fereshteh motamedi

Peroxisomes are essential organelles in lipid metabolism. They contain enzymes for β-oxidation of very long-chain fatty acids (VLCFA) that cannot be broken down in mitochondria. Reduced expression in hepatic acyl-CoA oxidase 1 (ACOX1), a peroxisome β-oxidation enzyme, followed by modification of the brain fatty acid profile has been observed in aged rodents. These studies have suggested a potential role for peroxisome β-oxidation in brain aging. This study was designed to examine the effect of hepatic ACOX1 inhibition on brain fatty acid composition and neuronal cell activities of young rats (200-250 g). 

A specific ACOX1 inhibitor, 10, 12- tricosadiynoic acid (TDYA), 100 μg/kg (in olive oil) was administered by daily gavage for 25 days in male Wistar rats. The brain fatty acid composition and electrophysiological properties of dentate gyrus granule cells were determined using gas chromatography and whole-cell patch-clamp, respectively. 

A significant increase in C20, C22, C18:1, C20:1, and a decrease of C18, C24, C20:3n6, and C22:6n3 were found in 10, 12- tricosadiynoic acid (TDYA) treated rats compared to the control group. The results showed that ACOX1 inhibition changes fatty acid composition similar to old rats. ACOX1 inhibition caused hyperpolarization of resting membrane potential, and also reduction of input resistance, action potential duration, and spike firing. Moreover, ACOX1 inhibition increased rheobase current and afterhyperpolarization amplitude in granule cells. 

The results indicated that systemic inhibition of ACOX1 causes hypo-excitability of neuronal cells. These results provide new evidence on the involvement of peroxisome function and hepatic ACOX1 activity in brain fatty acid profile and the electrophysiological properties of dentate gyrus cells.

Mitochondria and peroxisomes are tightly connected organelles that cooperate in lipid oxidation and maintenance of redox homeostasis. However, the peroxisome’s role in the modulation of the mitochondrial regulatory factors has remained unanswered. SIRT1- PGC-1α interaction as a pivotal pathway in energy expenditure leads to mitochondrial biogenesis. Histone deacetylase (HDAC)6 and HDAC10 also regulate mitochondrial dynamics. Mitochondrial dysfunction is a cause and/or consequence of aging and neurodegenerative disorders.

In this study, to disturb importing proteins into the peroxisomes, PEX5 was down-regulated in the dorsal hippocampus by lentivirus-mediated shRNA. The impact of PEX5 reduction on peroxisomes was explored by assessment of catalase activity, a regular peroxisome matrix enzyme, and PMP70 and PEX14 expression. Then, mitochondrial biogenesis factors, PGC-1α, and mitochondrial transcription factor A (TFAM) were measured by quantitative polymerase chain reaction and mitochondrial-related HDACs, SIRT1, SIRT3, HDAC6 and HDAC10, by western blotting. Besides, spatial learning and memory were assessed using the Morris water maze task.

Our results revealed a significant reduction of HDAC6 and SIRT1, alongside with decrease in mitochondrial biogenesis factors PGC-1α and TFAM, and no alteration in HDAC10 and SIRT3. Despite all observed changes, memory performance displayed no detectable alteration in the experimental groups. These data suggest the role of peroxisomes in modulating mitochondrial dynamics via regulation of HDAC6 and SIRT1 expression.

Peroxisome dysfunctions may occur upstream to mitochondrial failure and can be considered as a potential therapeutic target for aging and age-related disorders.

It has been shown that brain glucose metabolism impairment, obesity, and diabetes couldlead to cognitive decline and Alzheimer’s disease (AD) pathogenesis. Kisspeptin (KP) a G-proteincoupled receptor neuropeptide, has been suggested as a link between energy balance andreproduction. Some studies have shown that the attenuation of KP signaling decreases metabolismand energy expenditure. KP mRNAs and receptors are detected in the hippocampusand cause the promotion of excitatory synaptic responses through modulation of postsynapticsignaling. The purpose of this study was to investigate the effect of KP on spatial learning andmemory and its possible neuroprotective effect on Amyloid-Beta induced cognitive impairmentusing the Morris Water Maze (MWM) task in rats. The reference and reversal spatial learningand memory have been measured in this study. Rats were injected bilaterally by Aβ1-42 (2 μg/μL) or saline as a vehicle into the hippocampal CA1 area. One week later, KP-13 (1.5 or 2 μg/μL) was injected i.c.v before or after each training session for 3 days and memory was tested24 h later. The results showed KP-13 by itself could significantly enhance spatial memoryconsolidation and retrieval, and Aβ induced reversal and reference memory impairment wassignificantly ameliorated by KP-13. In Conclusion, it seems that KP-13 as a neuropeptide hasto enhance spatial memory properties and could be a possible neuroprotective peptide on amyloid-beta induced pathology.

Peroxisomes are single membrane cell organelles with a diversity of metabolic functions. Here we studied the peroxisomal dysfunction and oxidative stress after 3-nitropropionic acid (3-NP) induced neurotoxicity and the possible protective effects of oxytocin. Adult male and female rats were subjected to Oxt and/or 3-NP treatment. The antioxidant enzymes, Superoxide dismutase (SOD) and Catalase (CAT) activities as well as expression level of Peroxin 14 (Pex14), a marker for peroxisomal number and Peroxisomal membrane protein of 70 kDa (PMP70), a metabolic transporter in peroxisome in different brain regions of both sexes were studied. The results indicated that 3-NP significantly decreased the expression level of Pex14 and PMP70 in various studied areas in male and female rats. In addition, 3-NP reduced the SOD and CAT activity in different brain regions in both sexes. OXT treatment increased the expression level of peroxisomal proteins Pex14 and PMP70 which are representative of peroxisome performance improvement. Besides, it ameliorated the antioxidant system capability through increasing the activity of the SOD and CAT in all studied brain regions including Striatum, Hippocampus, Prefrontal Cortex and Amygdala with no differences in male and female rats. This study demonstrated that toxin 3-NP, could ultimately cause peroxisomal malfunction and so determines the contribution of peroxisomal dysfunction in the etiology of HD pathology. OXT significantly increased peroxisomal function and antioxidant system defense capability, therefore illustrates that OXT might be an alternate treatment approach for the neurodegenerative diseases like HD.

Opioids and cannabinoids are two important compounds that have been shown to influence the activity of magnocellular neurons (MCNs) of supraoptic nucleus (SON). The interaction between opioidergic and cannabinoidergic systems in various structures of the brain and spinal cord is now well established, but not in the MCNs of SON.
In this study, whole cell patch clamp recording of neurons in rat brain slice was used to investigate the effect of acute morphine and cannabinoid administration on spontaneous inhibitory and excitatory spostsynaptic currents (sIPSCs and sEPSCs) in MCNs.
Bath application of morphine produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency. In contrast, bath application of URB597 (fatty acid amide hydrolase (FAAH) inhibitor) produced a decrease in sEPSCs frequency but an increase in sIPSCs frequency. WIN55212-2 (cannabinoid receptor agonist) decreased both sIPSCs and sEPSCs frequencies of MCNs. Co-application of morphine and URB597 attenuated the effect of morphine on MCNs.
Taken together, these data indicated that at the cellular level, pharmacological augmentation of endocannabinoids could attenuate morphine effects on MCNs.

The effects of cannabinoids (CBs) on synaptic plasticity of hippocampal dentate gyrus neurons have been shown in numerous studies. However, the effect of repeated exposure to cannabinoids on hippocampal function is not fully understood. In this study, using field potential recording, we investigated the effect of repeated administration of the nonselective CB receptor agonist WIN55212-2, and the CB1 receptor antagonist AM251, on both short- and long-term synaptic plasticity in dentate gyrus (DG) of hippocampus. Drugs were administered three times daily for seven consecutive days into lateral ventricle of rats. Short term synaptic plasticity was assessed by measuring paired-pulse index (PPI) in DG neurons after stimulation of perforant pathway. Long-term plasticity was assessed through measurement of both population spike (PS) amplitude and field excitatory postsynaptic potential (fEPSP) slope after high frequency stimulation (HFS) of DG neurons. Repeated administration of WIN55212-2 not only significantly decreased PPI in 20, 30 and 50 ms intervals but also blocked LTP. This effect was reversed by pretreatment of rats with CB1 receptor antagonist AM251. Moreover, AM251 by itself increased PPI in 10 and 20 ms interval stimulations, but had no effect on HFS-induced PS amplitude and fEPSP slope. These results suggest that repeated administration of cannabinoids could impair short term and long term synaptic plasticity that may be due to desensitization of cannabinoid receptors and/or changes in synaptic spine density of hippocampus which leads to alteration in short and long term memories that remains to be elucidated.

The purpose of this study is to investigate the effect of Dorema ammoniacum on PTZ induced seizures in male rats. In chemical kindling، animals received pentylenetetrazol، 30mg/kg/48h، intraperitoneally and five different stages of seizure were appeared gradually and seizure parameters including maximum seizure stage (SS)، stage 4 latency (S4L)، and seizure duration (SD) were measured during 20 min after PTZ injection. Subsequently، the effects of Dorema ammoniacum (50 and 100mg/kg)، injected 30 min before PTZ، on these parameters were evaluated and compared with antiepileptic drug، phenobarbital (30 mg/kg، IP). Results showed that Dorema ammoniacum decreased SS and SD and increased S4L significantly (P<0. 001، P<0. 01، respectively). This antiepileptic effect was as much as 50%-60% of phenobarbital effects. On the basis of obtained results it may be concluded that Dorema ammoniacum has anticonvulsant effect on PTZ induced kindling model of epilepsy. Considering that Dorema ammoniacum increased the latency of seizure stages occurrence and reduced duration of different seizure stages (SD) and seizure stage (SS)، it may prevent spreading of epileptiform activity in the nervous system and contribute to turn off excessive neuronal firing.

Alzheimer’s disease (AD) has been suggested to be a form of neuroplasticity failure. In addition to long term maladaptive changes in synaptic function, short term synaptic plasticity that has a role in information processing can be affected in AD that was investigated in this study. Field excitatory post synaptic potential (fEPSP) from Stratum radiatum of CA1 neurons were recorded following Schaffer collateral stimulation in a rat model of Alzheimer’s disease (AD). 1 µl of Aβ 1-42 (5µg/µl) and 1 µl of ibotenic acid (5µg/µl) were injected in dorsal hippocampus of male rats for AD induction. For examining the short-term synaptic plasticity, paired pulse stimulations with inter pulse interval (IPI) of 20, 80, and 200 ms were applied and paired pulse index (PPI) was calculated. Results showed that although AD induction decreased basal synaptic responses especially at high stimulus intensity, this change was not significant (ANOVA; P>0.05). Also there were no significant changes in PPI of AD rats at different IPIs including 20 ms (%40.4±4.68, n=5), 80 ms (%129.8±4.1, n=5), and 200 ms (%129±6.8, n=5) in comparison with control ones (%75.2±5.08, %138±7.56, %108.4±2.09 respectively, n=5, P>0.05, unpaired t-test). Such results indicate that hippocampal Aβ treatment does not lead to impairment of basal synaptic response and short term synaptic plasticity.

Considering the increased activity of hypothalamic orexinergic neurons due to morphine administration, and its extensive projections to the hippocampus, it is probable that morphine effect on CA1 neuronal function is mediated by orexinergic system. So the effect of hippocampal orexin-1 receptors (OX1R) blockade on CA1 baseline synaptic response and short term synaptic plasticity was investigated. In this experimental study, animals received morphine 10 mg/kg/12h/(SC) for 10 days. SB-334867-A, OX1R antagonist (0.5μg/0.5 μl), was microinjected intrahippcampally for OX1R inhibition before each morphine injection. Baseline synaptic response and short term synaptic plasticity were evaluated by field potential recording. fEPSP was recorded from CA1 following Schaffer collaterals stimulation. After Input/Output construction, short term synaptic plasticity was induced by paired pulse stimulations. Chronic use of morphine did not affect the baseline synaptic response (p>0.05). SB- 334867-A microinjection in CA1 did not have any effect on baseline synaptic response in morphine dependent rats. Morphine increased paired pulse index (PPI) at 80 ms inter pulse interval (IPI, p<0.05). SB-334867-A pretreatment did not affect this morphine induced PPI change. The results suggest that orexin-1 receptors (OX1R) do not mediate the effect of morphine on baseline synaptic response and short term synaptic plasticity in CA1 area of the hippocampus.

The activity of the magnocellular neurons (MCNs) of supraoptic nucleus (SON) is regulated by a variety of excitatory and inhibitory inputs. Opioids are one of the important compounds that affect these inputs at SON synapses. In this study, whole-cell patch clamp recording of SON neurons was used to investigate the effect of acute and repeated morphine administration on spontaneous inhibitory and excitatory post synaptic currents (sIPSCs and sEPSCs) in MCNs. While acute bath application of morphine to brain slice of intact rat produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency, repeated in vivo administration of morphine produced opposite effect. Moreover, repetitive i.c.v. administration of morphine for three consecutive days caused significant increase in urine volume, but had no significant alteration in water consumption compared to control group. The increase in urine volume was consistent with a significant decrease in plasma arginine vasopressin (AVP) levels after repetitive i.p. morphine administration. The results suggest that acute administration of morphine stimulates whereas repeated administration of morphine inhibits the MCNs. Morphine-induced MCN inhibition could result in diminished plasma AVP levels and eventually an increase in urine volume of rats.

The dentate gyrus of hippocampus has long been considered as a focal point for studies on mechanisms responsible for the development of temporal lobe epilepsy (TLE). Change in intrinsic properties of dentate gyrus granule cells (GCs) has been considered as an important factor responsible in temporal lobe seizures. In this study, we evaluated the intrinsic properties of GCs, during acute phase of seizure (24h after i.p. injection of pilocarpine) compared to sham group using whole cell patch-clamp recordings. Our results showed a significant increase in the number of action potentials (APs) after applying depolarizing currents of 200pA (p<0.01) and 250pA (p<0.05) compared to sham group. The evaluation of AP properties revealed a decrease in half-width of AP in GCs of seizure group compared to sham group. Moreover, addition of BAPTA to pipette solution prevented changes in AP half-width in seizure group compared to sham group. In contrast, an increase in the amplitude of fast afterhyperpolarization was observed in GCs of seizure group compared to sham group. Also, GCs of seizure group showed a significant increase in both firing rate and instantaneous firing frequency at depolarizing currents of 200 pA (P<0.01) and 250 pA (P<0.05) compared to sham group. The changes in electrophysiological properties of GCs were attenuated after bath application of paxilline suggesting possible involvement of large conductance Ca2+- activated K+ channel (BK channel). Our results suggested the possible involvement of certain potassium channels in early changes of intrinsic properties of GCs which eventually facilitate TLE development.

The prostaglandin E2 (PGE2), a cyclooxygenase (COX) product, play critical roles in the synaptic plasticity. Therefore, long term use of COX inhibitors may impair the synaptic plasticity. Considering the wide clinical administration of aspirin and its unknown effects on information processing in the brain, the effect of aspirin and sodium salicylate on the short term synaptic plasticity was investigated.

Field excitatory post synaptic potential (fEPSP) from stratum radiatum of CA1 neurons were recorded following Schaffer collateral stimulation in rats receiving aspirin in drinking water (2 mg/ml) for 6 weeks or sodium salicylate (six injection of 300 mg/kg, IP, twice daily) for 3 days. In order to examine the short-term synaptic plasticity, paired pulse stimulations with inter pulse intervals (IPI) of 20, 80, and 200 ms were applied and paired pulse index (PPI) was calculated.

The data showed that both sodium salicylate and aspirin decreased basal synaptic responses, although this change was significant in the sodium salicylate group, but not in aspirin treated rats (ANOVA; P<0.001). Sodium salicylate significantly increased PPI at 20 ms IPI (%90.7±1.6, n=5Vs. control: %76.1±1.5, n=5). Also significant increase in PPI was observed in aspirin treated rats (%125.9±6.6, n=5) at 20 ms IPI compared to control ones (%76.3±2.4, n=5, P<0.05, unpaired t-test).

In summary, our study suggests that aspirin and sodium salicylate may affect synaptic transmission and short term synaptic plasticity in the rat hippocampus.

Cerebral hypoperfusion/ischemia (CHI) is a neurological disease where impaired hippocampus electrical activity and cognition caused by a serial pathophysiological events. This study aimed to evaluate the effects of chronic oral administration of grape seed extract (GSE) on passive avoidance memory and long-term potentiation (LTP) after permanent bilateral common carotid arteries occlusion (2CCAO) in male adult rats. Thirty-two adult male Wistar rats were randomly divided into: 1) Sham+Veh, 2) Isch+Veh, 3) Sham+GSE, 4) Isch+GSE. In order to make 2CCAO as an animal model of CHI, carotid arteries were ligatured and then cut bilaterally. To evaluation of passive avoidance memory, step-down latency (STL) was measured and LTP was recorded from hippocampal dentate gyrus (DG) after high frequency stimulation (HFS) in all rats. We found that memory was significantly impaired in rats after CHI (P<0.001) concomitant with hippocampal LTP inhibition (P<0.05, P1 and LTP48 respectively). GSE treatment significantly improved memory impairment and increased hippocampal LTP in rats with 2CCAO. Our results in present study suggest that GSE exhibits therapeutic potential for short-and long-term memories as well as LTP in DG, which is most likely related at least in part to its antioxidative and free radical scavenging actions.

Salvia verticillata is one of the salvia species which possesses remarkable antioxidant activity. In the present study, we investigated the possible effects of hydro-alcoholic extract from Salvia verticillata plant (SVE) in various models of anxiety, depression and seizure in mice. Mice were randomly divided into control (saline), SVE-treated and standard treatment groups. The SVE-treated groups received oral administration of various doses of SVE. As a standard treatment, diazepam and imipramine were used orally for anxiety/seizure and depression tests, respectively. The results of the study revealed that the plant extract produced significant anticonvulsant activity in maximal electroshock and pentylenetetrazol induced seizure models. Moreover, in forced swim test and tail suspension test of depression, SVE produced significant antidepressant effect in mice compared to control group. However, SVE did not show any effects on anxiety-like behavior of mice in elevated plus maze and light-dark tests. These results suggest potential therapeutic effects of the plant extract in seizure and depression.

The magnocellular neurons (MCNs) of the supraoptic nucleus (SON) play a crucial role in control of physiological and pathophysiologiccal condition due to two peptides that they synthesize, i.e. Oxytocin (OXT) and Vasopressin (AVP). The activity of MCNs is regulated by a variety of excitatory and inhibitory inputs. Opioid receptors are one of the important receptors in SON synapses. The aim of the present study is to evaluate the effect of acute morphine application on SON synapses and AVP release in rats. In this study, whole cell patch clamp recording of neurons in rat (70-100 g, 3–4 weeks old) brain slice preparations consisting of SON was used to investigate the effect acute of lowest effective dose of morphine (25μM) administration on spontaneous inhibitory and excitatory post synaptic currents (sIPSCs and sEPSCs) in MCNs. Also, AVP levels were measured in blood samples of rats using ELISA technique after the Morphine injection (30 mg/kg, ip). Bath application of morphine produced an increase in sEPSCs and a decrease in sIPSCs frequencies. Measurement of plasma AVP revealed an increase in hormone levels 45 min after systemic administration of morphine. P-values of less than 0.05 were considered statistically significant. It is suggested that acute administration of morphine stimulates the MCNs and AVP secretion.

REM sleep has a role in memory processing. The period of post-learning، that REM sleep is higher than normal level and deprivation of REM sleep impairs memory، is called paradoxical sleep windows (PSW). Methods and Materials: In this experimental study، male N. M. RI rats were trained in a two-way shuttle avoidance task (100 trials/one sessions) then memory retention was tested in next week. In electrophysiology section، different sleep-memory factors were recorded in basal level and 1-4 hours after training. In behavioral section، animals that reached 70% learning criterion (learner group) were deprived of PS in the two periods of 1-4 hours and 5-8 hours after learning by Maze water technique. The amount of REM sleep in group which gained 70% learning after 1-4 hours training، and group without it. In v. s of basic level، significantly increase (p0. 01). Other factors were showed no significant difference between two groups before of training. In behavioral section those animals were deprived in 1-4 hr post-learning show significant memory impairment (p0. 05). Paradoxical increased REM sleep is effective in memory consolidation after 1-4 hours training. This period can be consider as paradoxical sleep window.

The similarities between periaqueductal gray matter and the nucleus cuneiformis in both ultrastructural and functional levels suggest that this nucleus may play an important role in the morphine-induced analgesia. This study was designed to determine neuronal activity and responsiveness to peripheral morphine administration in the nucleus coneiformis of rat. In this study, neural activity of cuneiform neurons in response to peripheral administration of morphine was recorded by extracellular single unit recording technique. Firing rate of neurons was recorded in four groups: intact group (n=19) to determine the spontaneous (baseline) activity, saline group (n=20), morphine group (n=39) and morphine + naloxone group (n=12), before and after drug administration. Our findings showed that the firing rate in majority of cuneiform neurons decreased after morphine (3.8 mg/kg; SC) administration. Activity of neurons (n=39) in the cuneiform neurons was reduced significantly (P<0.01) after morphine injection (6.66±0.67 spike/sec) in comparison with pre-injection time (12.47±1.84 spike/sec) and the saline group (11.6±1.58 spike/sec). The firing rate and response pattern of many of neurons in response to peripheral application of morphine were reversed after naloxone injection (2 mg/kg; SC) in this nucleus. Based on the above findings, we suggest that the changes of activity pattern in spontaneous activity of cuneiform neurons in response to peripheral administration of morphine maybe resulted from direct action of morphine on opioid receptors in the nucleus cuneiformis. Nevertheless, the role of pain transmission and modulation pathways are still important in the antinociceptive effect of morphine as well.

Although formalin-induced activity in primary afferent fibers and spinal dorsal ‎horn is well described, the midbrain neural basis underlying each phase of behavior in ‎formalin test has not been clarified. The present study was designed to investigate the nucleus ‎cuneiformis (CnF)‎‏ ‏neuronal responses during two phases after subcutaneous injection of ‎formalin into the hind paw of rat.‎ In this study, seventy six male NMRI adult rats, weighing 230-320 g ‎were used. Control group (n=24), which was tested merely for determining spontaneous firing ‎rate of CnF neurons. Saline group (n=15) which received saline (50µl; s.c.) instead of ‎formalin into the plantar surface of hind paw after 15 min baseline recording. Formalin group ‎that formalin-induced neural activity of 37 cells simultaneously recorded from the CnF during ‎first phase (0-5 min) and second phase (15-60 min) of formalin test in 5-min intervals, using ‎an extracellular single unit recording technique.‎ The‏ ‏baseline firing rate of neurons in the CnF varied between 1.2 and 39.2 spikes/sec ‎and the average frequency of spontaneous activity over 1 h was 11.8 ± 1.1 spikes/sec. There ‎were three neural clusters after formalin injection. Neurons in cluster 1 (46%) exhibited ‎severe, transient excitatory response in the first (acute) phase while neurons in cluster 2 (35%) ‎exhibited tonic but long-lasting excitatory response in the second (chronic) phase. Cluster 3, a ‎small portion of neurons (about one fifth) which failed to show any evident responses to ‎formalin test. Our findings suggest that alteration of neural activity and pattern in the ‎spontaneous background of CnF neurons can be mediated a role in the transmission of ‎nociceptive information induced by the peripheral injection of formalin and can be discussed ‎in light of the role of these neurons in nociceptive information processing following ‎peripheral stimuli.‎

Evidences show that parental morphine addiction impairs CNS development, learning and memory in offsprings. Since long term potentiation (LTP) is a cellular mechanism of learning and memory, in this study the effect of parental morphine addiction on LTP induction in dentate gyrus by high frequency stimulation of perforant path was assessed. In this experimental study 40 female and 16 male rats (120-140 days old) were addicted by oral administration (32mg/kg, twice daily) of morphine for 5 days. Then male rats were placed with female in 5 groups: 1-test 1 group: addicted female rats (n=20) with non addicted male rats (n=8). 2- test 2 group: non addicted female rats (n=20) with addicted male rats (n=8). 3-test 3 group: addicted female rats (n=20) with addicted male rats (n=8). 4-sham control 1: female received dextrose 5% (n=20) with non addicted male rats (n=8). 5- sham control 2: male received dextrose 5% (n=8) with non addicted female rats (n=20. In pubert offsprings, LTP were induced in dentate gyrus by high frequency stimulation (HFS) of perforant path. The magnitude of potentiation was evaluated as percentage change in population spike (PS) amplitude or excitatory post synaptic potential slope (EPSP) at 5, 30, 60 and 120 minutes after HFS. All values were taken as the mean ±SE. Data were analyzed by two way ANOVA. Amplitude of population spike (PS) and slope of excitatory post synaptic potential(EPSP) 60 and 120 minutes after HFS in offsprings of test 1 and test 2 was less than sham controls (p<0.01). There were no difference between test 1 and test 2 and male and female rat offsprings in PS amplitude and EPSP slope. The results suggest that parental morphine addiction may cause learning deficiency through reduction of LTP in dentate gyrus. So, the side effects of parental morphine addiction in offsprings must be considered.

It has been reported that morphine tolerance does not develop in the presence of chronic pain. Therefore, this study was conducted to find out whether chronic inflammatory pain is able to eliminate or attenuate the developed tolerance to analgesic effect of morphine and also to investigate the role of lumbar spinal cord as a candidate site for this interaction. Tolerance was induced in adult male NMRI rats using daily injection of morphine at a dose of 20 mg/kg (i.p.) for 4 days, or using daily injection of morphine at a dose of 15 pg/rat (i.t.) for 7 days. Chronic inflammatory pain was induced using 50 µl of 5% formalin, injected into the hind paws. The antinociceptive effect of morphine at a dose of 10 mg/kg on day 5 (for i.p. treated rats) or morphine at a dose of 15 pg/rat on day 8 (for i.t. treared rats) were assessed using tail flick test. The results showed that those animals receiving saline (i.t. or i.p.) have potent analgesia (p<0.001), while animals treated with chronic morphine have only a weak analgesia for i.p. treatment (p<0.05). In addition, animals treated with both repeated morphine and 5% formalin (s.c.) into the hind paw showed potent analgesia (p<0.01). Meanwhile, the developed tolerance was reversed by chronic pain induction in the following days (p<0.01). It is concluded that chronic formalin-induced inflammatory pain, not only could prevent tolerance development, but also is able to reverse the developed tolerance to antinociceptive effect of morphine. Since in i.t.-treated animals, tolerance was induced in lumbar spinal cord level, it can be concluded that chronic formalin-induced inflammatory pain, as a stress (through HPA axis) or as a factor which directly exerts some modulations on pain transmission system, is able to prevent tolerance to analgesic effect of morphine through lumbar spinal cord.

Various physiological parameters including level of sex steroids undergo alterations following chronic administration of morphine. In this study, the effect of chronic administration of morphine on phasic and tonic pain was studied in morphine-dependent male and female rats in the presence and absence of gonads using formalin test. In addition, for evaluation of differences in dependency, withdrawal signs were observed using naloxone hydrochloride. For dependency induction, morphine sulphate was administered in drinking water for a period of 30 days. The results showed that although chronic pain is significantly greater in female rats than male ones; but this pain increases in male dependent rats and decreases in female dependent animals. Thus, no gender differences were found between male and female dependent rats. Furthermore, gonadectomy led to a significant decrease in chronic pain only in male dependent rats. Meanwhile, withdrawal signs were significantly greater in female dependent rats than male ones and gonadectomy did not influence these signs. It can be concluded that following morphine addiction, pain increases in male and decreases in female rats and morphine dependency is not affected by sex hormones.

Various physiological parameters including level of sex steroids undergo alterations following chronic administration of morphine. In this study, the effect of chronic administration of morphine on phasic and tonic pain was studied in morphine-dependent male and female rats in the presence and absence of gonads using formalin test. In addition, for evaluation of differences in dependency, withdrawal signs were observed using naloxone hydrochloride. For dependency induction, morphine sulphate was administered in drinking water for a period of 30 days. The results showed that although chronic pain is significantly greater in female rats than male ones; but this pain increases in male dependent rats and decreases in female dependent animals. Thus, no gender differences were found between male and female dependent rats. Furthermore, gonadectomy led to a significant decrease in chronic pain only in male dependent rats. Meanwhile, withdrawal signs were significantly greater in female dependent rats than male ones and gonadectomy did not influence these signs. It can be concluded that following morphine addiction, pain increases in male and decreases in female rats and morphine dependency is not affected by sex hormones.

The effectiveness of θ pattern primed-bursts (PBs) on development of primed-burst (PB) potentiation was investigated in layer II/III of the adult rat visual cortex in vitro. Experiments were carried out in the visual cortical slices. Population excitatory post-synaptic potentials (pEPSPs) were evoked in layer II/III by stimulation of either white mater or layer IV. To induce long-term potentiation (LTP), eight episodes of PBs were delivered at 0.1 Hz. Regardless of stimulation site, field potential recorded in layer II/III consisted of two components: a short latency and high amplitude response called pEPSP1, and a long latency and low amplitude response called pEPSP2. The incidence of LTP produced by PBs of layer IV was higher than that of the white mater tetanization. In contrast, PBs of both layer IV and white mater reliably induced LTP of pEPSP2 in layer II/III. It is concluded that PBs, as a type of activity pattern, of either white mater or layer IV can gain access to the modifiable synapses that are related to pEPSP2 in layer II/III, but accessibility of the modifiable synapses that are related to pEPSP1 depends on tetanization site. Relevancy of the results to the plasticity gate hypothesis is also discussed

The involvement of NMDA receptors and voltage-dependent calcium channels in augmentation of long-term potentiation (LTP) was investigated at the Schaffer collateral CA1 pyramidal cell synapses in hippocampal slices of morphine dependent rats, using primed-burst tetanic simulation. The amplitude of the population spike and its delay were measured as indices of increase in postsynaptic excitability. D,L-APV and nifedipine were used as an NMDA receptor antagonist and a voltage-dependent calcium channel blocker, respectively. The amount of LTP of the orthodromic population spike (OPS) was higher in slices from dependent rats. Perfusion of slices from control and dependent rats with ACSF containing D,L-APV (25 µ M) and delivering tetanic simulation showed that D,L- APV completely blocked the LTP of OPS in slices from both control and dependent rats, while nifedipine (10 µ M) attenuated the amount of LTP of OPS in dependent slices and had no effect on controls. The results suggest that the enhanced LTP of OPS in the CA1 area of hippocampal slices from morphine-dependent rats is primarily induced by NMDA receptor activity, and the voltage-dependent calcium channels may also be partially involved in this phenomenon.

The effects of chronic morphine administration on the development of long-term potentiation (LTP) were investigated at the Schaffer collateral-CA1 pyramidal cell synapses of the rat hippocampal slices using primed-bursts tetanic stimulation. Significant enhancement of orthodromic population spike (OPS) was found for all stimulus intensities after tetanic stimulation. OPS enhancement was greatest when tested with low to mid-range stimulus intensities (25, 50 and 100 µ A). There was also significant decrease in OPS delay. These responses were similar in slices from both control and morphine dependent rats. At all delivered stimulus intensities, the amount of LTP of OPS in slices from dependent rats was larger than that of control slices. However, these differences in LTP of OPS were significant at low stimulus intensities. These findings suggest that chronic morphine administration had induced changes in CA1 neurocircuitry which modulated synaptic plasticity during high frequency stimulation and appeared as augmented LTP and also inhibition of LTP decay.