Highlights 
• Two routine methods of Intracerebroventricular and microiontophoresis applications are used to study the cellular effects of bupropion on the Ventral Tegmental Area (VTA) dopaminergic neurons. 
• The dopaminergic VTA neuronal firings rates are extracted and assigned to evaluate the direct or indirect effects of bupropion. 
• Bupropion can modulate the synaptic activity and post-synaptic neuronal spiking by the pre- or post-synaptic effects.   
• Although the bupropion as an antidepressant, has excitatory effects on the dopaminergic neurons, its direct effect is inhibitory.
• The dissociation of direct and indirect effects of bupropion on the VTA dopaminergic neurons can explain some side effects of bupropion besides its anti-depressive property. 

Plain Language Summary 
Antidepressants comprise the major part of prescribed drugs worldwide. Bupropion was introduced as an antidepressant, but it was mainly used as smoke cessation. The mechanism of action of bupropion is not well known, and the wide range of its effects showed the complexity of its activities. This study examined the effects of indirect and direct application of bupropion on the cellular levels by intraventricular or iontophoretic methods, respectively.  The findings of this study showed that the general indirect effect of bupropion on the dopaminergic VTA neurons is dual; excitatory, and inhibitory, but its direct effect is inhibitory. The dose-related presence of bupropion can show the different effects on the dopaminergic VTA neurons. These findings could explain some opposite effects and also side effects of bupropion.

Highlights 
• Swim stress attenuated nociceptive behaviors in the first phase and increased the duration of interphase in the formalin test in a water-height-dependent manner. 
• Naloxone increased nociceptive behaviors in the first phase, interphase, and phase 2 of the formalin test.
• Involvement of endogenous opioid system demonstrated in the swim-stress-induced modulation of pain behaviors in phase 1, phase 2, and interphase of formalin test. 

Plain Language Summary 
Formalin test is commonly used as an animal model of tonic pain to evaluate the analgesic effects of drugs. Stress has an important role in the modulation of interphase. The interphase period in the formalin test may be an active process due to the activity of endogenous pain-suppressing mechanisms. Swim-stress-induced analgesia appears to be mediated through opioid and non-opioid mechanisms. Based on the previous studies, swim stress prolonged interphase or delayed the start of phase 2 in the formalin test. In addition, some studies have shown that naloxone can modulate only the interphase, while testosterone involves in phases 1 and 2 without affecting the interphase. We hypothesized that swim stress could modulate the nociceptive behaviors induced by formalin in phase 1, interphase, and phase 2, through interacting with the endogenous opioid system. 

Highlights 
• There should be no debate about the need for new analgesic medications.
• Some studies reported that psychostimulant drugs could increase opioid-induced analgesia.
• We tested the analgesic effects of methamphetamine (Meth), Buprenorphine (BUP), and their coadministration in rats.
• The combination of Meth and BUP increased reaction time more than these two alone.
• Meth increases the analgesic effects of BUP.

Plain Language Summary 
There is no doubt about providing access to pain medications for those with a serious illness such as cancer, especially in a palliative care stage. Millions of people still lack access to drugs such as morphine, and millions more have access to ineffective drugs and continue to suffer from poorly-controlled symptoms. Additionally, because of some adverse effects of opioid medications, such as respiratory depression, especially in higher doses, we aimed to explore ways for increasing the analgesic effects of opiate medications without an increase in those adverse effects. Buprenorphine is approved as an opioid analgesic (painkiller) for various types of pain. In this study, we tested the analgesic effects of methamphetamine, buprenorphine, and their coadministration in rats to find new medications and compounds for effective controlling of pain in end-stage patients. We proved that methamphetamine decreases pain sensation in rats. Also, methamphetamine increases the analgesic effects of buprenorphine, and this combination can be used for more analgesic effects. Furthermore, our study results implicate that psycho-stimulant drugs, such as methamphetamine are good candidates for enhancing the analgesic effects of opioid medications. 

Highlights 
• Depression in the offspring of morphine-exposed rats is higher than the offspring of the control group.
• Chronic stress produces an exaggerated effect on depression in offspring of morphine-exposed rats.
• Depression rate is higher in the children of addicts.

Plain Language Summary 
Addiction is a multifactorial disorder with genetic, neurobiological, and psychosocial aspects. Epigenetic changes are explained as an alteration in gene expression without altering in DNA sequences. Factors such as stress and substance abuse can cause epigenetic changes and produce psychiatric behaviors. Based on some evidence, 50% of hospitalized children for the psychiatric disorder had addicted parents. Alcohol-abusing parents increase the risk of mental health problems such as depression, suicidal attempts, antisocial behavior, and drug abuse in children. In this study, we investigated the effect of parental (maternal and or paternal) morphine exposure 10 days before gestation on the depression state of the offspring. We also evaluated chronic mild stress-induced depression in offspring by using chronic corticosterone injection as a model of mild chronic stress. We found that parental morphine exposure induced depression in offspring. Morphine can directly affect epigenetic germ cells, and this causes developmental changes in the embryo. The mechanisms which induce such trans-generational effect are unknown, and other research should be done to show the mechanisms of such effects.

Highlights 
• Functional or sensory loss may follow peripheral nerve injury. 
• Surgical techniques and stimulating nerve growth are necessary to protect nerve regeneration. 
• The oriented basement membrane and extracellular matrix component of the autologous degenerated skeletal muscle could conduit the regenerating nerve fibers.  
• Nerve growth factor (NGF) has a vital role in the nerve growth and survival of neurons and increase nerve regeneration and remyelination after nerve defect.
• Combination of autologous degenerated skeletal muscle with NGF and laminin has promising treatment in the peripheral nerve injury

Plain Language Summary 
Peripheral nerve injury results in disability, limitation of daily living, and higher expenses for the family. This lesion requires a comprehensive treatment that provides both a conduit for nerve conduction and essential materials for nerve growth. Epimysium around the muscle fiber and epineurium around the nerve fiber have the same structure. Both of them are necessary for nerve and muscle survival and their function.  In this study, the muscle fiber was removed from the autologous degenerated skeletal muscle and basement membrane, and epimysium was used as a conduit for the interrupted nerve. NGF is a neuropeptide that participated in the regulation of nerve growth, adhesion, migration, neuronal proliferation, and regeneration and remyelination of nerve fiber. Laminin is a component of the basement membrane and act as a surface substrate for nerve repair and produced mainly by Schwann cells. Histological of the distal segment after the transplantation in the region demonstrated that axons could grow and reach the distal part. The study results indicate autologous degenerated skeletal muscle along with NGF and Laminin could provide a useful environment for axonal regeneration and functional recovery.

Highlights 
• Clavulanic acid showed anti-allodynic and anti-hyperalgesic effects in animal models with neuropathic pain. 
• GLT1 protein decreased in the spinal cord of neuropathic animals.
• The antinociceptive effects of clavulanic acid in neuropathic rats depend on GLT-1 up-regulation.

Plain Language Summary 
Neuropathic pain is a challenge in clinical practice. The recommended drugs for the pain have many side effects with limited efficacy. Clavulanic Acid (CLAV) is a member of β-lactam antibiotics, such as penicillins and cephalosporins. It has been reported that CLAV has neuroprotective effects in some studies. In this work, chronic constriction injury (CCI) of sciatic nerve induced increased sensitivity to mechanical and cold stimuli. Administration of CLAV immediately after the injury could attenuate pain developed in CCI animals. Based on our results, glutamate transporter (GLT1) content decreased in CCI animals treated with normal saline. This protein is responsible for preventing the toxicity of glutamate to brain cells. The level of GLT1 was high after intraperitoneal administration of CLAV in the lumbar spinal cord of CCI rats. 

Highlights 
● Drug phases may significantly affect different abilities and functions in patients with Parkinson disease.
● Adopting a specific strategy in drug on- and drug off-phases enhances physical functions of these patients.
● It is crucial to choose the best time (drug on- or off-phase) for the examination of changes in different functions.

Plain Language Summary 
Balance impairment and the subsequent increasing fear of falling are two main problems in patients with Parkinson disease that can affect their level of independence in daily activities. The prolonged use of levodopa in these patients results in motor fluctuation, which disturbs various physical functions. Therapists should evaluate people with Parkinson disease in several aspects. First, the level of the disease severity and its impact on functional abilities should be examined. Second, therapists should be aware of drug responses. In this study, the effects of motor fluctuation in two drug phases (on- and off-phase) and severity of the disease were examined on balance, fear of falling, and independence in activities of daily living. The results showed significant relationships between patients’ physical functions and drug phases and disease severity. Considering these associations can lead to better planning of the assessment timing and the therapeutic strategy concerning the drug phase and the severity of the disease.

Highlights 
● Gene activation is the dominant actor in the interactome of migraine.
● Insulin has been found as the most significant related gene in migraine.
● Migraine could be a metabolism-dependent disorder.

Plain Language Summary
Migraine pain disturbs the patient’s lifestyle. There is a lot of information about migraine, however, its management still needs much research. In this study, the molecular aspects of migraine are evaluated to find its controllable biological factors. Targeting these factors may be useful in migraine treatment. The findings of this study showed that metabolism control, especially insulin regulation, plays a critical role in migraine. 

Highlights 
• Forced swim stress (FSS) induced the reinstatement of morphine seeking in rats.
• Orexin-1 receptor blockade in the intra-ventral tegmental area reduced morphine-induced reinstatement.
• Orexin-1 receptor blockade in the intra-ventral tegmental area reduced FSS-induced reinstatement.

Plain Language Summary 
 We designed this study to investigate effects of intra-VTA (ventral tegmental area) administration of SB334867 as an orexin-1 receptor (OX1R) antagonist on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine. The conditioned place preference (CPP) was induced by injecting morphine and the reinstatement by the administration of effective priming dose of morphine. The extinguished rats received an intra-VTA injection of SB334867 before effective priming dose injection of morphine. In others, the extinguished rats were given intra-VTA administration of SB334867 bilaterally and were subsequently tested for FSS- and morphine priming- induced reinstatement. Our results indicated that intra-VTA administration of SB334867 could inhibit morphine priming - and FSS-induced reinstatement of extinguished morphine seeking in the rats. It seems that OX1R in the VTA may be involved in the reward system and could play an important role in the effect of stress on reinstatement of morphine-seeking behaviors in this area. 

Highlights 
• Gamma-irradiation exposure causes significant endoplasmic reticulum (ER) stress-mediated apoptosis in mice hippocampus.
• WFS1 gene plays a part in inducing ER stress-mediated dysfunction in the hippocampus.
• Downregulation of nectin3 also suggests hampered episodic memories and loss of neurogenesis in the CA3 region of the hippocampus.
• Sostdc1 gene, which is predominantly found in the CA2 region of the hippocampus, is also reported to play a major role in the Wnt receptor signaling pathway. 
• Upregulation of ERK ½ protein expression post 10-Gy exposure of gamma radiation suggests ERK pathway-mediated cell death, which might be due to phosphorylation of pro-apoptotic signal.

Plain Language Summary 
Myelination is essential for normal brain functions. The significance of various radiation-induced brain disorders has been more apparent recently because of the pathology of numerous disorders of the brain in people exposed to various kind of ionizing radiation directly or indirectly. Furthermore, patients who have schizophrenia show a decreased density of glial cells and memory loss. The endoplasmic reticulum stress response is mediated by chaperone proteins and cause an imbalance in brain homeostasis. This study aims to understand the influence of Gamma-irradiation on mouse brain and study how molecular markers can be targeted for the early identification of radiation-induced brain disorders.

Highlights 
● Dextromethorphan significantly increased depression-like behavior in male rats.
● Cognitive functions were significantly impaired in both male and female rats. 
● Dextromethorphan did not cause morphological changes in brain histology. 

Plain Language Summary 
The recreational use of Dextromethorphan (DM), a major constituent of cough-syrups is increasing globally. Also, DM is currently under investigation to be used clinically for pain management. Little is known about the impact of DM abuse on behavioral patterns such as memory and depression. We examined DM effects on behaviors using rat models and their dependency on gender. Our result demonstrates that DM impairs memory functions of the brain in both male and female rats without morphological changes in the brain. Also, DM produced significant depression in male rats. Also, we report that DM impairs cognitive behaviors in both genders. Altogether, given the differential increase in substance abuse among males and rising global reports of depression-motivated suicides, the depressive effects of DM should be considered and investigated. 

Highlights 
● New possible drug targets (genes) are introduced for different types of pain.

Plain Language Summary 
Different types of pain as distressing experiences usually are associated with tissue injuries or damages. Several painkillers are introduced that each is characterized by beneficial or aversive effects. In this study, new drug targets are investigated to examine new painkillers. Among many candidates, six genes are determined, which may be suitable drug targets.