The effect of vitamin D supplementation on tobacco-related disorders in individuals with a tobacco use disorder: a randomized clinical trial.

Vitamin D deficiency in cigarette smokers (CS) might associate with several complications, including metabolic deficits, depression and anxiety. This study evaluated the effects of vitamin D on mental health symptoms, nicotine misuse, and biomarkers of metabolic diseases in individuals with a tobacco use disorder. A randomized, double-blind, placebo-controlled trial was conducted with 60 CS subjects receiving either 50,000 IU vitamin D supplements (n = 30) or placebo (n = 30) every 2 weeks for 24-weeks. Nicotine misuse, mental health scale, and metabolic parameters were measured before and after the intervention in the CS subjects. Compared with the placebo-group, after the 24-weeks intervention, serum 25 (OH) vitamin D levels increased in the intervention group (ß 2.96; 95% CI, 0.91, 5.01; P = 0.006). In addition, vitamin D supplementation significantly improved Beck Depression Inventory (BDI) (ß -2.06; 95% CI, -3.84, -0.28; P = 0.02). In addition, vitamin D administration significantly decreased fasting plasma glucose (FPG) (ß -4.56; 95% CI, -8.94, -0.19; P = 0.04), insulin (ß -0.50; 95% CI, -0.88, -0.13; P = 0.009), and homeostasis model of assessment-estimated insulin resistance (HOMA-IR) levels (ß -0.21; 95% CI, -0.33, -0.08; P = 0.001). Furthermore, vitamin D resulted in a significant elevation in total antioxidant capacity (TAC) (ß 81.20; 95% CI, 18.30, 144.11; P = 0.01), and plasma glutathione (GSH) levels (ß 73.05; 95% CI, 18.56, 127.54; P = 0.01), compared with the placebo-group. Administration of vitamin D for 24-weeks to CS subjects had beneficial effects on symptoms of depression and several metabolic biomarkers. While this preliminary study suggests that vitamin D might have beneficial effects, its clinical efficacy in individuals with a tobacco use disorder should be further validated in future clinical trials.

Vitamin D supplementation attenuates the behavioral scores of neuropathic pain in rats.

Objective(s): Neuropathic pain due to lesion or dysfunction of the peripheral or central nervous system is often refractory to the conventional analgesics. Currently, there is no proven treatment to prevent or cure neuropathic pain. A recent surge of new data suggests the potential effects of vitamin D in the medical community. This study was designed to determine whether acute or chronic vitamin D administration was effective in alleviating symptoms of neuropathic pain in a rat model of neuropathic pain. Materials and Methods: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in the rats that resulted in thermal hyperalgesia, mechanical, and cold allodynia. Results: Acute vitamin D injections (250, 500, and 1000 unit/kg i.p.) on the 7th, 14th, and 21st postoperative days could not attenuate mechanical and cold allodynia as well as heat hyperalgesia compared to CCI group. But when vitamin D (1000 unit/kg i.p.) administration was started on the first day after surgery and given daily until the 21st day, cold allodynia and heat hyperalgesia considerably were attenuated. However, no differences in paw withdrawal thresholds were observed. Conclusion: These results indicate that chronic vitamin D administrations can attenuate the behavioral scores of neuropathic pain in rats.

Anticonvulsant effects of thiamine on pentylenetetrazole-induced seizure in mice.

OBJECTIVES: Thiamine serves as a cofactor for several enzymes involved in brain function and neurotransmitters biosynthesis. Thiamine-dependent enzymes are important for oxidant stress defenses. Several studies have reported that thiamine deficiency in the central nervous system reduces seizure threshold. The present study was designed to investigate the effect of acute and chronic administration of thiamine alone and in combination with sub-effective dose of diazepam on pentylenetetrazole (PTZ)-induced tonic-clonic seizures in mice. METHODS: Animals were randomly divided into control and experimental groups. In experimental groups, thiamine (50, 100, and 200 mg/kg i.p.) was administered acutely or chronically (once a day, for 14 days). Slow intravenous infusion of PTZ (5 mg/ml) by infusion pump with a constant rate (0.3 ml/min) was used to induce clonic and tonic seizures. RESULTS: Acute injection of thiamine (50, 100, and 200 mg/kg i.p.) did not increase seizure threshold significantly, but chronic treatment with thiamine (200 mg/kg i.p.) increases the clonic and tonic seizure threshold. Moreover, the combination of sub-effective dose of thiamine (100 mg/kg) and diazepam (0.1 mg/kg) significantly increased seizure threshold and enhanced the anticonvulsant effect of diazepam at ineffective dose (0.1 mg/kg). DISCUSSION: Our results suggest that thiamine can be considered as a potential add-on treatment in deficient and non-deficient thiamine epileptic patients. Co-administration of this vitamin with classic antiepileptics to decrease the required doses of regular drugs may be recommended. Nevertheless, more well-designed studies may be executed to provide further accurate information.

Reversible inactivation of the lateral hypothalamus reversed high reward choices in cost-benefit decision-making in rats.

The Lateral hypothalamus (LH) is an important component of the networks underlying the control of feeding and other motivated behaviors. Cost-benefit decision-making is mediated largely by the prefrontal cortex (PFC) which strongly innervates the LH. Therefore, in the current study, we conducted a series of experiments to elucidate the role of the perifornical area of the lateral hypothalamus (PeF-LH) in effort and/or delay-based decision-making. We trained different groups of rats in a delay-based and/or an effort-based form of cost-benefit T-maze decision- making task in which they could either choose to pay the cost to obtain a high reward in one arm or could obtain a low reward in the other arm with no cost. During test days, the rats received local injections of either vehicle or lidocaine4% (0.5 µl/side), in the PeF-LH. In an effort-based decision task, PeF-LH inactivation led to decrease in high reward choice. Similarly, in a delay-based decision task animals' preference changed to a low but immediately available reward. This was not caused by a spatial memory or motor deficit. PeF-LH inactivation modified decision behavior. The results imply that PeF-LH is important for allowing the animal to pay a cost to acquire greater rewards.

Experiencing neonatal maternal separation increased pain sensitivity in adult male mice: Involvement of oxytocinergic system.

Early-life stress adversely affects the development of the brain, and alters a variety of behaviors such as pain in later life. In present study, we investigated how early-life stress (maternal separation or MS) can affect the nociceptive response later in life. We particularly focused on the role of oxytocin (OT) in regulating nociception in previously exposed (MS during early postnatal development) mice that were subjected to acute stress (restraint stress or RS). Further, we evaluated whether such modulation of pain sensation in MS mice are regulated by shared mechanisms of the OTergic and opioidergic systems. To do this, we assessed the underlying systems mediating the nociceptive response by administrating different antagonists (for both opioid and OTergic systems) under the different experimental conditions (control vs MS, and control plus RS vs MS plus RS). Our results showed that MS increased pain sensitivity in both tail-flick and hot-plate tests while after administration of OT (1µg/µl/mouse, i.c.v) pain threshold was increased. Atosiban, an OT antagonist (10µg/µl/mouse, i.c.v) abolished the effects of OT. While acute RS increased the pain threshold in control (and not MS) mice, treating MS mice with OT normalized the pain response to RS. This latter effect was reversed by atosiban and/or naltrexone, an opioid antagonist (0.5µg/µl/mouse, i.c.v) suggesting that OT enhances the effect of endogenous opioids. OTergic system is involved in mediating the nociception under acute stress in mice subjected to early-life stress and OTergic and opioidergic systems interact to modulate pain sensitivity in MS mice.

Quetiapine reverses paclitaxel-induced neuropathic pain in mice: Role of alpha2- adrenergic receptors.

OBJECTIVES: Paclitaxel-induced peripheral neuropathy is a common adverse effect of cancer chemo -therapy. This neuropathy has a profound impact on quality of life and patient's survival. Preventing and treating paclitaxel-induced peripheral neuropathy is a major concern. First- and second-generation antipsychotics have shown analgesic effects both in humans and animals. Quetiapine is a novel atypical antipsychotic with low propensity to induce extrapyramidal or hyperprolactinemia side effects. The present study was designed to investigate the effects of quetiapine on the development and expression of neuropathic pain induced by paclitaxel in mice and the role of α2-adrenoceptors on its antinociception. MATERIALS AND METHODS: Paclitaxel (2 mg/kg IP) was injected for five consecutive days which resulted in thermal hyperalgesia and mechanical and cold allodynia. RESULTS: Early administration of quetiapine from the 1st day until the 5th day (5, 10, and 15 mg/kg PO) did not affect thermal, mechanical, and cold stimuli and could not prevent the development of neuropathic pain. In contrast, when quetiapine (10 and 15 mg/kg PO) administration was started on the 6th day after the first paclitaxel injections, once the model had been established, and given daily until the 10th day, heat hyperalgesia and mechanical and cold allodynia were significantly attenuated. Also, the effect of quetiapine on heat hyperalgesia was reversed by pretreatment with yohimbine, as an alpha-2 adrenergic receptor antagonist. CONCLUSION: These results indicate that quetiapine, when administered after nerve injury can reverse the expression of neuropathic pain. Also, we conclude that α2-adrenoceptors participate in the antinociceptive effects of quetiapine.

Antinociceptive effects of maprotiline in a rat model of peripheral neuropathic pain: possible involvement of opioid system.

OBJECTIVES: Neuropathic pain remains a clinical problem and is poorly relieved by conventional analgesics. This study was designed to determine whether maprotiline administration was effective in alleviating symptoms of neuropathic pain and whether the antinociceptive effect of maprotiline mediated through the opioid system. MATERIALS AND METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats, which resulted in thermal hyperalgesia, and mechanical and cold allodynia. Maprotiline (10, 20 and 40 mg/kg, IP) was administered on the 7(th) and 14(th) days after surgery. To study the role of the opioid system in the antinociceptive effects of maprotiline, maprotiline (20 mg/kg, IP) was administered in combination with naloxone (1 mg/kg, SC) on the 7(th) post-surgery day. Behavioral tests were done at 45 min after drug injections on the 7(th) and 14(th) days after surgery. RESULTS: Systemic administration of maprotiline blocked heat hyperalgesia, cold allodynia and reduced mechanical allodynia. Also antihyperalgesic effect of maprotiline was reversed by pretreatment with naloxone. CONCLUSION: Our results suggest that maprotiline can be considered a potential therapeutic for the treatment of neuropathic pain, and the opioid system may be involved in the antihyperalgesic effects of maprotiline.

The anti-inflammatory effects of venlafaxine in the rat model of carrageenan-induced paw edema.

OBJECTIVES: Recently anti-inflammatory effects of antidepressants have been demonstrated. Venlafaxine belongs to newer antidepressants with serotonin norepinephrine reuptake inhibition property. The pain alleviating properties of venlafaxine in different pain models such as neurogenic pain, diabetic neuropathy, and fibromyalgia have been demonstrated. Anti-inflammatory effects of venlafaxine and also its underlying mechanisms remain unclear. The present study was designed to evaluate the anti-inflammatory effects of venlafaxine and determine possible underlying mechanisms. MATERIALS AND METHODS: We examined the anti-inflammatory effects of intraperitoneal (IP) and intracerebroventricular (ICV) administration of venlafaxine in the rat model of carrageenan-induced paw edema. RESULTS: Our results showed that both IP (50 and 100 mg/kg) and ICV (50 and 100 µg/rat) injection of venlafaxine inhibited carrageenan-induced paw edema. Also IP and ICV administration of venlafaxine significantly decreased myeloperoxidase (MPO) activity and interleukin (IL)-1ß and tumor necrosis factor (TNF)-α production. Finally, we tried to reverse the anti-inflammatory effect of venlafaxine by yohimbine (5 mg/kg, IP), an alpha2-adrenergic antagonist. Our results showed that applied antagonist failed to change the anti-inflammatory effect of venlafaxine. CONCLUSION: These results demonstrated that venlafaxine has potent anti-inflammatory effect which is related to the peripheral and central effects of this drug. Also we have shown that anti-inflammatory effect of venlafaxine is mediated mostly through the inhibition of IL-1ß and TNF-α production and decreases MPO activity in the site of inflammation.

Venlafaxine Attenuates Heat Hyperalgesia Independent of Adenosine or Opioid System in a Rat Model of Peripheral Neuropathy.

Primarily opioidergic and adenosine mechanisms are considered to be involved in the antinociceptive effects of antidepressants. This study was designed to determine the efficacy of acute venlafaxine administration in alleviating symptoms of neuropathic pain and the role of endogenous adenosine and opioid systems in this effect of venlafaxine. We have evaluated the effect of caffeine, a non-selective adenosine A1 and A2 receptor antagonist and naloxone as an antagonist of opioid receptors on the antinociceptive effects of venlafaxine. Chronic constriction injury of the sciatic nerve resulted in thermal hyperalgesia, mechanical and cold allodynia in the rats. Animals were received on the 7(th) day after surgery, when the model had been fully established, venlafaxine (20 and 40 mg/Kg i.p.), or venlafaxine (40 mg/Kg) in combination with caffeine (5 mg/Kg i.p.) or naloxone (1 mg/Kg s.c.). Rats were tested for thermal reaction latencies, mechanical and cold allodynia 45 min after drug injection. Acute venlafaxine (40 mg/Kg i.p.) administration consistently decreased the thermal hyperalgesia and this effect was not blocked by concomitant caffeine or naloxone administration. There was no effect by either drug or the drug combination on the tactile and cold allodynia. The results of this study indicate that venlafaxine (40 mg/Kg i.p.) is effective in alleviating thermal hyperalgesia and this effect is independent through manipulation of adenosine or opioid system. This observation demonstrates that venlafaxine, which is a mixed inhibitor of norepinephrine and serotonin reuptake, differs from the other antidepressants in the mechanism of its antinociception action.

Antinociceptive effects of venlafaxine in a rat model of peripheral neuropathy: role of alpha2-adrenergic receptors.

This study was designed to determine whether acute or chronic venlafaxine administration was effective in alleviating symptoms of neuropathic pain in a rat model of neuropathic pain, and whether the effect of venlafaxine involved manipulation of α2-adrenoceptors,by determining the effect of yohimbine, a α2-adrenoceptor antagonist on its actions. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in the rats that resulted in stimulus-evoked thermal hyperalgesia, tactile mechanical and cold allodynia. Acute venlafaxine injections (20 and 40 mg/kg i.p.) on the 7th, 14th and 21st postoperative days could not reduce tactile and cold hypersensitivity significantly compared to CCI group. But in these groups venlafaxine (40 mg/kg i.p.) blocked heat hyperalgesia. When venlafaxine (10 and 20mg/kg i.p.) administration was started on the first day after CCI and given daily until the 14th day, tactile hypersensitivity and heat hyperalgesia considerably were attenuated. But when venlafaxine (20mg/kg i.p.) treatment was initiated on the 10th day after CCI, once the model had been fully established, and given daily for 11 days, no differences in withdrawal thresholds were observed compared with CCI group however heat hyperalgesia significantly has been blocked. Also the effect of venlafaxine on heat hyperalgesia was reversed by pretreatment with yohimbine at all-time intervals. These results indicate that venlafaxine, when administered immediately after nerve injury, and for a sufficient period of time, can prevent the development and expression of neuropathic pain. Also we conclude that α2-adrenoceptors participate in the antinociceptive effects of venlafaxine.

Gabapentin enhances anti-nociceptive effects of morphine on heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain.

OBJECTIVES: Neuropathic pain is caused by lesions or diseases affecting the somatosensory system and often responds poorly to typical medications. In this study, we evaluated anti-nociceptive effects of morphine, gabapentin and their combination on heat hyperalgesia, cold and mechanical allodynia in chronic constriction injury (CCI) model of neuropathic pain in rats. MATERIALS AND METHODS: Morphine (2, 4 and 8 mg/kg) and gabapentin (5, 10 and 20 mg/kg) were administered either alone or in combination (morphine 2 mg/kg and gabapentin 5 mg/kg). RESULTS: Our results showed that morphine and gabapentin alone produce anti-nociceptive effects at higher doses (morphine 4 and 8 mg/kg and gabapentin 10 and 20 mg/kg) whereas their combination resulted in better analgesia at lower doses as compared to other treatment groups (morphine 2 mg/kg or gabapentin 5 mg/kg). CONCLUSION: These findings suggest that gabapentin potentiates the analgesic effects of morphine in the chronic constriction injury (CCI) model of neuropathic pain and combination of these drugs may be considered as a beneficial treatment for neuropathic pain.

The effect of progesterone on expression and development of neuropathic pain in a rat model of peripheral neuropathy.

Neuropathic pain results from lesions or diseases affecting the somatosensory system. The management of patients with chronic neuropathic pain remains a challenge. Several studies support the crucial role of neuroactive steroids in the modulation of pain. The present study was designed to investigate the effect of systemic administration of progesterone on expression and development of hyperalgesia and allodynia scores in chronic constriction injury model of neuropathic pain in rat. Progesterone at doses of 5, 10 and 15 mg/kg and its vehicle were injected intraperitoneally on days 1-13 after the surgery to study the effect of progesterone on development of neuropathic pain and only on 14th day post-surgery in order to assess its effect on expression of neuropathic pain.The chronic administration of progesterone significantly reduced the behavioral scores of cold- and mechano-allodynia and heat hyperalgesia but single dose of progesterone did not have any effect on behavioral scores of neuropathic pain. Our data indicate that the early chronic administration of progesterone prevents the development of neuropathic pain but its acute injection does not change the expression of neuropathic pain. These results suggest that progesterone could be considered as a new approach for management of neuropathic pain.

Exercise in the metabolic syndrome.

The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism.

Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system.

Lithium is a major drug for bipolar disorder and mania. Recently, many studies have shown the neuroprotective effect of lithium in different models of neurodegenerative diseases. The present study was carried out to examine the effect of lithium in a rat model of neuropathic pain induced by partial sciatic nerve ligation and the possible role of opioid system in this effect. To do so, animals received acute injection of saline, lithium (5, 10 and 15 mg/kg,) and naloxone (1 mg/kg) or the combination of naloxone (1 mg/kg) with lithium (10 mg/kg) intraperitoneally on the testing days. Thermal hyperalgesia, mechanical and cold allodynia were measured on the days 3, 5, 7, 10 and 14 after surgery. Lithium decreased thermal hyperalgesia scores with dose of 5, 10 and 15 mg/kg and cold and mechanical allodynia scores with dose of 10 and 15 mg/kg, significantly. The opioid antagonist naloxone prevented the effect of lithium on thermal hyperalgesia and mechanical allodynia while it did not show any effect on the acetone-induced cold allodynia. Our results suggest that lithium can be considered as a therapeutic potential for the treatment of some aspects of neuropathic pain and that the opioid system may be involved in the lithium-induced attenuation of thermal hyperalgesia and mechanical allodynia.

Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain.

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and treatment of neuropathic pain remains a challenge. The purpose of the present study was to examine the effect of ethosuximide, an anti-epileptic and relatively selective T-type calcium blocker and morphine, a prototypical opioid in the behavioral responses following the chronic constriction injury (CCI) model of neuropathic pain. Experiments were performed on eight groups (n=8) of male Sprague-Dawley rats (230-280 g). The animals were injected with saline, ethosuximide (100, 200, 300 mg/kg), morphine (4 mg/kg), and a combination of morphine (4 mg/kg) plus ethosuximide (100mg/kg, i.p.). The cold-and mechano-allodynia and thermal hyperalgesia were measured prior to surgery (the day 0) and 3, 5, 7, 14 and 21 days post surgery. Ethosuximide and morphine significantly decreased cold and mechano allodynia and thermal hyperalgesia. However, the co-administration of both drugs seems to be more effective than the ethosuximide or morphine alone on cold and mechano allodynia and thermal hyperalgesia .Our results suggest that ethosuximide block tactile and thermal hypersensitivity after the CCI model, also, ethosuximide potentiates the analgesic effects of morphine in neuropathic pain conditions and behavioral responses.

Causes of trauma in pregnant women referred to shabih-khani maternity hospital in kashan.

BACKGROUND: Trauma occurs in 7% of pregnancies and is a major cause of morbidity and mortality in the mother and fetus. OBJECTIVES: The present study was conducted in Kashan in 2009-2010 to evaluate the causes of trauma in pregnancy. PATIENTS AND METHODS: This descriptive study analyzed data from 32 pregnant women with trauma who were referred to the maternity hospital from 2009 to 2010. Data included age, gestational age, mother's occupation, cause of trauma, maternal-fetal complications, gravidity, and parity. The diagnosis of maternal and fetal complications was based on clinical examinations by a gynecologist and results of blood tests, urine analysis tests, and sonography. Data were analyzed as frequency distributions. RESULTS: the causes of trauma included falling (9 cases (28.1%)), abdominal trauma (8 cases ( 25%)), spousal feud (3 cases (9.4%)), motorcycle accident (2 cases (6.25%)), car accident (2 cases (6.25%)), falling from a motorcycle (2 cases (6.25%)), falling or fainting resulting in head trauma (1 case (3.1%)), pain from crossing over a bump in the car (1 cases (3.1%)), and unspecified causes (4 cases (12.55%)). The causes of traumas occurred between 5 and 40 weeks of gestation. In 17.2% of the cases, trauma occurred prior to 20 weeks of gestation. However, there was no significant relationship between the cause of trauma and maternal age or gestational age. Vaginal bleeding and retroplacental clots were reported in 2 (6.25%) cases and 1 (3.1%) case, respectively. CONCLUSIONS: Nearly half of the women presenting with trauma had experienced spousal feud or domestic violence; therefore, it is necessary to recognize spousal abuse and provide adequate support to traumatized pregnant women.

The duration of nicotine-induced attentional enhancement in the five-choice serial reaction time task: lack of long-lasting cognitive improvement.

There is evidence that nicotine-induced enhancements of cognition may persist for days or even weeks after the drug has been cleared, but the generality of this effect is not known. The objective was to determine the time course of nicotine's effects on performance of the five-choice serial reaction time task (5-CSRTT) when the drug is given acutely and chronically. In the 5-CSRTT, rats were trained to obtain food reinforcers by detecting light stimuli and then received daily postsession injections of nicotine (0.4 mg/kg) or saline. The dose-related effects of presession injections of various acutely administered doses of nicotine were then determined at three different times after injection, whereas controls received saline only (n=12). Finally, performance of all animals was tracked for 8 days after the end of all dosing with nicotine. Daily postsession administration of nicotine for 16 days had no effect on performance the next day. Acute presession administration of nicotine positively influenced several response indices, confirming previous results. Daily administration of nicotine over a total period of 50 days weakened the effect of nicotine on response accuracy, perhaps because of an elevation of the baseline, but had no effect on other measures of performance. The effects of presession nicotine were very clear in tests carried out at 10 or 25 min after injection, and were less consistent at 75 min. There were no persisting differences between the performance of rats as a function of previous histories of exposure to nicotine everyday for 50 days, either under baseline conditions or when task demands were increased. The data suggest that there are no effects of nicotine on attentional performance in the 5-CSRTT that persist after exposure to the drug has ended.