D2-like dopamine receptors blockade within the dentate gyrus shows a greater effect on stress-induced analgesia in the tail-flick test compared to D1-like dopamine receptors.

INTRODUCTION: Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain. METHODS: Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals. RESULTS: The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test. DISCUSSION: Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.

Trans-generational effects of parental exposure to drugs of abuse on offspring memory functions.

Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring's complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol.

N-acetylcysteine attenuates accumbal core neuronal activity in response to morphine in the reinstatement of morphine CPP in morphine extinguished rats.

Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.

Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat.

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management.

The integrative role of orexin-1 and orexin-2 receptors within the hippocampal dentate gyrus in the modulation of the stress-induced antinociception in the formalin pain test in the rat.

The stressful experiences, by triggering a cascade of hormonal and neural changes, can produce antinociception commonly referred to as stress-induced antinociception (SIA). Orexin neuropeptides have an essential role in stress responses and pain modulation. The dentate gyrus receives orexinergic projections and has been shown to be involved in pain processing. The current study investigated the possible role of orexin-1 and orexin-2 receptors (OX1r and OX2r, respectively) within the dentate gyrus in SIA in a rat model of formalin-induced pain behavior in one hind paw. Male Wistar rats weighing 230-250 g underwent stereotaxic surgery and a cannula was implanted in their brains, above the dentate gyrus region. Either SB334867 or TCS OX2 29 (OX1r and OX2r antagonists, respectively) was microinjected into the dentate gyrus region at a range of doses at 1, 3, 10, and 30 nmol (control group received DMSO 12% as vehicle), 5 min before the forced swim stress (FSS) exposure. The formalin test was performed to assess pain-related behaviors. The results indicated that FSS exposure relieves pain-related behavior in the early and late phases of the formalin test. Blockade of intra-dentate gyrus OX1 or OX2 receptors reduced the antinociceptive responses induced by FSS in the formalin test, with more impact during the late phase. Our findings support the potential role of intra-dentate gyrus orexin receptors as target sites of orexin neurons in painful and stressful situations. Therefore, understanding the exact mechanisms of SIA and the role of the orexinergic system in this phenomenon can lead to identifying the strategies to guide future research and offer a new approach to discovering new pain therapeutic agents.

The feasibility of the pretreatment verification of 2D dose distributions in radiation therapy with small fields using the electronic portal imaging device.

BACKGROUND: The present study aims to evaluate the performance of an Electronic portal imaging device (EPID) for measuring dosimetric parameters and for verification of dose in small photon fields. MATERIAL AND METHODS: In this study, the beam profiles were obtained using the amorphous silicon (a-Si) EPID for field sizes ranging from 1 × 1 to 10 × 10 cm 2 at energies 6 and 18 mega-voltage (MV). For comparison, the dosimetric parameters, including penumbra widths and field sizes, were measured with the pinpoint, diode, and Semiflex dosimeters. Finally, Rando Phantom was used to compare the two-dimensional (2D) Dose distribution between EPID and Treatment Planning System (TPS). RESULTS: In both 5 cm and 10 cm depths, there were large differences between the measured doses obtained from TPS, Pinpoint detector, and Farmer detector in 1 × 1 field size. The differences become negligible as the field sizes increase and from 3 × 3 field size to 10 × 10 field size, the maximum observed differences are 2 cGy and 2.4 cGy for 5 cm and 10 cm depths, respectively. The results indicate that the penumbra widths are smaller in the Gantry-Target (GT) direction compared to the Right-Left (RL) direction. The maximum difference (47.6%) was observed for EPID in the 10 × 10 field size, and the minimum difference (16.6%) was observed for TPS in the 1 × 1 field size. Finally, 2D dose distributions obtained by EPID and TPS exhibit excellent agreement. CONCLUSION: EPID is an excellent tool for the measurement of dosimetry parameters such as dose profiles, penumbra widths, field sizes, and pretreatment verification of 2D dose distributions, especially in small fields.

Similar functional roles of the Orexin-1 and Orexin-2 receptors within the dentate gyrus area of the hippocampus in the stress-induced antinociceptive responses in the acute pain model in the rat.

Studies establish that the brain's Orexin system is involved in pain modulation. Orexin-1 and orexin-2 receptors (OX1 and OX2r, respectively) are essential in responsiveness to stressful stimuli. Some evidence indicates that the hippocampus's dentate gyrus (DG) potentially modulates pain and stress. The present study examined the involvement of OX1 and OX2 receptors within the DG in response to acute pain after exposure to forced swim stress (FSS). Five to seven days post-stereotaxic surgery, the baseline tail-flick latency (TFL) was taken from the animal, then rats unilaterally received through an implanted cannula either different doses of OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), OX2r antagonist (TCS OX2 29; 1, 3, 10 and 30 nmol), or vehicle (0.5 µl solution of 12% DMSO). After 5 min, rats were exposed to the FSS for six minutes. Subsequently, the tail-flick test was conducted, and the TFLs were measured at the 60-min time set intervals. Results indicated that FSS produces antinociceptive responses in the tail-flick test. Two-way ANOVA analysis showed that Microinjection of OX1r and OX2r antagonists into the DG region of the brain reduced FSS-induced analgesia in the tail-flick test. The decrement effects of these two antagonists were almost the same. Additionally, results showed that the role of both receptors was the same in modulating stress-induced analgesia (SIA). These findings show that the orexin system in the hippocampal DG region might be partially involved in the SIA in acute pain.

Restraint stress potentiates sensitivity to the antinociceptive effect of morphine through orexin receptors in the ventral tegmental area.

Orexin signaling in the ventral tegmental area (VTA) plays a critical role in stress and addictive behaviors. On the other hand, exposure to stress potentiates behavioral sensitization to drugs of abuse such as morphine. This study aimed to elucidate the role of orexin receptors within the VTA in restraint stress (RS)-induced morphine sensitization. Adult male albino Wistar rats underwent stereotaxic surgery, and two stainless steel guide cannulae were bilaterally implanted into the VTA. Different doses of SB334867 or TCS OX2 29 as orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists were microinjected into the VTA five min before exposure to RS, respectively. A duration of three hours was considered for applying the RS, and 10 min after RS exposure, animals received a subcutaneous injection of an ineffective dose of morphine (1 mg/kg) for three consecutive days followed by a five-day drug/stress-free period. On the ninth day, the tail-flick test evaluated the sensitivity to the antinociceptive effects of morphine. The results demonstrated that the sole application of RS or morphine (1 mg/kg) could not induce morphine sensitization; however, concurrent application of RS and morphine could induce morphine sensitization. Besides, intra-VTA administration of OX1 R or OX2 R antagonists before paired administration of morphine and RS blocked morphine sensitization. The role of OX1 R and OX2 R in the induction of stress-induced morphine sensitization was almost identical. This study provides new insight into the role of orexin signaling in the VTA in the potentiation of morphine sensitization induced by RS and morphine co-administration.

Modulatory role of intra-accumbal dopamine receptors in the restraint stress-induced antinociceptive responses.

Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the mesolimbic dopaminergic pathway, plays a fundamental role in modulating pain and is differentially influenced by stressful events. Since we previously demonstrated the marked association of intra-NAc dopamine receptors with forced swim stress-evoked analgesia in acute pain state, this research was conducted to consider the contribution of intra-accumbal D1- and D2-like dopamine receptors to modulating effects of exposure to restraint stress in pain-related behaviors during the tail-flick test. Stereotaxic surgery was executed to implant a guide cannula within the NAc in male Wistar rats. On the test day, different concentrations of SCH23390 and Sulpiride as D1- and D2-like dopamine receptor antagonists, respectively, were unilaterally microinjected within the NAc. The vehicle animals received saline or 12 % DMSO (0.5 µl) instead of SCH23390 or Sulpiride into the NAc, respectively. Five minutes following receiving drug or vehicle, animals were restrained for 3 h and then their acute nociceptive threshold was measured for a 60-min period by the tail-flick test. Our data revealed that RS considerably enhanced antinociceptive reaction in acute pain states. The analgesia evoked by RS dramatically declined following blocking either D1- or D2-like dopamine receptors in the NAc, an effect was more noticeable by D1-like dopamine receptor antagonist. These findings indicated that intra-NAc dopamine receptors are considerably mediated in the RS-produced analgesia in acute pain states, suggesting their possible role in psychological stress and disease.

The stress-induced antinociceptive responses to the persistent inflammatory pain involve the orexin receptors in the nucleus accumbens.

Stress suppresses the sense of pain, a physiological phenomenon known as stress-induced analgesia (SIA). Brain orexin peptides regulate many physiological functions, including wakefulness and nociception. The contribution of the orexinergic system within the nucleus accumbens (NAc) in the modulation of antinociception induced by forced swim stress (FSS) remains unclear. The present study addressed the role of intra-accumbal orexin receptors in the antinociceptive responses induced by FSS during the persistent inflammatory pain model in the rat. Stereotaxic surgery was performed unilaterally on 106 adult male Wistar rats weighing 250-305 g. Different doses (1, 3, 10, and 30 nmol/ 0.5 µl DMSO) of orexin-1 receptor (OX1r) antagonist (SB334867) or OX2 receptor antagonist (TCS OX2 29) were administered into the NAc five minutes before exposure to FSS for a 6-min period. The formalin test was carried out using formalin injection (50 µl; 2.5%) into the rat's hind paw plantar surface, which induces biphasic pain-related responses. The first phase begins immediately after formalin infusion and takes 3-5 min. Subsequently, the late phase begins 15-20 min after formalin injection and takes 20-40 min. The findings demonstrated that intra-accumbal microinjection of SB334867 or TCS OX2 29 attenuated the FSS-induced antinociception in both phases of the formalin test, with the TCS OX2 29 showing higher potency. Moreover, the effect of TCS OX2 29 was more significant during the early phase of the formalin test. The results suggest that OX1 and OX2 receptors in the NAc might modulate the antinociceptive responses induced by the FSS.

Dose-volume parameters comparison of organs at risk between the prone and supine positions in pelvic tumors using 3D-CRT.

AIMS: Cancer is a major public health problem worldwide, the leading cause of death in developed countries. Radiotherapy is an important treatment for many malignancies. The main purpose of this study was to compare the two techniques of supine and prone in prostate and rectal cancers using DVH extraction parameters. METHODS AND MATERIAL: Clinical and dosimetry data of 41 rectal and prostate cancer patients were evaluated in both the supine and prone positions with belly board. Administered dose was daily 180 cGy. The four box fields in the first phase and two lateral fields in the second phase with 18 MV photon fields were used. Each patient underwent CT scan, at both the positions using a contrast agent with a full bladder. STATISTICAL ANALYSIS USED: By using IBM SPSS software v23, all the data were described. The normal distribution of the data was performed using the KS sample statistical test. For data analysis, paired t test was used in the normal data and the Wilcoxon test was used in the non-normal data. RESULTS: In patients with rectal cancer, there is no change in the received minimum dose by organs at risk. A significant decrease in received maximum dose, except for the prostate organ, could be due to the spatial proximity of the two organs to each other. Also, the received average dose in the small intestine was significantly reduced (P = 0.005). But in other organs, the dose reduction was not significant. In patients with prostate cancer, there is no change in the received minimum dose by OARs, except for the bladder organ (P = 0.003). Except the bladder organs (P = 0.011), there is no significant decrease in the received average dose by OARs. The maximum dose of the OARs is significantly reduced, except for the colon where there was not much overlap in the PTV, in addition to receiving the dose in the range. There was no significant relationship between CI in the rectal field and UI in the prostate field (P > 0.05), but there was a significant relationship between CI in the prostate field and UI in the rectal field with change in patient position. CONCLUSIONS: In the prone position, in both patients' groups, the OARs receive an optimal and better dose than the supine position, especially the small intestine organ in the rectal field and the bladder and rectum organs in the prostate field. However, it seems that this change in the position of rectal cancer patients is ineffective in reducing the dose of prostate and needs further investigation.

Thyroid function following radiation therapy in breast cancer patients: risk of radiation-induced hypothyroidism.

Background: Radiation exposure to the thyroid gland seems unavoidable in breast cancer (BC) patients receiving radiation therapy (RT) to the supraclavicular (SC) region. Hence, this study aimed to evaluate the effects of SC region RT on thyroid function and the prevalence of radiation-induced hypothyroidism (RIHT) in BC patients at regular intervals post-treatment. Materials and methods: Twenty-one patients with BC were enrolled in this analytical cross-sectional study by simple and convenient sampling, from March 2019 to March 2020. Thyroid function and the prevalence of RIHT were evaluated and compared by measuring the serum of thyroid-stimulating hormone (TSH) and free thyroxine hormone (fT4) levels before radiation therapy (pre-RT) and 3 and 6 months after radiation therapy (post-RT). The patients underwent 3 dimensional conformal. radiation therapy (3D CRT) of breast/chest wall, axillary, and supraclavicular lymph nodes with 50 Gy/25 fractions/5 weeks. The collected data were analyzed using SPSS software (version 20). Results: Serum levels of TSH increased at 3 and 6 months post-RT, this increase was not statistically significant (p > 0.05). Nevertheless, serum levels of fT4 were significantly elevated at 3 and 6 months post-RT (p < 0.01). A correlation was observed between the follow-up period and the incidence of RIHT, where it was 0% at 3 months and 9.5% at 6 months post-RT. RIHT was not significantly associated with any factors, including patient's age, type of surgery, thyroid gland dose, and thyroid gland volume. Conclusions: It seems that SC region RT does not have a significant adverse effect on the thyroid function among BC patients at 3 and 6 months post-treatment. Hence, a long-term follow-up with a larger sample size is suggested.

The modulatory role of dopamine receptors within the hippocampal cornu ammonis area 1 in stress-induced analgesia in an animal model of persistent inflammatory pain.

The intrinsic pain inhibitory mechanisms can be activated by fear, anxiety, and stress. Stressful experiences produce analgesia, referred to as stress-induced analgesia (SIA). Major components of the limbic system, including the ventral tegmental area, nucleus accumbens, amygdala, and hippocampus, are involved in the SIA. In this study, we tried to understand the role of dopamine receptors in the cornu ammonis area 1 (CA1) of the hippocampus in the forced swim stress (FSS)-induced analgesia. Stereotaxic surgery was unilaterally performed on 129 adult male Wistar rats weighing 220-280 g. SCH23390 (0.25, 1, and 4 µg/0.5 µl saline) or sulpiride (0.25, 1, and 4 µg/0.5 µl DMSO), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the CA1 area, 5 min before exposure to FSS for a 6-min period. The vehicle groups received saline or DMSO instead of SCH23390 or sulpiride, respectively. The formalin test was done using formalin injection (50 µl; 2.5%) into the plantar surface of the rat's hind paw immediately after exposure to FSS. The results demonstrated that FSS produces analgesia during the early and late phases of the formalin test. However, intra-CA1 microinjection of SCH23390 or sulpiride attenuated the FSS-induced analgesia in both phases of the formalin test. This study provides new insight into the role of D1- and D2-like dopamine receptors in the CA1 area in the FSS-induced analgesia during persistent inflammatory pain.

Orexin receptors in the CA1 region of hippocampus modulate the stress-induced antinociceptive responses in an animal model of persistent inflammatory pain.

Stress activates multiple neural pathways and neurotransmitters that often suppress pain perception, the phenomenon called stress-induced analgesia (SIA). Orexin neurons from the lateral hypothalamus project to entire brain structures such as the hippocampus. The present study examined this hypothesis that orexinergic receptors in the CA1 region of the hippocampus may play a modulatory role in the development of SIA in formalin test as an animal model of persistent inflammatory pain. One hundred-two adult male Wistar rats were administered with intra-CA1 orexin-1 receptor (OX1r) antagonist, SB334867, at the doses of 3, 10, 30, and 100 nmol or TCS OX2 29 as orexin-2 receptor (OX2r) antagonist at the doses of 1, 3, 10, and 30 nmol. Five min later, rats were exposed to forced swim stress (FSS) for a 6-min period. Then, pain-related behaviors induced by formalin injection were measured at the 5-min blocks during a 60-min period of formalin test. The current study indicated that solely stress exposure elicits antinociception in the early and late phases of the formalin test. The FSS-induced analgesia was prevented by intra-CA1 administration of SB334867 or TCS OX2 29 during either phase of the formalin test. Moreover, the contribution of the OX2r in the mediation of analgesic effect of stress was more prominent than that of the OX1r during both phases of the formalin test. It is suggested that OX1r and OX2r in the CA1 region of the hippocampus are involved in stress-induced analgesia in the animal model of persistent inflammatory pain.

Insulin replacement prevents the acquisition but not the expression of morphine-induced conditioned place preference in streptozotocin-induced diabetic rats

Abstract Insulin receptors have distributed in all brain regions, including the nucleus Accumbens (NAc), and where is implicated in the reward properties of drugs. It is well known that insulin signaling can regulate dopamine release. Therefore, in the present study, we tried to examine the effect of insulin replacement on the acquisition and expression of morphine-induced conditioned place preference (CPP) in diabetic rats. Forty-eight male Wistar rats were divided into two non-diabetic (Naïve) and diabetic groups rendered by a single injection of streptozotocin (STZ). These groups separately received insulin (10U/kg) or saline (1 ml/kg) one hour prior to morphine administration (5mg/kg;s.c.) during conditioning days (acquisition phase) or post-conditioning day (expression phase) in the CPP paradigm. In this paradigm, conditioning score (CS) and locomotion activity were recorded by Ethovision. The STZ-induced diabetic rats displayed higher CS compared to naïve rats (P<0.05). This effect was abolished in all diabetic rats that received insulin during conditioning days but not the expression phase. This study has provided evidence that insulin plays a modulatory role in morphine-induced CPP, and insulin replacement during the acquisition phase could reduce the rewarding properties of morphine in diabetes conditions through a possible modulating effect on dopamine release in the NAc region

Systemic administration of N-acetylcysteine during the extinction period and on the reinstatement day decreased the maintenance of morphine rewarding properties in the rats.

Many animal studies and early clinical trials suggested that N-acetylcysteine (NAC) may benefit addiction treatment. The present study tried to evaluate whether chronic administration of systemic NAC during the extinction period and acute administration of systemic NAC on the reinstatement day could reduce the maintenance of the morphine rewarding properties in the conditioned place preference (CPP) paradigm in the rats. Ninety-six adult male Wistar rats (190-220 g) were examined with morphine (7 mg/kg; sc) and saline (1 mL/kg; sc) during the 3-day conditioning phase in the CPP paradigm. After the acquisition of morphine CPP, different doses of NAC were daily administered during the extinction period (5, 10, 25, and 50 mg/kg; ip), or 30 min before the CPP test on the reinstatement day (2, 5, 10, 25, and 50 mg/kg; ip). Conditioning score and locomotor activity were recorded by the video tracking system and Ethovision software after acquisition on the post-conditioning day, the extinction period, and reinstatement day. Daily NAC administration in high doses (25 and 50 mg/kg; ip) reduced extinction-responding compared with the vehicle-control group during the extinction period. Although a single injection of NAC in doses 10, 25, 50 mg/kg decreased the reinstatement of morphine-induced CPP, two lower doses (2 and 5 mg/kg) could not significantly reduce the CPP scores. These are the first data suggesting that NAC's application during the extinction period could attenuate the morphine reward-associated behaviors in the rats. Moreover, NAC could inhibit the reinstatement of morphine CPP, which adds to the growing appreciation that the NAC may have potential therapeutic use in combating morphine dependence. It can be consistent with the hypothesis of the involvement of the glutamatergic system in the pathophysiology of addiction.

Cannabidiol microinjection into the nucleus accumbens attenuated nociceptive behaviors in an animal model of tonic pain.

Cannabidiol, the major non-psychoactive constituent of Cannabis, has attracted much attention as a therapeutic agent for intractable chronic pain in many conditions. Nucleus accumbens (NAc) as a major site of action of cannabinoids is one of the main mediators of several analgesic agents especially in the persistent pain condition. The present study aimed to investigate the effect of cannabidiol microinjection into the NAc on the modulation of nociception induced by formalin injection into the rat's paw. Adult male Wistar rats weighing 220-250 g were underwent stereotaxic surgery for unilateral (right or left side) cannula placement into the NAc. After one week recovery period, intra-NAc administration of the cannabidiol or its vehicle, DMSO was performed in a volume of 0.5 µl, five minutes before the formalin test. The formalin test was performed using 50 µl injection of formalin (2.5%) into the plantar surface of the rat's hind paw. Intra-accumbal administration of cannabidiol attenuated the nociceptive responses during the early and late phases of the formalin test in a dose-dependent manner. However, the antinociceptive effect of cannabidiol was significantly higher in the late phase of the formalin test than that in the early phase. Therefore, a non-psychoactive cannabinoid, cannabidiol may be developed as therapeutic agents in conditions, such as persistent inflammatory pain for which primary treatments are insufficient or not possible.

Investigation of Collapsed-cone Algorithm Accuracy in Small Fields and Heterogeneous Environments.

BACKGROUND: The use of small fields has increased by the emergence of advanced radiotherapy. Dose calculations of these fields are complex and challenging for many reasons such as lack of electrical equilibrium even in homogeneous environments, and this complexity will increase in presence of heterogeneity. According to the importance of delivery the accurate prescription dose to the target volume in the patient's body, the dose calculation accuracy of used commercial algorithms in clinical treatment planning systems (TPS) should be evaluated. OBJECTIVE: The present study aims to evaluate the accuracy of Collapsed-cone dose measurement algorithm in Isogray treatment planning system. MATERIAL AND METHODS: In this analytical study, the measurements were made in tissue equivalent solid water phantom with lung and bone heterogeneities by Pinpoint dosimeter (0.015 cm3 sensitive volume) in several radiation fields (1×1 to 5×5 cm2). The phantoms were irradiated with 6, 10 and 18 MV photon beams and finally, the results of experimental calculations were compared with treatment planning outputs. RESULTS: In all setups, the maximum deviation occurred in the field of 1×1 cm2. Then, the maximum deviation was observed for 2×2 cm2 field size; however, it was up to 5% for homogeneous water phantom and lung heterogeneity. In 3×3 cm2 and larger fields, there was a good agreement between the results of the TPS and experimental dosimetry. The maximum deviation was observed in water-bone heterogeneity. CONCLUSION: This algorithm was able to pass the standard audit criteria, but it is better to be used more cautiously in bone heterogeneity, especially in low energies.

The role of pre-pubertal training history on hippocampal neurotrophic factors and glucocorticoid receptor protein levels in adult male rats.

Neurotrophic factors play an integral role in hippocampal plasticity, and interaction with HPA axis components, especially glucocorticoid receptors (GR), can mediate the structural and functional changes. In the present work, we investigated the long-term effects of combined exercise training (CET) and voluntary physical activity in an enriched environment (EE) in the pre-pubertal period on hippocampal neurotrophic factors and GR. For this purpose, a longitudinal study was designed. After three weeks, all rats were kept in the standard cages without any interventions until adulthood. Western blot analysis revealed a significant increase in hippocampal BDNF and VEGF protein levels in both EE and CET groups (P < 0.001), along with an increase in GR protein levels. In addition, EE decreased serum corticosterone levels compared to CET (P < 0.05). Serum insulin-like growth factor-1 (IGF-1) levels did not demonstrate remarkable changes between groups. Training interventions during sensitive developmental periods may produce profound and long-lasting effects on the hippocampus, at least in part by interactive effects of neurotrophic factors cascades and GR.

Restraint Stress Potentiated Morphine Sensitization: Involvement of Dopamine Receptors within the Nucleus Accumbens.

Sensitization to psychostimulant drugs, as well as morphine, subjected to cross-sensitization with stress. The development of morphine sensitization is associated with enhancements in dopamine overflow in the Nucleus accumbens (NAc). This study aimed to examine the role of accumbal D1/D2-like dopamine receptors in restraint stress (RS) induced sensitization to morphine antinociceptive effects. Adult male Wistar rats weighing 220-250 g underwent stereotaxic surgery. Two stainless steel guide cannulae were bilaterally implanted, 1 mm above the NAc injection site. Different solutions of SCH-23390, as a D1-like receptor antagonist or sulpiride, as a D2-like receptor antagonist, were microinjected into the NAc five min before exposure to RS. Restraint stress lasted for 3 h, 10 min after RS termination; animals received a subcutaneous injection of morphine (1 mg/kg) for 3 consecutive days. The procedure was followed by a 5-day drug and/or stress-free period. After that, on the 9th day, the nociceptive response was evaluated by the tail-flick test. The results revealed that intra-NAc administration of D1/D2-like dopamine receptor antagonists, SCH-23390 or sulpiride, respectively, blocked morphine sensitization-induced by RS and morphine co-administration in rats for three consecutive days. This work provides new insight into the determinant role of accumbal dopamine receptors in morphine sensitization produced by RS-morphine co-administration.