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Tina Matini,1 Amir Haghparast,1 Laleh Rezaee,2 Sakineh Salehi,2,3 Azita Tehranchi,4 Abbas Haghparast2 1School of Dentistry, International Branch of Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Department of Medicine, Ardabil Medical Sciences Branch, Islamic Azad University, Ardabil, Iran; 4Dental Research Center, Research Institute of Dental Sciences, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, IranCorrespondence: Abbas HaghparastNeuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P O Box 19615-1178, Tehran, IranTel/ Fax +98-21-2243-1624Email Haghparast@yahoo.comAzita TehranchiDental Deformities Research Center, Dental Research Institute, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, IranEmail Azitatehranchi@yahoo.comIntroduction: The ventral tegmental area (VTA), as one of the classical components of the brain reward circuitry, shares large neural networks with the pain processing system. We previously showed the role of VTA dopamine receptors in modulation of lateral hypothalamus (LH)-induced antinociception in acute pain conditions. However, considering the fact that the neural systems involved in the mediation of tonic pain are not the same as those that mediate phasic pain. In the present study, we aimed to examine the role of intra-VTA dopamine receptors in LH-induced antinociceptive responses during tonic orofacial pain conditions.Methods: Male Wistar rats weighing 230– 250 g were implanted with two separate cannulae into the LH and VTA on the same side. Different solutions of carbachol (62.5, 125 and 250 nM), as a non-selective cholinergic receptor agonist that activates the LH projecting neurons, were microinjected into the LH. In the other groups, D1-like dopamine receptor antagonist, SCH-23390 (0.25, 1 and 4 μg/03 μL saline) or D2-like dopamine receptor antagonist, Sulpiride (0.25, 1 and 4 μg/0.3 μL DMSO 12%) were microinjected into VTA, 5 min prior intra-LH carbachol (250 nM), then subjected to orofacial formalin test. Intra-LH carbachol microinjection dose-dependently attenuated biphasic orofacial pain.Results: Intra-VTA administration of SCH-23390 or Sulpiride dose-dependently decreased intra-LH carbachol-induced antinociception during both phases of orofacial formalin test with further effects in the late phase.Discussion: The findings suggest that chemical stimulation of the LH by carbachol possibly activates the orexin projecting neurons and subsequently, the VTA dopaminergic neurons involved in the orofacial pain modulation. Detecting such neural circuitry offers an alternative approach in the development of more efficient therapies for such debilitating pain conditions.Keywords: pain, D1-like dopamine receptor, D2-like dopamine receptor, ventral tegmental area, lateral hypothalamus, orofacial formalin test

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The role of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented individually. The present study aimed to investigate the role of dopamine receptors of the VTA in the modulation of the LH stimulation-induced antinociception during both phases of the formalin test as an animal model of tonic pain. In this study, male Wistar rats were unilaterally implanted with two guide cannulae in the VTA and LH. In two separate groups, animals received different doses (0.25, 1, and 4 μg/rat) of D1- or D2-like dopamine receptor antagonists (SCH-23,390 or Sulpiride, respectively) into the VTA before intra-LH injection of carbachol (22.83 ng/rat) following formalin injection (50 μL; s.c.) into their contralateral hind paws. The blockade of these two receptors reduced intra-LH carbachol-induced antinociception during both phases of the formalin test. This reduction during the late phase of the formalin test was more than that of the early phase. The results indicated that LH stimulation-induced antinociception was mediated by D1- and D2-like dopamine receptors in the VTA, and so, the neural pathway projecting from the LH to the VTA contributes to the modulation of formalin-induced nociception in the rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Involvement of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented. In this study, we investigated the role of orexin 1 (OX1) and orexin 2 (OX2) receptors within the VTA in modulation of the LH-induced antinociception during both phases of orofacial formalin test. Male adult Wistar rats weighing 230-250 g were unilaterally implanted with two stainless steel guide cannulae in the VTA and LH. In two separate supergroups, animals received SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist), at the doses of 3, 10, and 30 nM/rat into the VTA before intra-LH microinjection of carbachol (250 nM/rat) as a nonselective cholinergic receptor agonist for chemical stimulation of orexinergic neurons in this region. Rats were subcutaneously injected with 1% formalin (50 µl; s) into the orofacial region, 5 min after intra-LH microinjection of carbachol or saline. The blockade of both orexin receptors in the VTA reduced intra-LH carbachol-induced antinociception. However, this effect was greater during the late phases of the orofacial formalin test. The blockade of the OX1 but not OX2 receptors in the VTA affect the pain-related behaviors during the early phase, and also, the contribution of OX2 receptor to modulate the LH-induced antinociceptive responses was greater than OX1 receptor during the late phase of orofacial formalin test. The results indicated the neural pathway projected from the LH to the VTA contributes to the modulation of formalin-induced orofacial pain. Orexinergic drugs might be considered as therapeutic agents for inflammatory pain treatment.

Dopamine is the predominant catecholamine neurotransmitter in the mammalian brain which has been shown to play a critical role in antinociceptive process. Previous studies have shown that the role of CA1 region of the hippocampus in antinociception induced by stimulation of the lateral hypothalamus (LH) through the dopaminergic system in tonic pain. In this study, we tried to assess the involvement of intra-hippocampal D1- and D2-like dopamine receptors in the LH stimulation-induced antinociception during the tail-flick test as an animal model of acute pain. Ninety-five male Wistar rats were unilaterally implanted with two separate cannulae into the LH and CA1. Animals received intra-CA1 infusion of SCH-23390 (0.25, 1 and 4 µg/rat), as a D1-like dopamine receptor antagonist and sulpiride (0.125, 0.25, 1 and 4 µg/rat), as a D2-like dopamine receptor antagonist, 2 min before intra-LH administration of carbachol (250 nM/rat). The antinociceptive effects of SCH-23390 and sulpiride were measured by using a tail-flick analgesiometer and represented as the maximal possible effect (%MPE). Also, the locomotion tracking apparatus was used to measure the locomotor activity of animals. Results showed that intra-CA1 administration of SCH-23390 or sulpiride could prevent the intra-LH carbachol-induced antinociception. This effect was a little more dominant after blocking the D2-like dopamine receptor in the CA1. These findings revealed that D1- and D2-like dopamine receptors within the CA1 play an important role in antinociceptive responses induced by chemical stimulation of the LH. It could be suggested that dopamine receptors in the CA1 were triggered by LH orexinergic projections., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Lateral hypothalamus (LH) contains a large population of orexinergic neurons. Many studies have investigated the function of these neurons and it is clear that they are involved in pain modulation. The nucleus accumbens (NAc) receives many orexinergic projections, and accumbal neurons express both receptors of orexin (OX1R and OX2R). In this study, we investigated the role of accumbal orexinergic receptors in the LH-induced antinociception during formalin-induced orofacial pain. Male adult Wistar rats weighing 230-250 g were used in this study. Cannulae were unilaterally implanted in their skull for microinjections. SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist) at the doses of 3, 10 and 30 nM were injected into the NAc with/without intra-LH microinjection of carbachol (250 nM/rat). Carbachol was used for chemical stimulation of orexinergic neurons in the LH. Our results showed that intra-LH carbachol following injection of formalin into animals' upper lip reduced nociception in both phases of formalin test. SB334867 and TCS OX2 29 were able to reduce LH-induced antinociception in both phases. Although the highest dose of SB334867 and TCS OX2 29 (30 nM) was effective in both phases, the TCS OX2 29 but not SB334867 at the dose of 10 nM could not reduce the antinociceptive responses induced by LH stimulation during the first (early) phase. It suggests that contribution of accumbal orexinergic receptors in the first phase of formalin test is more than the second (late) phase, and these results provide further evidence for the involvement of orexinergic system in the modulation of inflammatory orofacial pain.

Relapsing to drugs of abuse is a challenging problem in treatment of addiction and stress is believed to be a major risk factor in relapse to drugs. The hippocampus region and dopamine signaling play a critical role in reward-related behaviors. The purpose of this study is to identify the involvement of D1- and D2-like receptors in the CA1 region of hippocampus in the reinstatement induced by a combination of food deprivation stress and a sub-threshold dose of morphine in extinguished morphine-conditioning place preference in rats. Adult male rats treated with one specific doses of SCH-23390 or sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) as D1- and D2-like receptors antagonists into the CA1 in separate groups, following the conditioning and extinction phase of morphine-conditioning place preference, before initiating the food deprivation stress on the last day of extinction. Then, the food deprived animals examined for reinstatement by injection of the sub-threshold dose of morphine (0.5 mg/kg, s.c.) on reinstatement day. Conditioning place preference scores and locomotor activities were recorded during test. Our results showed that combination of food deprivation stress and a sub-threshold dose of morphine induced the reinstatement of morphine-conditioning place preference. The induced reinstatement was decreased by two higher doses of SCH-23390 (2 and 4 µg/0.5 µl vehicle/side). However, the sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) could not reduce the reinstatement. Results showed that the role of D1-like receptor in the CA1 region was more prominent than D2-like receptor in reinstatement induced by food deprivation stress and re-exposure to morphine. Therefore the D1-like receptor in the CA1 might be a potential therapeutic target for treatment of opiate addiction.

Aim: The purpose of this study is to optimize treatment planning in carbon ion radiotherapy, taking into account the effect of tumour hypoxia., Background: In conventional hadron therapy, the goal is to create a homogenous dose in the tumour area and, thus, achieve a uniform cell survival level. Since the induction of a specific damage to cells is directly influenced by the level of hypoxia in the tissue, the varying oxygen pressure in the different regions of hypoxic tumours would disrupt the uniformity of the cell survival level., Materials and Methods: Using the Geant4 Monte Carlo Code, the physical dose profile and dose-averaged linear energy transfer were calculated in the tumour. Then, the oxygen enhancement ratio in different areas of the tumour were compared with different pressures., Results: Modulations of radiation intensities as well as energies of ion beams were calculated, both considering and disregarding the effect of hypoxia, and the required dose profiles were compared with each other. Cell survival levels were also compared between the two methods. An equation was obtained for re-modulating the beams in the presence of hypoxia, and radiation weighting factors were extracted for the beam intensities., Conclusion: The results show that taking the effect of hypoxia into account would cause the reduction of average doses delivered to the tumour tissues up to 1.54 times. In this regard, the required dose is reduced by 1.63 times in the healthy tissues before the tumour. This will result in an effective protection of healthy tissues around the tumour., (© 2019 Greater Poland Cancer Centre. Published by Elsevier B.V. All rights reserved.)

Addiction to opioids is an important global problem. Published research has indicated the powerful rewarding effects of drug use, which in the case of opiates like morphine may lead to drug addiction and maladaptive decision making with negative social consequences. In-depth comprehension of the role of responsible mechanisms in addiction can lead us to better and more effective treatments for drug dependence. Continuing previous work in our laboratory, in this study we aimed to investigate the role of dopamine D1- and D2-like receptors in the dentate gyrus (DG) on the reinstatement of drug-seeking behavior induced by the combination of forced swim stress and a subthreshold dose of morphine on extinguished morphine-conditioned place preference in rats. The rats were bilaterally implanted with 2 separate cannulas into the DG region. After the extinction phase of morphine-conditioned place preference, the animals received different doses (0.5, 2, and 4 μg per 0.5 μL vehicle/side) of SCH-23390 or sulpiride on the reinstatement day and were tested for the combination of forced swim stress and a subthreshold dose of morphine in discrete groups. Our findings indicated that D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The reduction was more robust in groups of animals that received sulpiride as compared with SCH-23390. Our results showed a role for DG dopamine receptors in relapse to drugs of abuse, the activity of which may be induced by exposure to a stressor like forced swim stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The activation of glial cells affects the neuronal excitability in the spinal cord. Therefore, in this study, we tried to find out the modulatory role of spinal glial cells in the excitability of wide dynamic range (WDR) neurons, induction of the long-term potentiation (LTP) and development of neuropathic pain by L5 spinal nerve transection model in the rats. Forty-eight adult male Wistar rats were used to measure the paw withdrawal threshold to mechanical stimuli and also, to carry out the spinal extracellular single unit recording experiments. In these experiments, spinal nerve ligation (SNL) and a daily injection of propentofylline (1 mg/kg, ip) as a glial cell inhibitor agent, 1 h following nerve ligation during 7-day post-SNL period, were performed. Our findings showed that the mechanical allodynia, and synaptically-evoked firing were caused LTP in the Aδ-fiber, C-fiber and lesser in the Aβ-fiber after high frequency stimulation. Daily injection of propentofylline considerably decreased LTP induction in the Aδ- and C-fibers (P < .001). It was concluded that glial cell activation mediates LTP induction in the spinal cord following peripheral nerve injury. It seems that pain modulatory role of glial cells is partly parallel to changes in neural excitability of the WDR neurons in the dorsal horn of spinal cord., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Role of the orexinergic system in pain modulation is well studied and involvement of the spinal orexin-1 receptors is well documented. In this study, we examined role of the spinal orexin-2 receptors in modulation of inflammatory pain in rat. Fifty-one adult male Wistar rats were implanted unilaterally with a guide cannula into the LH and intrathecal tubing in the lumbar space between L4 and L5. Chemical stimulation of LH by carbachol (250 nM/0.5 µL saline) induced remarkable analgesia during the two phases of formalin test and Intrathecal administration of different doses of TCS OX2 29 (10, 30 and 100 µM/ 0.5 µL DMSO) prior to LH stimulation, dose-dependently antagonized the antinociceptive effect of the LH-stimulation during the two phases of formalin test. The effect size of the TCS OX2 29 was η 2  = 0.47 and η 2  = 0. 87 for the early and late phases of the test, respectively. Also, intrathecal administration of TCS OX2 29 alone (without stimulation of the LH) had no significant effect on formalin induced pain-related behaviors. Our results showed that spinal orexin-2 receptors are involved in modulation of the LH-stimulation induced analgesia in a persistent inflammatory pain model. These findings may suggest spinal orexin-2 receptors in particular and the orexin system in general as a useful therapeutic target for treatment of chronic pains.

Reward-seeking and relapse to drug use are two characteristics of addiction and reports have indicated the role of hippocampal structures in reward learning. To find the best ways of treatment, the understanding of the neurobiological mechanisms of reward and its involved factors is a must. For this reason, in the present study, we aimed to investigate the role of D1- and D2-like dopamine receptors and compared their activities in the CA1 region, focusing on the reinstatement induced by forced swim stress (FSS) or the combination of FSS and a subthreshold dose of morphine in extinguished morphine-CPP in rats. The rats were bilaterally implanted by two separate cannulas into the CA1 region. The animals received different doses of SCH23390 or sulpiride (0.5, 2, and 4 µg/0.5 µl vehicle/side) into the CA1 region on the reinstatement day and were tested for FSS-induced reinstatement or the combination of FSS and a subthreshold dose of morphine in separate groups. Our findings indicated that the D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The behavioral results were more prominent in the groups of animals that received SCH23390 as compared to sulpiride. The data may suggest a role for the dopamine receptors in the CA1 region in relapse to drugs of abuse, which may be induced by exposure to a stressor.

Pain control in opioid-dependent individuals is a clinical complication. The present study investigated the effects of different doses of amitriptyline in the three stages of the formalin test in morphine-dependent rats (MDRs). Morphine dependency was induced using the oral method, and then, amitriptyline-induced antinociceptive effects were measured at 4 doses (2.5, 5, 10, and 20 mg/kg) and compared with the control group in a formalin-based model of pain. There was no observed antinociceptive effect in the MDRs and morphine-naïve rats (MNRs) in phase I. In the interphase, amitriptyline induced pain suppression at doses of 5 and 20 mg/kg. In phase II, at doses of 5, 10, and 20 mg/kg, the hypoalgesic effect on pain-related behaviors was seen in the MNRs. In MDRs, amitriptyline at doses of 2.5 and 5 mg/kg caused the hyperalgesic effect, whereas at 10 and 20 mg/kg doses, it induced a hypoalgesic effect. A significant attenuation was observed in the latency to fall from the accelerating rotarod at doses of 10 and 20 mg/kg in the MDRs, and at a dose of 20 mg/kg in the MNRs. Data showed that amitriptyline dose-dependently induced paradoxical hypo- and hyper-algesic effects in MDRs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: Design of a numerical method for creating spread-out Bragg peak (SOBP) and evaluation of the best parameter in Bortfeld Model to this aim in oxygen ion therapy., Background: In radiotherapy, oxygen ions have more biological benefits than light beams. Oxygen ions have a higher linear energy transfer (LET) and larger relative biological effectiveness (RBE) than lighter ones., Materials and Methods: For the design of the spread-out Bragg peak (SOBP) for oxygen beam, we designed a numerical method using the Geant4 Monte Carlo simulation code, along with matrix computations., Results: The profiles of the Bragg Peak have been calculated for each section in the target area by the Geant4 tool. Then, in order to produce SOBP smoothly, a set of weighting factors for the intensity of oxygen ion radiation in each energy was extracted through a numerically designed method. This method was tested for producing SOBP at various widths and at different depths of a phantom. Also, weighting factors of intensity for producing a flat SOBP with oxygen ions were also obtained using the Bortfeld model in order to determine the best parameters. Then, the results of the Bortfeld model were compared with the outcomes of the method that was developed in this study., Conclusions: The results showed that while the SOBP designed by the Bortfeld model has a homogeneity of 92-97%, the SOBP designed by the numerical method in the present study is above 99%, which in some cases even closed to 100%.

Orexins are produced in the restricted regions of the lateral hypothalamus (LH). However, orexinergic receptors and projections are localized in wide regions like nucleus accumbens, ventral tegmental area, periaqueductal gray area and spinal cord which are involved in the pain modulation. This study was carried out to investigate the effects of intrathecal administration of orexin-1 receptor antagonist (SB-334867) in the spinal antinociception induced by intra-LH administration of carbachol (cholinergic receptor agonist) in both early and late phases of pain related behaviors in formalin test. In this study, pain-related behaviors (pain scores) were evaluated using the formalin test during 5-min block intervals for a 60-min period in seventy male Wistar rats were given SB-334867 (3, 10, 30 and 100 μM/10 μl) or vehicle (DMSO 12%; 10 μl) intrathecally following intra-LH administration of carbachol (250 nM/rat). Our data showed that intra-LH injection of carbachol attenuated the formalin-induced biphasic pain responses, and intrathecal administration of SB-334867 dose-dependently decreased LH stimulation-induced antinociceptive responses during both phases. Moreover, administration of different doses of SB-334867 during the early phase were more effective than those during the late phase. The antinociceptive role of orexinergic system in the formalin test through a neural pathway from the LH to the spinal cord provides evidence that orexins can be useful in therapeutic targets for pain relief., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although it is apparent that chromosome complement mediates sexually dimorphic expression patterns of some proteins that lead to functional differences, there has been insufficient evidence following the manipulation of the male-specific region of the Y chromosome (MSY) gene expression during neural development. In this study, we profiled the expression of 23 MSY genes and 15 of their X-linked homologues during neural cell differentiation of NTERA-2 human embryonal carcinoma cell line (NT2) cells in three different developmental stages using qRT-PCR, Western blotting, and immunofluorescence. The expression level of 12 Y-linked genes significantly increased over neural differentiation, including RBMY1, EIF1AY, DDX3Y, HSFY1, BPY2, PCDH11Y, UTY, RPS4Y1, USP9Y, SRY, PRY, and ZFY. We showed that siRNA-mediated knockdown of DDX3Y, a DEAD box RNA helicase enzyme, in neural progenitor cells impaired cell cycle progression and increased apoptosis, consequently interrupting differentiation. Label-free quantitative shotgun proteomics based on a spectral counting approach was then used to characterize the proteomic profile of the cells after DDX3Y knockdown. Among 917 reproducibly identified proteins detected, 71 proteins were differentially expressed following DDX3Y siRNA treatment compared with mock treated cells. Functional grouping indicated that these proteins were involved in cell cycle, RNA splicing, and apoptosis, among other biological functions. Our results suggest that MSY genes may play an important role in neural differentiation and demonstrate that DDX3Y could play a multifunctional role in neural cell development, probably in a sexually dimorphic manner.