Restraint stress-induced antinociceptive effects in acute pain: Involvement of orexinergic system in the nucleus accumbens.

The complicated relevance between stress and pain has been identified. Neurotransmitters and neuropeptides of various brain areas play a role in this communication. Pain inhibitory response is known as stress-induced analgesia (SIA). The studies demonstrated that the nucleus accumbens (NAc) is critical in modulating pain. As a neuropeptide, orexin is crucially involved in initiating behavioral and physiological responses to threatening and unfeeling stimuli. However, the role of the orexin receptors of the NAc area after exposure to restraint stress (RS) as acute physical stress in the modulation of acute pain is unclear. One hundered twenty adult male albino Wistar rats (230-250 g) were used. Animals were unilaterally implanted with cannulae above the NAc. The SB334867 and TCS OX2 29 were used as antagonists for OX1r and OX2r, respectively. Different doses of the antagonists (1, 3, 10, and 30 nmol/0.5 µl DMSO) were microinjected intra-NAc five minutes before exposure to RS (3 hours). Then, the tail-flick test as a model of acute pain was performed, and the nociceptive threshold (Tail-flick latency; TFL) was measured in 60-minute time set intervals. According to this study's findings, the antinociceptive effects of RS in the tail-flick test were blocked during intra-NAc administration of SB334867 or TCS OX2 29. The RS as acute stress increased TFL and deceased pain-like behavior responses. The 50 % effective dose values of the OX1r and OX2r antagonists were 12.82 and 21.64 nmol, respectively. The result demonstrated contribution of the OX1r into the NAc was more remarkable than that of the OX2r on antinociceptive responses induced by the RS. Besides, in the absence of RS, the TFL was attenuated. The current study's data indicated that OX1r and OX2r into the NAc induced pain modulation responses during RS in acute pain. In conclusion, the findings revealed the involvement of intra-NAc orexin receptors in improving SIA.

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.

Blockade of mGluR5 in nucleus accumbens modulates calcium sensor proteins, facilitates extinction, and attenuates reinstated morphine place preference in rats.

Numerous findings confirm that the metabotropic glutamate receptors (mGluRs) are involved in the conditioned place preference (CPP) induced by morphine. Here we focused on the role of mGluR5 in the nucleus accumbens (NAc) as a main site of glutamate action on the rewarding effects of morphine. Firstly, we investigated the effects of intra-NAc administrating mGluR5 antagonist 3-((2-Methyl-1,3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP; 1, 3, and 10 µg/µl saline) on the extinction and the reinstatement phase of morphine CPP. Moreover, to determine the downstream signaling cascades of mGluR5 in morphine CPP, the protein levels of stromal interaction molecules (STIM1 and 2) in the NAc and hippocampus (HPC) were measured by western blotting. The behavioral data indicated that the mGluR5 blockade by MTEP at the high doses of 3 and 10 µg facilitated the extinction of morphine-induced CPP and attenuated the reinstatement to morphine in extinguished rats. Molecular results showed that the morphine led to increased levels of STIM proteins in the HPC and increased the level of STIM1 without affecting STIM2 in the NAc. Furthermore, intra-NAc microinjection of MTEP (10 µg) in the reinstatement phase decreased STIM1 in the NAc and HPC and reduced the STIM2 in the HPC. Collectively, our data show that morphine could facilitate brain reward function in part by increasing glutamate-mediated transmission through activation of mGluR5 and modulation of STIM proteins. Therefore, these results highlight the therapeutic potential of mGluR5 antagonists in morphine use disorder.

Hippocampal D1-like dopamine receptor as a novel target for the effect of cannabidiol on extinction and reinstatement of methamphetamine-induced CPP.

Methamphetamine (METH) is a major health problem without effective pharmacological treatment. Cannabidiol (CBD), a component of the Cannabis sativa plant, is believed to have the potential to inhibit drug-related behavior. However, the neurobiological mechanisms responsible for the effects of CBD remain unclear. Several studies have proposed that the suppressing effects of CBD on drug-seeking behaviors could be through the modulation of the dopamine system. The hippocampus (HIP) D1-like dopamine receptor (D1R) is essential for forming and retrieving drug-associated memory. Therefore, the present study aimed to investigate the role of D1R in the hippocampal CA1 region on the effects of CBD on the extinction and reinstatement of METH-conditioned place preference (CPP). For this purpose, different groups of rats over a 10-day extinction period were administered different doses of intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl, Saline) as a D1R antagonist before ICV injection of CBD (10 µg/5 µl, DMSO12%). In addition, a different set of animals received intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl) before CBD injection (50 µg/5 µl) on the reinstatement day. The results revealed that the highest dose of SCH23390 (4 µg) significantly reduced the accelerating effects of CBD on the extinction of METH-CPP (P < 0.01). Furthermore, SCH23390 (1 and 4 µg) in the reinstatement phase notably reversed the preventive effects of CBD on the reinstatement of drug-seeking behavior (P < 0.05 and P < 0.001, respectively). In conclusion, the current study revealed that CBD made a shorter extinction period and suppressed METH reinstatement in part by interacting with D1-like dopamine receptors in the CA1 area of HIP.

The role of orexin receptors within the CA1 area in the acquisition and expression of methamphetamine place preference.

Treatment of Methamphetamine (METH) use disorder has become a crucial public health issue. The orexin system manipulation has provided promising evidence to attenuate addictive-like behaviors. This study explored the role of the orexin 1 receptor and orexin 2 receptor (OX1R and OX2R) in the CA1 area of the hippocampal formation in the acquisition and expression of METH-induced place preference. Animals were subjected to bilateral administration of different dosages (1, 3, 10, and 30 nmol/0.5 µl DMSO per side) of a selective OX1R antagonist, SB334867, or selective OX2R antagonist, TCS OX2 29 into the CA1 area throughout the conditioning phase or once on the post-conditioning phase in separate control and experimental groups. Behavioral data revealed that both OX1R (10 nmol; P < 0.01 and 30 nmol; P < 0.001) and OX2R (10 nmol; P < 0.05 and 30 nmol; P < 0.001) antagonism during the conditioning phase could block the formation of METH place preference dose-dependently. In addition, intra-CA1 microinjection of SB334867 on the post-conditioning phase attenuated the expression of METH place preference in a dose-dependent manner (3 nmol; P < 0.05, 10 nmol; P < 0.01 and 30 nmol; P < 0.001) whereas intra-CA1 administration of TCS OX2 29 only at the highest dosage (30 nmol) declined the expression of METH place preference (P < 0.01). It was also indicated that the suppressive effects of orexin receptor blockade on the METH-seeking behavior in the CA1 area were anatomically specific to this area. These findings support the possibility of targeting the orexin system to develop novel and successful pharmacological options for the treatment of METH dependence.

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.

Impairment of value-based decision-making in morphine-dependent rats is partly related to neural connectivity between the anterior cingulate cortex and basolateral amygdala.

Previous studies have established that the amygdala specifically the basolateral amygdala (BLA), has a fundamental role in decision-making. The present study aimed to investigate functional and neural synchronization between the BLA and anterior cingulate cortex (ACC) while making effort-choice decisions regarding pre-morphine dependence and morphine dependence times. A T-maze decision-making task with a differential outlay (great vs. small effort) and benefit (great vs. small reward) was done, and local field potentials from the BLA and ACC were assessed simultaneously. Results illustrated that in pre-morphine dependence time, when the animals made great reward/great effort decisions, there was a neural synchronization between both regions in beta and gamma frequency bands; and also, in delta, theta, beta, and gamma frequencies while expending effort and climbing the barrier. However, in morphine-dependent rats, during low reward/low effort choice and also during expending low effort, there was just a weak neural coherence in gamma frequency. Besides, there was neural synchronization in theta, beta, and gamma frequencies during reaching great reward in pre-morphine dependence time. Nevertheless, during reaching low reward in morphine dependence time, there was a weaker coherence in beta and gamma compared to pre-morphine dependence. These findings showed that functional and neural coherence between the BLA and ACC has a fundamental role in making the effort-based decision and expending effort. Preference for low reward/low effort, and decrease in expending effort in morphine-dependent rats is partly associated with the changes in the neural coherence between the BLA and ACC.

Blocking the dopaminergic receptors within the hippocampal dentate gyrus reduced analgesic responses induced by restraint stress in the formalin test.

Previous studies have shown that various receptors, including dopamine receptors, are expressed in the hippocampal dentate gyrus (DG). Besides, indicatively, dopamine receptors play an essential role in the modulation of pain perception. On the other hand, stressful experiences can produce analgesia, termed stress-induced analgesia (SIA). The current study examined the probable role of dopamine receptors within the DG in antinociception induced by restraint stress (RS). Ninety-seven male albino Wistar rats were unilaterally implanted with a cannula in the DG. Animals received intra-DG microinjections of SCH23390 or Sulpiride (0.25, 1, and 4 µg/rat) as D1-and D2-like dopamine receptor antagonists, respectively, five minutes before RS. Ten minutes after the end of the induction of RS for three hours, 50 µl 2.5% formalin was injected subcutaneously into the plantar surface of the hind paw to induce persistent inflammatory pain. Pain scores were evaluated at 5-minute intervals for 60 minutes. These findings showed that; exposure to RS for three hours produced SIA in both phases of the formalin test, while this RS-induced analgesia was attenuated in the early and late phases of the formalin test by intra-DG microinjection of SCH23390 and Sulpiride. The results of the present study suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in the induced analgesia by RS.

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.

Orexin receptors in the hippocampal dentate gyrus modulated the restraint stress-induced analgesia in the animal model of chronic pain.

Previous studies have shown that stressful stimuli induced an adaptive response of reduced nociception, known as stress-induced analgesia (SIA). Since orexin neuropeptides are involved in pain modulation, and orexin neurons, primarily located in the lateral hypothalamus (LH), project to various hippocampal regions, such as the dentate gyrus (DG), the current study aimed to examine the role of orexin receptors within the DG region in the restraint SIA in the animal model of chronic pain. One hundred-thirty adult male Wistar rats (230-250 g) were unilaterally implanted with a cannula above the DG region. Animals were given SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol, 0.5 µl/rat) into the DG region as orexin-1 receptor (OX1r) and orexin-2 receptor (OX2r) antagonists, respectively, five min before exposure to a 3-hour restraint stress (RS) period. Animals were then undergone the formalin test to assess pain-related behaviors as the animal model of chronic pain. The results showed that RS produces an analgesic response during the early and late phases of the formalin test. However, intra-DG microinjection of OX1r and OX2r antagonists attenuated the restraint SIA. OX2r antagonist was more potent than OX1r antagonist in the early phase of the formalin test, while OX1r antagonist was little more effective in the late phase. Predominantly, it could be concluded that the orexinergic system in the DG region might act as a potential endogenous pain control system and a novel target for treating stress-related disorders.

Intra-accumbal orexinergic system contributes to the stress-induced antinociceptive behaviors in the animal model of acute pain in rats.

Stress and pain are interleaved at numerous levels - influencing each other. Stress can increase the nociception threshold in animals, long-known as stress-induced analgesia (SIA). Orexin is known as a neuropeptide that modulates pain. The effect of stress on the mesolimbic system in the modulation of pain is known. The role of the intra-accumbal orexin receptors in the modulation of acute pain by forced swim stress (FSS) is unclear. In this study, 117 adult male albino Wistar rats (270-300 g) were used. The animals were unilaterally implanted with cannulae above the NAc. The antagonist of the orexin-1 receptor (OX1r), SB334867, and antagonist of the orexin-2 receptor (OX2r), TCS OX2 29, were microinjected into the NAc in different doses (1, 3, 10, and 30 nmol/0.5 µl DMSO) before exposure to FSS for a 6-min period. The tail-flick test was carried out as an assay nociception of acute pain, and the nociceptive threshold [tail-flick latency (TFL)] was measured for 60-minute. The findings demonstrated that exposure to acute stress could remarkably increase the TFLs and antinociceptive responses. Moreover, intra-accumbal microinjection of SB334867 or TCS OX2 29 blocked the antinociceptive effect of stress in the tail-flick test. The contribution of orexin receptors was almost equally modulating SIA. The present study's findings suggest that OX1r and OX2r within the NAc modulate stress-induced antinociceptive responses. The intra-accumbal microinjection of orexin receptors antagonists declares inducing antinociceptive responses by FSS in acute pain. Proposedly, intra-accumbla orexinergic receptors have a role in the development of SIA.

Contribution of the intra-hippocampal orexin system in the regulation of restraint stress response to pain-related behaviors in the formalin test.

Stress-induced antinociception (SIA) is due to the activation of several neural pathways and neurotransmitters that often suppress pain perception. Studies have shown that the orexin neuropeptide system is essential in pain modulation. Therefore, this study aimed to investigate the role of orexinergic receptors in the hippocampal CA1 region in modulating SIA response during the formalin test as an animal model of inflammatory pain. The orexin-1 receptor (OX1r) antagonist, SB334867, at 1, 3, 10, and 30 nmol or TCS OX2 29 as an orexin-2 receptor (OX2r) antagonist at the same doses were microinjected into the CA1 region in rats. Five minutes later, rats were exposed to restraint stress (RS) for 3 h, and pain-related behaviors were monitored in 5-min blocks for the 60-min test period in the formalin test. Results showed that applying RS for 3 h reduced pain responses in the early and late phases of the formalin test. The main findings showed that intra-CA1 injection of orexin receptor antagonists reduced the antinociception caused by stress in both phases of the formalin test. In addition, the contribution of OX2r in mediating the antinociceptive effect of stress was more prominent than that of OX1r in the early phase of the formalin test. However, in the late phase, both receptors worked similarly. Accordingly, the orexin system and its two receptors in the CA1 region of the hippocampus regulate SIA response to this animal model of pain in formalin test.

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.

Blockade of the orexin-2 receptors within the ventral tegmental area facilitates the extinction and prevents the reinstatement of methamphetamine-seeking behavior.

Repeated use of methamphetamine (METH) causes severe effects on the central nervous system, associated with an increased relapse rate. The orexinergic system is highly implicated in the reward circuitry and may be a promising target for treating psychostimulant dependency. The present study aimed to investigate the involvement of the orexin system, mainly the orexin-2 receptors (OX2R) in the ventral tegmental area (VTA) in the extinction and reinstatement of METH-seeking behavior using a conditioned place preference (CPP) paradigm. To this end, animals received METH (1 mg/kg; sc) for a 5-day conditioning period. Then, in the first set of experiments, different groups of rats were given intra-VTA TCS OX2 29 (1, 3, 10, or 30 nmol/0.3 µl DMSO) as an OX2R antagonist over a 10-day extinction period. In another experiment, after the extinction period, a different set of animals received a single dose of TCS OX2 29 (1, 3, 10, or 30 nmol) before the priming dose of METH (0.25 mg/kg; sc) on the reinstatement day. The results revealed that TCS OX2 29 (10 and 30 nmol) remarkably facilitated the extinction of rewarding properties of METH (P < 0.001 for both doses). Furthermore, TCS OX2 29 (3, 10, or 30 nmol) significantly suppressed the METH-induced reinstatement (3 nmol; P < 0.05, 10 nmol; P < 0.01, and 30 nmol; P < 0.001). In conclusion, the current study revealed that the orexinergic system, specifically the VTA OX2R, is involved in METH-seeking behaviors and that manipulation of this system can be considered a potential therapeutics in treating METH dependency.

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.

The role of orexin-1 receptors within the ventral tegmental area in the extinction and reinstatement of methamphetamine place preference.

Targeting the orexin system has recently been identified as one of the promising options for treating drug addiction. It may be more feasible and achievable if we investigate the accurate function of the orexin system in brain areas implicated in reward and addiction, such as the ventral tegmental area (VTA) by animal reward models. This study investigated the contribution of the orexin system, mainly the orexin-1 receptors (OX1R) in the VTA, in the extinction and reinstatement of methamphetamine (METH) related memories in the conditioned place preference (CPP) model. Animals after the acquisition of METH place preference were subjected to two separate sets of extinction and reinstatement experiments to receive various concentrations of selective OX1R antagonist, SB334867 into the bilateral VTA before extinction sessions (1, 3, and 10 nmol/0.3 µl DMSO per side) or only on the reinstatement phase (3, 10, and 30 nmol/0.3 µl DMSO per side), respectively. Intra-VTA infusion of SB334867 throughout the extinction phase could remarkably facilitate the extinction process and decrease the maintenance of reinforcing effects of METH at the highest dosage (10 nmol; p < 0.0001). Data also indicated a single microinfusion of SB334867 into the VTA before reinstatement of the METH-seeking behavior could considerably prevent the relapse of previously formed reward-context memories (10 nmol; p < 0.01 and 30 nmol; p < 0.001). The present study provided evidence supporting the potential therapeutic effects of the orexin system modulation, specifically in the VTA, on different stages of METH-induced place preference.

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.

The Dopaminergic System Modulates the Electrophysiological Activity of the Suprachiasmatic Nucleus Dependent on the Circadian Cycle.

The suprachiasmatic nucleus of the hypothalamus (SCN) controls mammalian circadian rhythms. Circadian rhythms influence the dopaminergic system, and dopaminergic tone impresses the physiology and behavior of the circadian clock. However, little is known about the effect of dopamine and dopamine receptors, especially D1-like dopamine receptors (D1Rs), in regulating the circadian rhythm and the SCN neuron's activity. Therefore, the present study aimed to investigate the role of the D1Rs in SCN neural oscillations during the 24-h light-dark cycle using local field potential (LFP) recording. To this end, two groups of rats were given the SKF-38393 (1 mg/kg; i.p.) as a D1-like receptor agonist in the morning or night. LFP recording was performed for ten minutes before and two hours after the SKF-38393 injection. The obtained results showed that diurnal changes affect LFP oscillations so that delta relative power declined substantially, whereas upper-frequency bands and Lempel-Ziv complexity (LZC) index increased at night, which is consistent with rodents' activity cycles. The D1Rs agonist administration in the morning dramatically altered these intrinsic oscillations, decreasing delta and theta relative power, and most of the higher frequency bands and LZC index were promoted. Some of these effects were reversed at the night after the SKF-38393 injection. In conclusion, findings showed that the SCN's neuronal activities are regulated based on the light-dark cycle in terms of population neural oscillatory activity which could be affected by dopaminergic stimulation in a time-dependent way.