Noradrenergic Pathways Research Articles

Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain.

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.

Spinal cord stimulation modulates supraspinal centers of the descending antinociceptive system in rats with unilateral spinal nerve injury.

BackgroundThe descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine β-hydroxylase (DβH)] in the spinal dorsal horn.ResultsIntrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DβH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DβH in the spinal dorsal horn.ConclusionsThe serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.

Clinical utility of guanfacine extended release in the treatment of ADHD in children and adolescents.

Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric illness in children and adolescents. Several stimulant medications, such as methylphenidate and amphetamine derivatives, are available to treat ADHD in pediatric patients. Nonstimulant medications are more preferred by some parents, other caregivers, and patients because they lack the abuse potential of stimulant medications. In the US, one available nonstimulant option is guanfacine extended release (XR). As a selective α2A adrenergic receptor, guanfacine acts on the central noradrenergic pathways and cortical noradrenergic targets to improve working memory and attention. The XR formulation of guanfacine, compared with the immediate-release formulation, is more effective for the long-term management of ADHD and is associated with fewer adverse effects. Available data also indicate that guanfacine XR is superior to atomoxetine and is as effective as the nonselective α2 adrenergic receptor agonist, clonidine XR. The most common adverse effects associated with guanfacine XR are somnolence, fatigue, bradycardia, and hypotension. Somnolence is the most often cited reason for discontinuation. Guanfacine XR is also labeled for use as an adjuvant to stimulant treatment for ADHD. A similar profile of adverse effects as reported with monotherapy is reported when guanfacine XR is “added on” to stimulant therapy with somnolence as the most commonly reported adverse event. This review discusses the clinical efficacy and patient preference of guanfacine XR based on available published data on the safety, relative effectiveness, and tolerance of this medication to treat ADHD.

Distinct pathways for norepinephrine- and opioid-triggered antinociception from the amygdala.

The amygdala has an important role in pain and pain modulation. We showed previously in animal studies that α2 -adrenoreceptor activation in the central nucleus of the amygdala (CeA) mediates hypoalgesia produced by restraint stress, and that direct application of an α2 -agonist in this region produces analgesia. In the present animal experiments, we investigated the pathways through which α2 -sensitive systems in the CeA produce behavioural analgesia. The CeA has dense connections to a descending pain modulatory network, centred in the midbrain periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM), which is implicated in various forms of stress-related hypoalgesia and which mediates the antinociceptive effect of morphine applied in the basolateral amygdala. We investigated whether this circuit mediates the hypoalgesic effects of α2 -adrenergic agonist administration into the CeA as well as the contribution of endogenous opioids and cannabinoids. We also tested the possibility that activation of α2 -receptors in the CeA produces antinociception by recruitment of noradrenergic pathways projecting to the spinal cord. Hypoalgesia resulting from bilateral application of the α2 -adrenergic agonist clonidine in the CeA was not reversed by chemical inactivation of the RVM or by systemic injections of naloxone (μ-opioid antagonist) or rimonabant (CB1 antagonist). By contrast, spinal α2 -receptor blockade (intrathecal idazoxan) completely prevented the hypoalgesic effect of clonidine in the CeA, and unmasked a small but significant hyperalgesia. In rats, adrenergic actions in the CeA mediating hypoalgesia require spinal adrenergic neurotransmission but not the PAG-RVM pain modulatory network, or opiate or cannabinoid systems.

Pontine A7 and A5 noradrenergic neuronal groups mediate long‐term facilitation of hypoglossal motor activity induced by episodic airway obstruction

In obstructive sleep apnea (OSA), decreased noradrenergic activation of genioglossus muscle during REM sleep results in repetitive upper airway occlusion, a neurodegenerative process that aggravates with age. Episodic end‐expiratory airway occlusion simulating OSA in anesthetized rats has been shown to induce a vagally‐mediated and noradrenergic‐dependent long‐term facilitation (LTF) of genioglossus muscle activity (Tadjalli et al, J Neurosci, 2010). To identify the brainstem noradrenergic pathways mediating this effect, we applied episodic end‐expiratory tracheal occlusion (10 sec x 12 episodes) in 6 urethane‐anesthetized rats to induce genioglossus LTF and reveal corresponding cFos expressions in the affected brainstem pathways, in comparison to 3 control rats in which tracheal occlusion was not performed. We found that the percentage of cFos immunopositive neurons was significantly higher in A7 and A5 noradrenergic groups in experimental rats than that in control rats (32.9±5.3% vs. 0.7±0.7% for A7 and 34.8±7.2% vs. 5.4±5.4% for A5, P<0.01), while the expression of cFos was not significantly changed in A6 (locus coeruleus) and other medullary noradrenergic groups. In the second group of experiments, we examined the LTF induction after inhibition of A7 or A5 by microinjection of α2‐adrenoreceptor agonist clonidine. We found that after inhibition of either A7 (n=8) or A5 (n=4), the induction of genioglossus LTF was blocked. These studies demonstrated that the pontine noradrenergic neuronal groups A7 and A5 played a key role in the vagally‐mediated genioglossus LTF which, once fully developed, may help to defend against recurrent OSA. (Supported by HL093225)

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models. CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine β-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation. The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine β-hydroxylase-saporin. Dopamine β-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine β-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Chronic Pain, Affective Spectrum Disorders and Treatment with Antidepressants

Affective spectrum disorders include mood and anxiety disorders, while term functional somatic syndrome describes disorders with chronic pain as dominant symptom, without patognomonic tissue damage, such as fibromialgia, irritable bowel syndrome, headache. Hypothesis of central neuropathic pain explains possibility of descendent inhibitor mechanism of pain deficiency, including noradrenergic and serotonergic projections, or possibility that central suprasegmental sensitisation within the nociceptive pathway, triggered by emotional stressors can caused pain symptoms in both. Serotonergic and noradrenergic pathways and voltage sensitive channels are include in that mechanism. Modern psychopharmacology can improve treatment fot both. Therapeutic action of SSRI's, SNRI's and alfa 2 delta ligands succesfully can increase neurotransmission in malfunctioning CNS pathways and reduce symptoms. Our clinical trial was conducted during 2013/2014. with 57 patient 32 female, 25 male, diagnosed as tension headache, without brain damage or disease, with depressive symptoms. Aim of the trial was to explore usefulness of antidepressant treatment for one of the common functional somatic syndromes as headache. Diagnostic instruments used were HAM-D 17, CGI, personal diary with registered frequency of headache attakcs were sour documents also. Patient treated with fluoxetine 20 mg daily, during 6 month and instructed to use personal diaries to. Diagnostic instruments were used at base line and after the treatment, when diaries reviewed also. Results showed that iimprovement in scores at HAM-D and CGI's scales was remarkable and frequency of headache attacks lowered. Conclusion was that antidepressants can bee effective in an typical functional somatic syndrome and can improve therapeutic approaches for remarkable large group of patients.

Depression and Parkinson's Disease: Role of the Locus Coeruleus

Depression affects around 35% of patients with Parkinson's disease. There are some overlapping symptoms between both illnesses, and some evidence seems to suggest that there may exist a common underlying etiological factor, namely changes in cortico-striatal-thalamo-cortical circuits and in the locus coeruleus . To review the potential role of locus coeruleus alterations in patients with Depression and comorbid Parkinson's disease. A literature review was performed through MEDLINE and PsycINFO using the terms 'Depression”, 'Parkinson's disease”, 'neurobiology”, ' locus coeruleus ”, ' substantia nigra ”, 'neuromelanin”, 'neuroimaging”, 'magnetic resonance imaging”, 'Positron emission tomography”. All articles found were selected according to their adequacy to the subject in question. Noradrenergic pathways are important in the pathophysiology of Depression in Parkinson's disease. Magnetic Resonance Imaging (MRI) studies, with neuromelanin measurements have shown there is neuronal loss not only in the substantia nigra but also in the locus coeruleus . These changes in the locus coeruleus are different when patients with Parkinson's disease are compared with schizophrenic and normal controls. Patients with comorbid Depression and Parkinson's disease have a reduced uptake of [11C]RTI-32 in the locus coeruleus , with an inverse relationship between those changes and symptom severity. There is a higher prevalence of histopathologic changes (neuronal loss 7 times higher, gliosis) in the locus coeruleus of depressed vs. non-depressed patients with Parkinson's disease. These findings seem to substantiate the potential role of noradrenergic pathways in the aetiology of Depression in Parkinson's disease.

Involvement of Descending Serotonergic and Noradrenergic Systems and their Spinal Receptor Subtypes in the Antinociceptive Effect of Dipyrone.

The antinociceptive effect of dipyrone is partly due to its action upon pain-related central nervous system structures. Despite intensive research, the precise mechanisms mediating its analgesic effects remain unclear. Here, we aimed to determine whether neurotoxic destruction of descending inhibitory pathways affect dipyrone-induced antinociception and whether various spinal serotonergic and adrenergic receptors are involved in this antinociception. The nociceptive response was assessed by the tail-flick test. Mice injected with dipyrone (150, 300, 600 mg/kg, i.p.) elicited dose-related antinociception. The neurotoxins 5,7-dihydroxytryptamine (50 μg/mouse) and 6-hydroxydopamine (20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. 3 days after neurotoxin injections, a significant reduction in the antinociceptive effect of dipyrone was observed. Intrathecal administration of monoaminergic antagonists (10 μg/mouse), the 5-HT2a antagonist ketanserin, the 5-HT3 antagonist ondansetron, the 5-HT7 antagonist SB-258719, α1-adrenoceptor antagonist prazosin, α2-adrenoceptor antagonist yohimbine, and the β-adrenoceptor antagonist propranolol also attenuated dipyrone antinociception. We propose that descending serotonergic and noradrenergic pathways play pivotal role in dipyrone-induced antinociception and spinal 5-HT2a, 5-HT3, and 5-HT7-serotonergic and α1, α2, and β-adrenergic receptors mediate this effect.

The role of the dorsal noradrenergic pathway of the brain (locus coeruleus) in the regulation of liver cytochrome P450 activity

Our previous study conducted after intracerebroventricular DSP-4 injection showed an important stimulating role of a brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 (CYP) expression. The aim of the present research was to study involvement of the dorsal noradrenergic pathway of the brain (originating from the locus coeruleus) in the expression of liver cytochrome P450. The experiment was carried out on male Wistar rats. Local injection of 6-hydroxydopamine to the locus coeruleus selectively decreased noradrenaline level in the brain (e.g. in the hypothalamus). The serum concentration of the growth hormone rose, while that of the thyroid hormones or corticosterone remained unchanged. A comparative study into cytochrome P450 isoform activity revealed significant increases in the activity of liver CYP2C11 and CYP3A after administration of 6-hydroxydopamine. The observed increase in the activity of CYP2C11 positively correlated with that in CYP protein level, while the enhanced activity of CYP3A was not accompanied with a simultaneous change in the enzyme protein. A 5-day-injection of noradrenaline into the lateral ventricles produced opposite effects on the CYP isoforms. It is concluded that damage to or activation of the dorsal noradrenergic innervation of the periventricular nucleus of the hypothalamus containing somatostatin (a growth hormone release-inhibiting factor) may be responsible for the changes observed in the activity of isoforms CYP2C11 and CYP3A that are regulated by the growth hormone. The obtained results indicate that the dorsal noradrenergic pathway plays an inhibitory (but not a crucial) role in the neuroendocrine regulation of cytochrome P450.

Supraspinal Projection of Serotonergic and Noradrenergic Pathways Modulates Nociceptive Transmission in the Lower Urinary Tract of Rats

To investigate the effect of descending serotonergic and noradrenergic pathways on nociception in the lower urinary tract (LUT). Female Sprague-Dawley rats were used. Following intraperitoneal administration of Vehicle or Milnacipran (30 mg/kg), which is one of serotonin-noradrenaline reuptake inhibitors (SNRI), 0.1% AA was infused into the bladder in normal (n = 4, each) and spinal cord injury (SCI) (n = 4, each) rats for 2 h on consciousness, and c-Fos, 5-HT and DβH were stained using immunohistochemistry at the L6 spinal cord as spinal areas associated with LUT. In SCI rats, 5-HT or DβH-positive fibers were not observed at the L6 spinal cord, while there were many 5-HT and DβH-positive fibers in normal rats. The total number of c-Fos-positive cells was significantly increased in SCI rats compared to Normal rats (209.4 ± 7.1 in Normal, 336.4 ± 28.9 in SCI, P < 0.05), which indicated that interruption of supraspinal modulation enhances nocieptive transmission in the LUT. Regarding the effect of Milnacipran administration, the number of c-Fos-positive cells was significantly decreased at all region of the L6 spinal cord in normal rats (P < 0.05), while this reduction was not observed in SCI rats. This result demonstrated that administration of SNRI attenuates nocieptive transmission in the LUT, indicating that 5-HT and noradrenaline work as mediators of endogenous analgesic mechanisms through the supraspinal descending pain pathways. Supraspinal projections of descending serotonergic and noradrenergic pathways to the lower lumbar spinal cord modulate nocieptive transmission in the LUT. Administration of SNRI attenuates nocieptive transmission in the LUT, which could result from enhancement of modulating descending serotonergic and noradrenergic pathways.

Agomelatine beyond borders: current evidences of its efficacy in disorders other than major depression.

Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine’s antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression.

A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation.

Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist guanfacine (3 mg/day) versus placebo (0 mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared with placebo, altered prefrontal activity during a cognitive-control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging, and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.

P92 - Psychiatric disorders and omega-3 fatty acids

Psychiatric disorders, especially mood disorders in children and adolescent are serious problem of all over the world in the field of child and adolescent psychiatry. In the recent years mood disorders occur in the earlier age. The prevalence of major depression (MD) is about 1-2% in preadolescent children and 3-8% in adolescents. When the major depression is not treated there is a big risk of worsening of symptoms, risk of suicide and development of comorbid disorders. The quality of life of the patient and its family is decreasing in the whole view.The molecular basis of major depression is not well known. The main pathomechanism of MD is in noradrenergic, serotonergic and dopaminergic pathway dysregulation, nutition factors, which can influence structure and metabolism of lipids. It was found decreased level of omega 3 fatty aids (FA), increased ratio of omega 6/omega 3 FA in the serum and in erythrocyte membrane.It is supposed that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants and that membrane phospholipids can be repaired by dietary supplementation of fatty acids. Omega-3 fatty acids may also participate in modulation of membrane fluidity, which influences the transmission of neurotransmitters. The membrane fluidity is affected by the ratio of phospholipids to free cholesterol. In addition, activation of the inflammatory response was found in depressive patients through increased production of pro-inflammatory cytokines (IL-1b, IL-6, interferon gamma, TNF-alpha) and eicosanoids (prostaglandin E2) in blood and cerebrospinal fluid. This results in increased lipid peroxidation and degradation of polyunsaturated fatty acids, which may result in increased oxidative stress. Omega-3 fatty acids also stimulate anti-inflammatory cytokines (IL-10) or inhibit the cyclooxygenase, platelet aggregation and formation of eicosanoids. The potential molecular mechanisms will be discussed.

Evaluation of the noradrenergic pathway and alpha-2 and beta-receptors in the modulation of the analgesia induced by transcutaneous electric nerve stimulation of high and low frequencies

Transcutaneous electric nerve stimulation is a noninvasive method used in clinical Physiotherapy to control acute or chronic pain. Different theories have been proposed to explain the mechanism of the analgesic action of transcutaneous electric nerve stimulation, as the participation of central and peripheral neurotransmitters. The aim of this study was to evaluate the involvement of noradrenergic pathway and of the receptors alfa-2 and beta in the modulation of analgesia produced by transcutaneous electric nerve stimulation of high and low frequency in Wistar rats after chronic treatment with propranolol or yohimbine intraperitoneally. Animals weighing 200 to 300 g were divided into 9 groups (n=8), which were obtained nociceptive thresholds through the Tail Flick before and after application of TENS for comparing the change of pain. The administration of yohimbine or propranolol at a dose of 3 mg/kg was effective in antagonizing the analgesia induced by high (150 Hz) and low (10 Hz) frequency transcutaneous electric nerve stimulation according to ANOVA test followed by Duncan post hoc test (p<0.05). Thus, it is suggested the involvement of alpha-2 and beta noradrenergic receptors in the modulation of transcutaneous electric nerve stimulation-induced analgesia.

Noradrenergic Mechanisms Controlling Urethral Smooth and Striated Muscle Function in Urethral Continence Reflex in Rats.

To investigate the role of noradrenergic pathways in the urethral continence reflex during abdominal compression in rats. Under urethane anesthesia, urethral baseline pressure (UBP) and urethral pressure response (UPR) during momentary abdominal compression using a 100 g weight was measured using a transurethral microtransducer-tipped catheter placed at the middle urethra in Sprague-Dawley female rats. Following intravenous (i.v.) application of hexamethonium or α-bungarotoxin to block urethral smooth or striated muscle function, respectively, the effects of terazosin, an α1 -adrenoceptor (AR) antagonist (0.3 mg/kg, i.v.), medetomidine, an α2 -AR agonist (0.3 mg/kg, i.v.) or nisoxetine, a norepinephrine reuptake inhibitor (1 mg/kg, i.v.) followed by terazosin on UBP and UPR were examined. After hexamethonium pretreatment, terazosin did not alter UBP or UPR, whereas medetomidine significantly decreased UPR by 28% without UBP changes. Nisoxetine significantly increased UPR by 64%, which was eliminated by terazosin, but UBP was not altered by nisoxetine. After α-bungarotoxin pretreatment, UBP and UPR were significantly decreased by terazosin or medetomidine. Nisoxetine induced significant increases in UBP and UPR by 16 and 15%, respectively, which were antagonized by terazosin. These results suggest that: the baseline activity and reflex contraction of urethral smooth muscle are decreased by α1 -AR inhibition or α2 -AR stimulation; the reflex contraction of urethral striated muscle is decreased by α2 -AR stimulation, but not by α1 -AR inhibition; and nisoxetine increases baseline and reflex activity of smooth muscle in addition to striated muscle reflex activity by α1 -AR stimulation. These findings will be useful to understand nerve-mediated urethral closure mechanisms.

Anti-Epileptic and Anti-Psychotic Effects of Ipomoea reniformis (Convolvulaceae) in Experimental Animals

Ipomoea reniformis (IR) Choisy is claimed in Indian traditional medical practice to be useful in the treatment of epilepsy and neurological disorders. In the present study, methanolic extract of IR was evaluated for anti-epileptic and anti-psychotic activities in rodent models using standard procedures. Besides evaluating epileptic and behavioural parameters, neurotransmitters such as gamma-amino butyric acid (GABA) in epilepsy and in psychosis, dopamine, noradrenaline and serotonin contents were estimated in the rodent brain. IR extract pretreatment for 15 days reduced maximal electro shock, isonicotinyl hydrazine (INH) and pentylenetetrazole (PTZ)-induced seizures and also significantly inhibited the attenuation of brain GABA levels by INH and PTZ in mice. These findings suggest that the observed beneficial effect of IR extract in epilepsy may be by enhancing the GABAergic system. The extract also inhibited apomorphine-induced climbing and stereotyped behaviours and showed significantly reduced levels of brain dopamine, noradrenaline and serotonin which may be due to blocking of central dopaminergic, noradrenergic and serotonergic pathways or by enhancing the GABAergic system. The results of the present study suggest that the title plant possesses anti-epileptic and anti-psychotic activities in rodents.

Tyrosine hydroxylase TH01 9.3 allele in the occurrence of sudden infant death syndrome in Swiss Caucasians.

Catecholamines, especially noradrenalin, are essential in the control of respiration and arousal. Thus, an impaired production of these neurotransmitters may contribute to the occurrence of sudden infant death syndrome (SIDS). The first step of the noradrenergic synthesis pathway is catalyzed by the enzyme tyrosine hydroxylase (TH). The TH-encoding gene contains a tetrameric short tandem repeat in intron 1 (TH01), with allele 9.3 reported to be associated with SIDS in German infants. We investigated the allelic frequency of the TH01 marker in 171 Swiss SIDS infants and 500 healthy and gender-matched Caucasian adults. In our study population, the allelic frequency of the 9.3 allele is similarly distributed in SIDS cases and controls (27.2% vs. 25.6%; p-value=0.562). Nevertheless, the TH-encoding gene is only one of several genes involved in the noradrenergic biosynthesis pathway. Therefore, further genetic investigations are required with focus on the whole noradrenergic signaling system.

The effects of tramadol on norepinephrine and MHPG releasing in locus coeruleus in formalin test in rats: a brain stereotaxic study.

The relationship between tramadol, as an antinociceptive drug, and locus coeruleus (LC), the main noradrenergic nucleus of the brain that affects regulation and modulation of pain through descending noradrenergic pathways was investigated. Male Sprague-Dawley rats were divided into four groups of 10 rats. The rats were fixed in stereotaxic instrument and then a probe was inserted into LC. Pain was induced by subcutaneous injection of 50 μl of 2.5% formalin 40 minutes after initiation of microdialysis in right hind paw, and nociceptive pain scores were calculated every 5 minutes. Subsequently noradrenaline (NA) and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were collected and measured by microdialysis of locus coeruleus in freely moving rats every 15 minutes during formalin injection. Nociceptive pain scores observed in formalin test had the highest nociceptive sensation 5 minutes after injection. Significant rises in concentrations of NA and MHPG, in samples taken between 30 and 45 min after initiation of the locus coeruleus microdialysis, coincided with the peak of the pain after injection of formalin. According to concurrency of the highest nociceptive sensation and peak of NE and MHPG concentrations, tramadol can indirectly affect the LC by blocking the pain signals from different parts of the brain such as periaqueductal gray mater, central nucleus of amygdale or the spinal cord.

Roles of the spinal glutamatergic pathway activated through α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors and its interactions with spinal noradrenergic and serotonergic pathways in the rat urethral continence mechanisms

To investigate the role of the glutamatergic pathway and its relationship to noradrenergic and serotonergic pathways in modulation of the urethral continence reflex during sneezing in rats. In female Sprague-Dawley rats under urethane anesthesia, the effects of an α-amino-3-hydroxy-5-meth-ylisoxazole-4-propionic acid (AMPA) glutamate receptor antagonist, a norepinephrine reuptake inhibitor and a serotonin [5-hydeoxytripitamine (5-HT)]2B/2C agonist on the amplitude of urethral responses during sneezing (AURS), urethral baseline pressure (UBP), and sneeze-induced leak point pressure (S-LPP) were investigated. Intrathecal application (i.t.) of NBQX disodium salt (an AMPA receptor antagonist) decreased AURS dose-dependently by approximately 60% without affecting UBP and caused stress urinary incontinence (SUI) during sneezing in 60% of normal rats. Nisoxetine (i.t.), a norepinephrine reuptake inhibitor, and mCPP (i.t.), a 5-HT(2B/2C), agonist increased AURS, and NBQX (i.t.) abolished these excitatory effects of nisoxetine (i.t.) and mCPP (i.t.), whereas nisoxetine (i.t.) and mCPP (i.t.) did not enhance AURS in the presence of NBQX (i.t.). These results indicate that the glutamatergic pathway acting through AMPA receptors plays a crucial role on the active urethral closure reflex during sneezing at the spinal level, and noradrenergic and serotonergic pathways modulate the reflex via the spinal glutamatergic system in rats.