Academic journal article Iranian Journal of Psychiatry

Effects of Estrogen Receptor Modulators on Morphine Induced Sensitization in Mice Memory

Academic journal article Iranian Journal of Psychiatry

Effects of Estrogen Receptor Modulators on Morphine Induced Sensitization in Mice Memory

Article excerpt

Large body of evidence indicate that abuse of such drugs as morphine affects neuronal plasticity in brain areas related to motivation and reward (1). Besides, previous studies revealed that morphine and other opioid agents can affect learning and memory (2). The above mentioned effect has been shown both in positive and negative aspects by diverse studies (3, 4). These divergences may be due to different experimental paradigms (2, 3) such as acute or chronic drug administration (2, 4). Many studies have pointed out that acute administration of opioids diminishes learning and memory processes in different types of memory assessment tasks (5-7), and this destruction can be antagonized by naloxone (8-10). Some studies revealed that the pre-training administration of morphine inhibits the acquisition of memory in different paradigms such as y-maze model (11), active or passive avoidance (12) and operant tasks (13). It has been shown that chronic exposure to morphine results in learning impairment in Morris water maze (4). Also, it was reported that frequent exposure to morphine slowed acquisition but did not reduce memory retention in water maze task (2). Repeated administration of morphine pursued by a drug-free status can induce sensitization which in turn results in long-lasting augmentation of morphine behavioral effects (14, 15). The sensitization induced pathways are complex which represents a cascade of events involving either neurotransmitter systems or brain regions such as nucleus accumbens, ventral tegmental area and the hippocampus (16). Behavioral sensitization demonstrated drug-induced neuroadaptive long-term changes in reward-associated pathways in the brain (17).

It has been proved that several effects of acute and chronic exposure to morphine are expressed differently on the basis of gender such as anti-nociception (18), locomotion (19) and development of tolerance and dependence (20). Moreover, according to previous researches, estrogen has been demonstrated to influence learning and memory (21), while its efficacy varies with task study design (22), types of memory (23), and the duration of hormone administration (24).

According to previous reports, estrogen plays a considerable role in induction of acute tolerance to morphine induced analgesia (25). Moreover, it has been reported that morphine-associated contextual memory can be diminished by tamoxifen, and this impairment might be banned by estradiol treatment (26). On the other hand, spinal kappa- and mu-opioid receptor hetero-dimerization can be modified via spinal synthesis of estrogen and simultaneous signaling by membrane estrogen receptors and female-specific spinal morphine antinociception (27). Many studies have been conducted on estrogen and morphine interactions, but there are no reports on the effects of estrogen towards morphine induced sensitization in mice learning .

The purpose of this study was to evaluate the effects of various doses of estradiol valerate and raloxifene (a selective estrogen receptor modulator; SERM) on morphine induced sensitization in mice memory.

Material and Methods


Male adult NMRI mice (bred in animal department, School of Pharmacy, with ISO17025 license) weighing 20.2-29.4 g were used in the present study. The animals were housed in a temperature/moisture controlled (22±3°C/45-55% humidity) colony room and were maintained in a 12-h light/dark cycle with free access to food and water, except during experiments. Experiments were done between 10:00 a.m. and 3:00 p.m. Animals were adapted to the laboratory conditions for at least 72 hours prior to experiments. Each treatment group included ten animals. The protocols were carried out according to national guidelines for animal care and use which was approved by the Ethics Committee of the institute.

Drugs and Chemicals:

Morphine sulphate was purchased from Temad (Iran). Estradiol valerate, raloxifene and ultra- filterated sesame oil (as a vehicle for estradiol) were purchased from Iran Hormone Company. …

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