgery.Results: At rest, pain and overall analgesia satisfaction scores were not significantly different between the two groups. During mobilization, the subcutaneous group had lower pain score and it was significant at 12 hour, 16 hour, and 20 hour after operation (p<0.05). There was no inter-group difference in postoperative Mini Mental Status scores. The incidence of side effects was similar in two groups.Conclusion: It was concluded that subcutaneous morphine is a satisfactory alternative to intramuscular morphine after cesarean section.

This research was designed to study sexual differences in place conditioning induced by morphine in offspring born of female Wistar rats mated with drug-naïve males. Mothers were exposed to morphine during the 14th-16th days of gestational. Control dams were simply saline-injected. Female and male virgin offspring born of morphine-treated or saline-treated mothers were separately housed until become fully matured. A 3-day schedule of an unbiased conditioning procedure was used to the induce conditioning to morphine (2.5-7.5 mg/Kg, SC) in the offspring. According to the results, female offspring born of saline-administered mothers were morphine place-conditioned at lower doses of opioid (2.5 mg/Kg) in comparison to the males. An increase in locomotor activity in the females at 7.5 mg/Kg of opioid was also revealed. In contrast, administration of morphine (2.5-7.5 mg/Kg, SC), induced a significant aversion in either sexes of offspring born of morphine-exposed mothers. Moreover, female offspring of this category acquired more pronounced aversion at higher doses of morphine than males. In addition, a significant morphine-dose effect (7.5 mg/Kg, SC) on locomotor activity of these females’ offspring was observed. This study may highlight sex differences in conditioning effects induced by morphine between offspring derived of morphine-treated mothers and those of saline-treated.