Orexin-1 Receptor Antagonist SB-334867 Enhances Formalin-Induced Nociceptive Behaviors in Adult Male Rats.

Background: Orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. Neurons that produce orexin are scattered mediolaterally within the Dorsomedial Hypothalamus (DMH) and the lateral hypothalamus. In the current research, we assessed the impact of prolonged application of the antagonist of Orexin Receptor 1 (OXR1) on nociceptive behaviors in adult male rats. Methods: Sixteen Wistar rats received subcutaneous (s.c.) injections of the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle repetitively from Postnatal Day 1 (PND1)-PND30. On the 30th day following the final application of the OXR1 antagonist formalin-provoked pain was evaluated by injecting formalin. Results: Administration of the OXR1 antagonist in the long-term augmented the formalin-provoked nociceptive behaviors in interphase and phase II of the formalin-induced pain. Conclusion: Current results showed that the continued inhibiting OXR1 might be implicated in formalin-induced nociceptive behaviors. Therefore, the present study highlighted the effect of orexin on analgesia.

Heterosynaptic plasticity-induced modulation of synapses.

Plasticity is a common feature of synapses that is stated in different ways and occurs through several mechanisms. The regular action of the brain needs to be balanced in several neuronal and synaptic features, one of which is synaptic plasticity. The different homeostatic processes, including the balance between excitation/inhibition or homeostasis of synaptic weights at the single-neuron level, may obtain this. Homosynaptic Hebbian-type plasticity causes associative alterations of synapses. Both homosynaptic and heterosynaptic plasticity characterize the corresponding aspects of adjustable synapses, and both are essential for the regular action of neural systems and their plastic synapses.In this review, we will compare homo- and heterosynaptic plasticity and the main factors affecting the direction of plastic changes. This review paper will also discuss the diverse functions of the different kinds of heterosynaptic plasticity and their properties. We argue that a complementary system of heterosynaptic plasticity demonstrates an essential cellular constituent for homeostatic modulation of synaptic weights and neuronal activity.

The Implication of Hypocretin in Drug Abuse and Arousal in the Brain Stem.

Hypocretin (orexin, Hcrt) neurons located in the lateral hypothalamus (LH) project widely into the brain and are thus responsible for the physiological action of the hypocretin complex. Hypocretin is involved in both arousal and addiction, and brainstem areas such as the locus coeruleus (LC), paragigantocellularis (PGi), and dorsal raphe (DR) contribute to these functions. In the present review, we focus on the effect of Hcrt on drug abuse and arousal in the brainstem.

NMDA Receptors in the Rat Paraventricular Thalamic Nucleus Reduce the Naloxone-induced Morphine Withdrawal.

BACKGROUND: NMDA receptors have a significant role in the development of opioid physical dependence. Evidence demonstrated that a drug of abuse enhances neuronal excitability in the Paraventricular Nucleus (PVT). The current research studied whether blocking NMDA receptors through the administration of MK801 in the PVT nucleus could affect the development of Morphine (Mor) dependence and hence the behavioral indices induced by morphine withdrawal in rats. METHODS: Male Wistar rats weighing 250-300 g were used. For induction of drug dependence, we injected Mor subcutaneously (s.c.) (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two groups in which the NMDA receptor antagonist, MK801 (20 mM in 0.1 ml), or its vehicle were applied into the PVT nucleus for 7 days before each Mor administration. On day 8, after injection of naloxone (Nal, 2.5 mg/kg, i.p.), withdrawal behaviors were checked for 25 min. RESULTS: The current results demonstrated that the blockade of the NMDA receptor in the PVT nucleus significantly increased withdrawal behaviors provoked by the application of Nal in morphinedependent (Mor-d) rats. CONCLUSION: We concluded that the NMDA receptor in the PVT nucleus changes the development of Mor dependence.

Aromatherapy for the brain: Lavender's healing effect on epilepsy, depression, anxiety, migraine, and Alzheimer's disease: A review article.

Neurological diseases affect the nervous system, including the brain, spinal cord, cranial nerves, nerve roots, autonomic nervous system, neuromuscular junctions, and muscles. Herbal medicine has long been used to cure these diseases. One of these plants is lavender, which is composed of various compounds, including terpenes, such as linalool, limonene, triterpenes, linalyl acetate, alcohols, ketones, polyphenols, coumarins, cineole, and flavonoids. In this review, the literature was searched using scientific search engines and databases (Google Scholar, Science Direct, Scopus, and PubMed) for papers published between 1982 and 2020 via keywords, including review, lavender, and neurological disorders. This plant exerts its healing effect on many diseases, such as anxiety and depression through an inhibitory effect on GABA. The anti-inflammatory effects of this plant have also been documented. It improves depression by regulating glutamate receptors and inhibiting calcium channels and serotonergic factors, such as SERT. Its antiepileptic mechanism is due to an increase in the inhibitory effect of GABA and potassium current and a decrease in sodium current. Therefore, many vegetable oils are also used in herbal medicine. In this review, the healing effect of lavender on several neurological disorders, including epilepsy, depression, anxiety, migraine, and Alzheimer's disease was investigated. All findings strongly support the traditional uses of lavender. More clinical studies are needed to investigate the effect of the plants' pharmacological active constituents on the treatment of life-threatening diseases in humans. The limitations of this study are the low quality and the limited number of clinical studies. Different administration methods of lavender are one of the limitations of this review.

A Review of the Physiological Role of Hypocretin in the Ventral Tegmental Area in Reward and Drug Dependence.

Orexin (OX, hypocretin: HCRT) as a neuropeptide is produced in a distinct population of neurons in the posterior lateral hypothalamus (LH). OX neurons implicate in reward function. OX makes a main input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. OX, through OX receptors (OXR1, OXR2) activates VTA dopamine (DA) neurons. VTA neurons are involved in reward processing and motivation. In this review, we will discuss the OX effect on addiction through VTA activation and related areas of the brain.

Neuroprotective effects of coenzyme Q10 on neurological diseases: a review article.

Neurological disorders affect the nervous system. Biochemical, structural, or electrical abnormalities in the spinal cord, brain, or other nerves lead to different symptoms, including muscle weakness, paralysis, poor coordination, seizures, loss of sensation, and pain. There are many recognized neurological diseases, like epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, autosomal recessive cerebellar ataxia 2 (ARCA2), Leber's hereditary optic neuropathy (LHON), and spinocerebellar ataxia autosomal recessive 9 (SCAR9). Different agents, such as coenzyme Q10 (CoQ10), exert neuroprotective effects against neuronal damage. Online databases, such as Scopus, Google Scholar, Web of Science, and PubMed/MEDLINE were systematically searched until December 2020 using keywords, including review, neurological disorders, and CoQ10. CoQ10 is endogenously produced in the body and also can be found in supplements or foods. CoQ10 has antioxidant and anti-inflammatory effects and plays a role in energy production and mitochondria stabilization, which are mechanisms, by which CoQ10 exerts its neuroprotective effects. Thus, in this review, we discussed the association between CoQ10 and neurological diseases, including AD, depression, MS, epilepsy, PD, LHON, ARCA2, SCAR9, and stroke. In addition, new therapeutic targets were introduced for the next drug discoveries.

Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer's disease.

BACKGROUND: Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat's model of Alzheimer's disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aß). METHODS: Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aß, 4. pretreatment (Vin + Aß): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aß(1-42), 5. treatment (Aß + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aß + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus. RESULTS: Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aß group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP). CONCLUSIONS: Vin could significantly prevent the Aß effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aß on hippocampal synaptic plasticity.

Effectiveness of coenzyme Q10 on learning and memory and synaptic plasticity impairment in an aged Aß-induced rat model of Alzheimer's disease: a behavioral, biochemical, and electrophysiological study.

RATIONALE: Aging is the major risk factor for Alzheimer's disease (AD), and cognitive and memory impairments are common among the elderly. Interestingly, coenzyme Q10 (Q10) levels decline in the brain of aging animals. Q10 is a substantial antioxidant substance, which has an important role in the mitochondria. OBJECTIVE: We assessed the possible effects of Q10 on learning and memory and synaptic plasticity in aged ß-amyloid (Aß)-induced AD rats. METHODS: In this study, 40 Wistar rats (24-36 months old; 360-450 g) were randomly assigned to four groups (n = 10 rats/group)-group I: control, group II: Aß, group III: Q10; 50 mg/kg, and group IV: Q10+Aß. Q10 was administered orally by gavage daily for 4 weeks before the Aß injection. The cognitive function and learning and memory of the rats were measured by the novel object recognition (NOR), Morris water maze (MWM), and passive avoidance learning (PAL) tests. Finally, malondialdehyde (MDA), total antioxidant capacity (TAC), total thiol group (TTG), and total oxidant status (TOS) were measured. RESULTS: Q10 improved the Aß-related decrease in the discrimination index in the NOR test, spatial learning and memory in the MWM test, passive avoidance learning and memory in the PAL test, and long-term potentiation (LTP) impairment in the hippocampal PP-DG pathway in aged rats. In addition, Aß injection significantly increased serum MDA and TOS levels. Q10, however, significantly reversed these parameters and also increased TAC and TTG levels in the Aß+Q10 group. CONCLUSIONS: Our experimental findings suggest that Q10 supplementation can suppress the progression of neurodegeneration that otherwise impairs learning and memory and reduces synaptic plasticity in our experimental animals. Therefore, similar supplemental Q10 treatment given to humans with AD could possibly provide them a better quality of life.

Underlying mechanisms of long-term potentiation during the inhibition of the cannabinoid CB1 and GABAB receptors in the dentate gyrus of hippocampus.

BACKGROUND: The release of various neurotransmitters and thereby the excitability of neuronal circuits are regulated by the endocannabinoid system in an activity-dependent manner. Hippocampal long-term potentiation (LTP) is augmented in cannabinoid type 1 (CB1) receptor-deficient mice. CB1 receptors exist on GABAergic axon terminals in the hippocampus. In our previous work, we showed that CB1 antagonists increased the population spike (PS) amplitude, field excitatory post-synaptic potential (fEPSP), and the LTP induction in the dentate gyrus (DG) of the rat hippocampus while the GABAB antagonist decreased these parameters. Determining the underlying mechanisms of the pre- and/or postsynaptic locus of LTP expression is of great importance. In this study, we investigated whether LTP alteration acutely caused by CB1 and GABAB receptor antagonists (AM251 and CGP55845, respectively) happens at the postsynaptic or presynaptic regions, or at both. Therefore, the paired-pulse ratio (PPR) was assessed prior to and following the LTP induction in the studied groups. METHODS: Male Wistar rats were randomly assigned to the groups of control, AM251, CGP55845, CGP55845 + AM251. A high-frequency stimulation (HFS) of the perforant path (PP) was used to induce LTP in the DG region. RESULTS: Statistical analysis revealed that AM251 produced significant increase in excitatory postsynaptic potential (EPSP) slope and amplitude of PS. Conversely, administration of CGP55845 produced decrease in slope of EPSP. The current results indicated that the PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination. CONCLUSIONS: It can be concluded that the site causing LTP expression is, at least in part, the postsynaptic site because PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination.

Preventive impacts of vitamin C on memory damage caused by unpredictable chronic mild stress in relation to biochemical parameters in the hippocampus of male rats.

The present study focused on examining the impact of vitamin C (Vit C) administration on the function of memory and the status of oxidative stress (OS) in the hippocampal area of the brain using an unpredictable chronic mild stress (UCMS) model in rats. To this end, 50 male Wistar rats (11-12 weeks of age at the start of the study) were assigned to five groups of six animals, including control, UCMS, UCMS + Vit C 50 mg/Kg, UCMS + Vit C 100 mg/Kg, and UCMS + Vit C 400 mg/Kg. The animals received daily intraperitoneal injections of Vit C at a certain time (9 am) before the initiation of a stressor. UCMS, including a progression of typical stressors, was applied for four weeks. Subsequently, using the passive avoidance (PA) and Morris water maze (MWM) tests were performed to investigate learning and memory. Eventually, hippocampal tissues were evaluated in terms of OS criteria. The results revealed that the latency to enter the dark chamber (P < 0. 01 and P < 0.05, PA test) and the time spent in the target quadrant (P < 0.0001, MWM test) were shorter in the UCMS group, while latency to discover the platform was longer (P < 0.05 and P < 0.001, MWM test) compared to the control group. However, UCMS decreased the content of thiol (P < 0.0001), as well as the activities of catalase (P < 0.0001) and superoxide dismutase (P < 0.0001), whereas the concentration of malondialdehyde (P < 0.01) increased in the hippocampal region of the brain in comparison to the control group. Interestingly, Vit C treatment reversed the mentioned effects of UCMS. Therefore, the latency to enter the dark chamber (P < 0. 05 and P < 0.01,1 and 24 h after the shock, PA test, UCMS + Vit C 400) and the time spent in the target quadrant (P < 0. 01 and P < 0.05, MWM test, UCMS + Vit C 400 and UCMS + Vit C 100, respectively) were longer in the UCMS + Vit C groups. Moreover, Vit C increased the content of thiol (P < 0.05, UCMS + Vit C 400), as well as the activity of catalase (P < 0.001, UCMS + Vit C 400) and superoxide dismutase (P < 0.0001, UCMS + Vit C 400, UCMS + Vit C 100), whereas the concentration of malondialdehyde (P < 0. 05 and P < 0.01, UCMS + Vit C 100, UCMS + Vit C 400) decreased in the hippocampal region of the brain in comparison to the UCMS group. Overall, these results suggest that Vit C could reverse UCMS-induced learning and memory impairment possibly through the modulation of brain OS.Key points Memory and learning impairments were induced by unpredictable chronic mild stress (UCMS)Vitamin C could prevent cognitive impairments caused by UCMS in rats by attenuation of oxidative stress in the brain.

Reciprocal Interaction of Pain and Brain: Plasticity-induced Pain, Pain-induced Plasticity, and Therapeutic Targets.

Considerable functional and structural alterations, or plasticity, in the central nervous system (CNS) are accompanied by numerous chronic pain syndromes. Sensitization of the peripheral (primary hyperalgesia) or central (secondary hyperalgesia) nervous system as unhelpful neuroplasticity may result in stimulus-induced pain (hyperalgesia and allodynia). Furthermore, nociception induces extensive plasticity in the peripheral and central neural systems in pathological disease states. Diseaseinduced plasticity at both structural and functional levels is evident as alterations in different molecules, synapses, cellular function and network activity. In the present article, we review plasticityinduced pain and pain-induced plasticity. Moreover, we will review the pain matrix. Furthermore, we will focus on recent developments of CNS alterations in long-lasting pain in some clinical entities encountered in rehabilitation. These clinical entities comprise nonspecific low back pain, complex regional pain syndrome, postamputation phantom pain, fibromyalgia, and chronic pain after spinal cord injury. Moreover, we will review the clinical treatment for the inhibition of pathological pain.

Upregulation of Connexins in the Rat Hippocampal and Cortical Neurons Following Blockade of NMDA Receptors During Postnatal Development.

BACKGROUND: Interneural gap junctional coupling represents neural development that decreases during the postnatal period. The decrease of gap junction function coincides with the main period of chemical synapse creation and increment of synaptic activity during postnatal weeks 1 to 3. METHODS: Here, we have assessed the role of chemical synapses on connexin (Cx) expression in neurons and glial cells of hippocampal and cortical neurons. We characterized the impact of NMDA receptors blockade on the expression of Cx36 and Cx43 proteins by western blot analysis in postnatal day (PND)14 and PND28. MK801 was injected subcutaneously from the first day of birth until 14 or 28 days, depending on the experimental groups. Saline was injected in the same volumes in the control group. RESULTS: Early postnatal blockade of the NMDA subtype of glutamate receptors by the non-competitive antagonist dizocilpine maleate (MK801) arrested the developmental reduction in gap junctions during the initial postnatal weeks. Expression of Cx43 declined in PND28 compared to PND14 in visual cortex (VC) neurons. Also, we found that the expression of Cx36 and Cx43 augmented in the rats' VC in PND28 following the blockade of NMDA receptors. Expression of Cx36 declined in PND28 compared to PND14 in hippocampal neurons. Also, we found that the expression of Cx36 augmented in the rats' hippocampal neurons in PND14 and PND28 following a blockade of NMDA receptors. CONCLUSION: These results suggest that the postnatal enhancement in glutamatergic synaptic activity is associated with the loss of gap junctional connections and downregulation of Cx36 and Cx43 between developing neurons and glial cells.

Dopamine as a Potential Target for Learning and Memory: Contributing to Related Neurological Disorders.

It is well established that learning and memory are complex processes. They involve and recruit different brain modulatory neurotransmitter systems. Considerable evidence points to the involvement of dopamine (DA) in learning and memory. Manifestations of the synaptic spatial localization of the effect of DA have gained a great deal of interest. Despite the molecular cloning of the five DA receptor subtypes, the underlying signaling of the DA receptors in spatial learning and memory is less compelling. Fluctuations in the DA level in the brain are associated with many diseases that comprise deficits in learning and memory, including Parkinson's disease, Huntington's disease, schizophrenia, and Alzheimer's disease. This review aims to briefly summarize existing information regarding the memory performance modified by DA. The signaling of the DA system, particularly examining the origin of DA-modulated memory, is also discussed. Then, several kinds of memories in which DA plays a critical role, including reward signaling, working memory, and long-term plasticity, as well as memory consolidation, are also described. Finally, memory impairment in some DA-related neurological disorders is also examined.

Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems.

Immune-mediated inflammatory diseases (IMIDs) are a group of common heterogeneous disorders, characterized by an alteration of cellular homeostasis. Primarily, it has been shown that the release and diffusion of neurotransmitters from nervous tissue could result in signaling through lymphocyte cell-surface receptors and the modulation of immune function. This finding led to the idea that the neurotransmitters could serve as immunomodulators. It is now manifested that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Increasing data indicate that there is a crosstalk between inflammation and alterations in neurotransmission. The primary goal of this review is to demonstrate how these two pathways may converge at the level of the neuron and glia to involve in IMID. We review the role of neurotransmitters in IMID. The different effects that these compounds exert on a variety of immune cells are also reviewed. Current and future developments in understanding the cross-talk between the immune and nervous systems will undoubtedly identify new ways for treating immune-mediated diseases utilizing agonists or antagonists of neurotransmitter receptors.

Orexin system in the ventral tegmental area is implicated in the rewarding properties of methamphetamine.

Overwhelming evidence has revealed that the orexins (OXs) and their receptors in the mesolimbic system participate in modulating psychostimulants and rewarding impacts. The current study aimed to elucidate the role of OX receptors in the ventral tegmental area (VTA) in the acquisition and expression phases of methamphetamine (METH)-induced conditioned place preference (CPP). In the first set of experiments, animals bilaterally received OX receptor 1 (SB 334867) or OX receptor 2 (TCS OX2 29) antagonist (1, 3, 10, and 30 nmol/0.3 µL DMSO 12%) in the VTA before each METH session over the acquisition phase to evaluate the role of OX receptors in the acquisition of METH-induced CPP. In the next set of experiments, animals bilaterally received antagonists at the same doses in the VTA before the post-conditioning test to illustrate the role of OX receptors in the expression of METH-induced CPP. Current data demonstrated that administering both antagonists in the VTA diminished both acquisition and expression phases of METH-induced CPP. However, the suppressive effects of both OX receptor antagonists were more potent in the acquisition phase of METH-CPP than those in the expression phase. Overall, it seems that the OX receptors in the VTA are implicated in developing the rewarding properties of METH.

Structure, Distribution, Regulation, and Function of Splice Variant Isoforms of Nitric Oxide Synthase Family in the Nervous System.

Nitric oxide (NO) is a small molecule produced by nitric oxide synthase (NOS) with various physio-pathological functions in the body. There are three main NOS isoforms, including the endothelial (eNOS), inducible (iNOS), and neuronal NOS (nNOS), that exist in the peripheral organs and nervous systems of humans and rodents. Moreover, NOS includes other identified NOS isoforms, such as retinal Muller glial cells (mNOS), mitochondrial (mtNOS), penile (PnNOS), testis-specific (TnNOS), and invertebrate Drosophila NOS (dNOS), which are the lesser-known types. It is proposed that the versatile functions of NOS isoforms depend on various NOS splice variant subtypes and their expression in the neural (e.g., brain, and spinal cord) and non-neuronal tissues (e.g., lung, kidney, liver, and GI tract). Therefore, this review summarizes the NOS subtypes, splice variants, targeted splicing expression in the body, and their proposed physio-pathological functions. At last, alternative NOS subtypes and isoforms, which have previously received scant attention, will be addressed in this article.

Neuroprotective effect of geraniol on neurological disorders: a review article.

BACKGROUND: Neurological disorders are structural, biochemical, and electrical abnormalities that affect the peripheral and central nervous systems. Paralysis, muscle weakness, tremors, spasms, and partial or complete loss of sensation are some symptoms of these disorders. Neurorehabilitation is the main treatment for neurological disorders. Treatments can improve the quality of life of patients. Neuroprotective substances of natural origin are used for the treatments of these disorders. METHODS AND RESULTS: Online databases, such as Google Scholar, PubMed, ScienceDirect, and Scopus were searched to evaluate articles from 1981-2021 using the Mesh words of geraniol (GER), neurological disorders, epilepsy, spinal cord injury (SCI), Parkinson's diseases (PD), and depression. A total of 87 studies were included in this review. GER with antioxidant, anti-inflammatory, and neuroprotective effects can improve the symptoms and reduce the progression of neurological diseases. GER exhibits neuroprotective effects by binding to GABA and glycine receptors as well as by inhibiting the activation of nuclear factor kappa B (NF-κB) pathway and regulating the expression of nucleotide-binding oligomerization of NLRP3 inflammasome. In this study, the effect of GER was investigated on neurological disorders, such as epilepsy, SCI, PD, and depression. CONCLUSION: Although the medicinal uses of GER have been reported, more clinical and experimental studies are needed to investigate the effect of using traditional medicine on improving lifethreatening diseases and the quality of life of patients.

Neural correlates and potential targets for the contribution of orexin to addiction in cortical and subcortical areas.

The orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. This variety of functions can be described by a united function for orexins in translating states of heightened motivation, for example during physiological requirement states or following exposure to reward opportunities, into planned goal-directed behaviors. An addicted state is characterized by robust activation of orexin neurons from the environment, which triggers downstream circuits to facilitate behavior directed towards obtaining the drug. Two orexin receptors 1 (OX1R) and 2 (OX2R) are widely distributed in the brain. Here, we will introduce and describe the cortical and subcortical brain areas involved in addictive-like behaviors and the impact of orexin on addiction.

Administration of Orexin-A into the Rat Thalamic Paraventricular Nucleus Enhances the Naloxone Induced Morphine Withdrawal.

OBJECTIVE: Orexin neuropeptides are implicated in physical dependence on opioids and expression of withdrawal symptoms in drug abuse. The paraventricular nucleus of the midline thalamus (PVT) has a high expression of orexin receptors. The current research studied the effect of orexin-A in the PVT area on the development of behavioral indices produced by morphine withdrawal in rats. METHODS: Male Wistar rats weighing 250-300 gr were utilised. To produce drug dependence, morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) was injected at an interval of 24 hrs for 7 days. To assess the involvement of the orexin in withdrawal syndrome, we injected orexin-A (100 µM, 200 nl) into the PVT for 7 days before each morphine injection. On the day after the last injection of morphine, naloxone (2.5 mg/kg, i.p.) was injected to elicit the morphine withdrawal symptoms which were observed and checked for 25 min. RESULTS: The results of the current research showed that the orexin-A in PVT enhances the severity of behavioral symptoms prompted by the injection of naloxone in drug-dependent rats. CONCLUSIONS: These observations imply that targeting the orexin receptors in PVT might exhibit a new therapeutic strategy for the future treatment of dependence.