Introduction: Previous studies have indicated that the voluntary and swimming exercise decreases the severity of the physical and psychological dependence on morphine in morphine-dependent and withdrawn rats. The aim of the present study was to investigate the effects of the forced treadmill exercise during the induction of morphine dependence on naloxone-precipitated morphine withdrawal signs and anxiety like behavior.Materials and Methods: Rats were injected with increasing doses of morphine (8, 16, 26, 36, 46, 56 and 64 mg/kg, daily, s.c.) over a period of 7 days in which they were also trained at mild intensity on a treadmill for 30 min of daily. The anxiety-like behaviors were tested 2h after receiving morphine injection (56 mg/kg) using the elevated plus-maze (EPM) on day 8. Then, the severity of morphine dependence was measured after an acute injection of naloxone (0.4mg/kg, IP), 2h after receiving morphine injection (56 mg/kg) according to a modified version of the Gellert–Holtzman scale on day 9.Results: The results showed that the withdrawal graded signs including abdominal contractions, weight loss, and overall Gellert–Holtzman score and among the checked signs; consisted of diarrhea, irritability and teach chattering were decreased in treadmill runner morphine-dependent rats than the sedentary rats. Also, the results showed that the treadmill runner morphine-dependent rats exhibited an increase in time spent in, and entries into, the EPM open arms than the sedentary morphine-dependent groups.Conclusion: Our findings indicated that the forced treadmill exercise during the induction of morphine dependence diminished the severity of dependence on morphine and anxiety like behavior. Thus, forced treadmill exercise may decrease some of the behavioral consequences of physical and psychological dependence on morphine.

In this study, physical dependence in male hypothyroid Swiss-Webster mice was investigated by evaluating of morphine withdrawal signs. Animals were divided into four groups: control, morphine dependent, hypothyroid and hypothyroid morphine dependent. Hypothyroidism was induced by administering propylthioracil (PTU) 0.1% for 2 weeks into drinking water of the animals. Animals at control groups only received tap water. Morphine dependency was induced by intraperituneal injection of morphine hydrochloride for 4 days according to Marschall method. Withdrawal signs were evaluated 1 hour after the last administration of morphine by intraperituneal injection of naloxone in experimental groups. The results of the present study showed that morphine dependence was greater in hypothyroid animals compared to control and dependent groups and withdrawal signs were more serious (P<0.05). These results suggest that hypothyroidism could affect on morphine dependence by possible altering in numbers or affinities of the opioid receptors in the nervous system.

Background: Opioids are the principal drugs of choice for managing acute severe pain,however, physical dependence is still reported as one of the main limiting factors in the clinical application of these drugs. In the present study, the effect of Ganoderma lucidum was assessed on morphine dependence in mice. Methods: A 19-day administration schedule was applied to induce morphine dependence in male adult NMRI mice. The mice were given intraperitoneal (i. p. ) morphine sulfate once daily in an increasing dose of 10, 20, and 40 mg/kg. Then, G. lucidum hydroalcoholic extract (12. 5, 25, and 50 mg/kg, i. p. ) was given to the mice from days 10 to 18. Another group of mice received single doses of the extract (50, 100, and 200 mg/kg, i. p. ) only on the 19th day. Naloxone (3 mg/kg, i. p. ) was used to precipitate withdrawal syndrome. Normal saline and diazepam (0. 25 mg/kg) were used as the negative and positive controls, respectively. Results: The administration of single doses of G. lucidum extract (100 and 200 mg/kg, i. p. ) significantly decreased the number of jumps, leanings, and diarrhea in mice subjected to morphine dependence. The repeated administration of G. lucidum extract (25 and 50 mg/kg for nine days) significantly attenuated the number of jumps, leanings, and diarrhea in morphine-dependent mice. Conclusions: Overall, G. lucidum extract attenuates induced morphine dependence and inhibits withdrawal syndrome symptoms in mice.

Background and purpose: Opiates are traditionally used for the treatment of pain. Chronic consumption of opiates such as morphine (MOR) induces tolerance and dependence. This study aimed to investigate the effects of valsartan (VAL), as an angiotensin II receptor blocker, on the induction and expression of MOR analgesic tolerance and physical dependence in rats. Experimental approach: MOR 10 mg/kg was injected s. c. twice a day for 7 days to induce tolerance and dependence. For evaluating the effect of VAL on the induction of MOR analgesic tolerance and physical dependence, 20 mg/kg VAL was administered orally (once a day) during the 7 days of the examination period. The tail-flick test was performed every day. On day 7, 5 mg/kg naloxone () was injected s. c. into the morphinedependent rats and the rats were monitored for 30 min for the frequency of withdrawal signs such as jumping, diarrhea, defecation, head tremor, rearing, scratching, sniffing, teeth chattering, and wet-dog shake. For evaluating the effect of VAL on the expression of MOR-analgesic tolerance and physical dependence, 45 min before the last MOR injection, VAL was administered only on day 7. The tail-flick test was performed and naloxone was injected into the addicted rats and they were monitored for 30 min for the frequency of withdrawal signs such as jumping, diarrhea, defecation, head tremor, rearing, scratching, sniffing, teeth chattering, and wet-dog shake. Findings/Results: Our results revealed that the co-administration of VAL with MOR for 7 consecutive days reduced the induction of MOR tolerance. Moreover, VAL administration for 7 days along with MOR reduced the frequency of diarrhea and defecation in naloxone-injected animals. Conclusion and implications: According to the results presented in this study, chronic administration of VAL prevented the induction of MOR-analgesic tolerance and dependence in rats.

Objective: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice.Materials and Methods: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively) during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p.) was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination.Results: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p.) significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days) and also single injection of thymoquinone (40 mg/kg, on the fourth day) attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg) produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg).Conclusion: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine.

Background: Anxiety is one of the comorbid disorders of opioid addiction, which leads to opioid abuse or persuades people to engage in opioid abuse. Evidence revealed that morphine exposure before conception changes the offspring’s phenotype. The current study aimed to investigate the influence of morphine dependence and abstinence on anxiety-like behavior in morphineexposed and drug-naïve offspring. Methods: Adult male and female rats were treated with morphine or vehicle for 21 days. Then, all rats were left without drug treatment for 10 days. A morphine-exposed female rat was mated with either a vehicle-exposed or morphine-abstinent male. According to parental morphine exposure, the offspring were categorized into four distinct groups: (1) control (both drug-naïve parents), (2) paternal morphine-exposed, (3) maternal morphine-exposed, and (4) biparental morphine-exposed. The anxiety-like behavior was measured in adult male offspring using open field and elevated plus-maze tests before morphine exposure (naïve), 21 days after morphine exposure (dependence), and ten days after the last morphine exposure (abstinence). Findings: The results indicated that anxiety-like behavior increased before morphine exposure in maternal and biparental morphineexposed offspring (P<0. 05). However, after morphine exposure, the anxiety level did not change among the groups. Ten days after the last morphine exposure, anxiety-like behavior increased only in biparental morphine-exposed offspring (P<0. 05). Conclusion: The offspring of morphine-abstinent parents exhibited an anxious phenotype. Disruption of the HPA axis was seen in the progeny of maternal and biparental morphine-exposed rats. Indeed, morphine exposure for 21 days did not change anxiety-like behavior in these offspring which might be correlated to disruption of HPA axis in them.

Background: Exercise deprivation has been concluded to have some negative effects on psychological well-being. This study was conducted to find out whether exercise deprivation may lead to morphine dependence in rats.Methods: Forty male Wistar rats weighing 162±9 g were housed in clear plastic cages in groups of two under standard laboratory conditions. The study had two phases. In phase I, the animals were randomly divided into exercised (E) and unexercised (UE) groups (n=20 each) and treadmill running was performed based on a standard protocol for three weeks. At the end of the training period, plasma b -endorphin levels were determined in four rats from each group. In phase II, the animals were provided with two bottles, one containing tap water and the other 25 mg/l morphine sulfate in tap water for a total of 12 weeks. At the end of this phase naloxone was injected intraperitoneally to precipitate morphine withdrawal.Findings: There was no significant difference between UE and E groups in morphine consumption (mg/kg/wk) [group: F (1, 14) =0.2, P=0.690; time: F(11, 154) =18.72, P<0.001; interaction: F (11, 154) =1.27, P=0.245]. No statistically significant difference between the two groups of animals was seen regarding withdrawal signs.Conclusion: The study showed that discontinuation of exercise does not increase the tendency of morphine dependence in rats.