Peripheral Noradrenergic Systems Research Articles

Dysfunction of the noradrenergic system drives inflammation, α-synucleinopathy, and neuronal loss in mouse colon.

Clinical and pathological evidence revealed that α-synuclein (α-syn) pathology seen in PD patients starts in the gut and spreads via anatomically connected structures from the gut to the brain. Our previous study demonstrated that depletion of central norepinephrine (NE) disrupted brain immune homeostasis, producing a spatiotemporal order of neurodegeneration in the mouse brain. The purpose of this study was 1) to determine the role of peripheral noradrenergic system in the maintenance of gut immune homeostasis and in the pathogenesis of PD and 2) to investigate whether NE-depletion induced PD-like α-syn pathological changes starts from the gut. For these purposes, we investigated time-dependent changes of α-synucleinopathy and neuronal loss in the gut following a single injection of DSP-4 (a selective noradrenergic neurotoxin) to A53T-SNCA (human mutant α-syn) over-expression mice. We found DPS-4 significantly reduced the tissue level of NE and increased immune activities in gut, characterized by increased number of phagocytes and proinflammatory gene expression. Furthermore, a rapid-onset of α-syn pathology was observed in enteric neurons after 2 weeks and delayed dopaminergic neurodegeneration in the substantia nigra was detected after 3-5 months, associated with the appearance of constipation and impaired motor function, respectively. The increased α-syn pathology was only observed in large, but not in the small, intestine, which is similar to what was observed in PD patients. Mechanistic studies reveal that DSP-4-elicited upregulation of NADPH oxidase (NOX2) initially occurred only in immune cells during the acute intestinal inflammation stage, and then spread to enteric neurons and mucosal epithelial cells during the chronic inflammation stage. The upregulation of neuronal NOX2 correlated well with the extent of α-syn aggregation and subsequent enteric neuronal loss, suggesting that NOX2-generated reactive oxygen species play a key role in α-synucleinopathy. Moreover, inhibiting NOX2 by diphenyleneiodonium or restoring NE function by salmeterol (a β2-receptor agonist) significantly attenuated colon inflammation, α-syn aggregation/propagation, and enteric neurodegeneration in the colon and ameliorated subsequent behavioral deficits. Taken together, our model of PD shows a progressive pattern of pathological changes from the gut to the brain and suggests a potential role of the noradrenergic dysfunction in the pathogenesis of PD.

Noradrenaline induces peripheral antinociception by endogenous opioid release.

The aim of this study was to investigate this involvement in not inflammatory model of pain and which opioid receptor subtype mediates noradrenaline-induced peripheral antinociception. Noradrenaline is involved in the intrinsic control of pain-inducing pro-nociceptive effects in the primary afferent nociceptors. However, inflammation can induce various plastic changes in the central and peripheral noradrenergic system that, upon interaction with the immune system, may contribute, in part, to peripheral antinociception. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2μg) into the plantar surface of the right hind paw and the paw pressure test to evaluated the hyperalgesia was used. Noradrenaline (NA) was administered locally into right hind paw of Wistar rat (160-200g) alone and after either agents, α2-adrenoceptor antagonist yohimbine, α1-adrenoceptor antagonist prazosin, β-adrenoceptor antagonist propranolol, μ-opioid antagonist clocinnamox, δ-opioid antagonist naltrindole and κ-opioid antagonist nor-binaltorfimina. In addition, the enkephalinase inhibitor bestatin was administered prior to NA low dose. Intraplantar injection of NA induced peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed, in dose dependent manner, by intraplantar injection of yohimbine, prazosin, propranolol, clocinnamox and naltrindole. However, injection of nor-binaltorfimina did not alter antinociception of NA after PGE2 hyperalgesia. Bestatin intensified the antinociceptive effects of low-dose of NA. Besides the α2-adrenoceptor, the present data provide evidence that, in absence of inflammation, NA activating α1 and β-adrenoceptor induce endogenous opioid release to produce peripheral antinociceptive effect by μ and δ opioid receptors.

The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline

Experiments on canine lateral saphenous vein segments have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates a segment by diffusion from its microcirculation (vasa vasorum). The effects it causes contrast with those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected – star patterns need darkness, sound patterns, quietness – has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance is believed to be responsible for inflammatory and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia. Finally, the shift in the balance caused by the slow physiological increase in plasma noradrenaline concentration in life is believed to be responsible for ageing.

The beneficial effects of meditation: contribution of the anterior cingulate and locus coeruleus.

During functional magnetic resonance imaging studies of meditation the cortical salience detecting and executive networks become active during “awareness of mind wandering,” “shifting,” and “sustained attention.” The anterior cingulate (AC) is activated during “awareness of mind wandering.” The AC modulates both the peripheral sympathetic nervous system (SNS) and the central locus coeruleus (LC) norepinephrine systems, which form the principal neuromodulatory system, regulating in multiple ways both neuronal and non-neuronal cells to maximize adaptation in changing environments. The LC is the primary source of central norepinephrine (C-NE) and nearly the exclusive source of cortical norepinephrine. Normally activated by novel or salient stimuli, the AC initially inhibits the SNS reflexively, lowering peripheral norepinephrine and activates the LC, increasing C-NE. Moderate levels of C-NE enhance working memory through alpha 2 adrenergic receptors, while higher levels of C-NE, acting on alpha 1 and beta receptors, enhance other executive network functions such as the stopping of ongoing behavior, attentional set-shifting, and sustained attention. The actions of the AC on both the central and peripheral noradrenergic systems are implicated in the beneficial effects of meditation. This paper will explore some of the known functions and interrelationships of the AC, SNS, and LC with respect to their possible relevance to meditation.

Effects of propiverine hydrochloride, an anticholinergic agent, on urethral continence mechanisms and plasma catecholamine concentration in rats

Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats. Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested. Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased. Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.

Effect of the Cold Pressor Test on Memory and Cognitive Flexibility

Cognitive flexibility is affected by stress. The cold pressor test is a known adrenergic stressor that impairs memory, but the effect on cognitive flexibility is unknown. Sixteen subjects were given cognitive flexibility and memory tasks with and without one hand immersed in cold water. Memory was impaired in the cold pressor condition but there was no effect on cognitive flexibility. The lack of a cold pressor effect on cognitive flexibility may result from an isolated effect on the peripheral noradrenergic system, whereas indirect effects due to nociception on memory may occur.

Estrogen modifies stress response of catecholamine biosynthetic enzyme genes and cardiovascular system in ovariectomized female rats

Estrogen is likely involved in the gender specific differences in coping with stress. Activation of catecholamine (CA) biosynthetic enzyme gene expression in central and peripheral CA systems plays a key role in response to stress and in regulation of the cardiovascular system. Here we examined whether estradiol can modulate response of hypothalamic-pituitary-adrenal axis (HPA), gene expression of enzymes related to CA biosynthesis in several noradrenergic locations, tetrahydrobiopterin (BH4) concentration and blood pressure (BP) in response to immobilization stress (IMO) of ovariectomized female rats. Rats were injected with 25 μg/kg estradiol benzoate (EB) or sesame oil once daily for 16 days and subsequently exposed to two hours of IMO. The IMO triggered elevation in plasma ACTH was lessened in EB-pretreated animals. However, estradiol did not alter the IMO-elicited rise of tyrosine hydroxylase mRNA levels in adrenal medulla (AM) and in the nucleus of solitary track (NTS) compared with controls. The response of GTP cyclohydrolase I (GTPCH) mRNA in AM to IMO was also similar in both groups. Several responses to IMO in EB-treated rats were reversed. Instead of IMO-elicited elevation in dopamine β-hydroxylase mRNA levels in the locus coeruleus, GTPCH mRNA and BH4 levels in the NTS, they were reduced by IMO. In a parallel experiment, BP was monitored during restraint stress. The elevation of BP in response to single or repeated restraint stress was sustained during 2 h in controls and reduced after 70 min stress in EB treated rats. One month after withdrawal of EB treatment, the BP response to restraint was similar to that of rats which never received EB. The results demonstrate that estrogen can modulate responses to stress affecting HPA axis, CA biosynthesis, in central and peripheral noradrenergic systems, and BP.

Effects of acute restraint stress on tyrosine hydroxylase mRNA expression in locus coeruleus of Wistar and Wistar-Kyoto rats

Norepinephrine (NE) is thought to play a role in the stress response, and may be involved in stress-related psychopathological conditions such as depression or anxiety. Heterogeneity in individual responses to the same stressor suggest that a genetic susceptibility to the effects of stress may contribute to such pathology. To address possible mechanisms underlying this genetic aspect of the stress response, we examined acute stress-induced changes in mRNA expression for several components of the NE system in the locus coeruleus (LC) and adrenal medullae of stress-susceptible Wistar-Kyoto (WKY) rats and their parent Wistar (W) strain. Expression of tyrosine hydroxylase (TH), NE transporter (NET) and α 2A receptor mRNA were measured in the LC by in situ hybridization 30 min and 2 h after the onset of 30 min restraint stress. Adrenal TH mRNA was measured by slot blots. No basal differences were observed for any measure, but in the LC, expression of TH mRNA increased by 40% in W rats at 30 min ( n=8, p<0.05) and returned toward baseline by 2 h, while WKY rats showed only a non-significant 29% increase at 2 h. In contrast, adrenal TH mRNA expression increased in WKY rats at 2 h ( n=3, p<0.05), with no significant change in W rats. NET and α 2A mRNA were unaltered by restraint stress in both strains. Differences in the stress-reactivity of TH gene expression in the central and peripheral noradrenergic systems may be related to differences in behavioral coping strategies and autonomic responsivity to stress in these strains, and suggest that differences in noradrenergic reactivity may contribute to genetic susceptibility to stress-related pathology.

Oral physostigmine in alzheimer's disease: Effects on norepinephrine and vasopressin in cerebrospinal fluid and plasma

Physostigmine is a cholinesterase inhibitor which enhances central and peripheral cholinergic activity. In this study, we explored in persons with Alzheimer's disease (AD) the effects of an acute dose of physostigmine in patients receiving chronic physostigmine treatment on the activity of the cholinergically regulated noradrenergic and arginine vasopressin (AVP) systems. Specifically, we estimated the effects of sustained release oral physostigmine on central and peripheral noradrenergic and AVP systems by measuring norepinephrine (NE) and AVP in cerebrospinal fluid (CSF) and plasma. Lumbar punctures were performed in both physostigmine and no drug treatment conditions. In some subjects the effects of physostigmine on the plasma AVP response to the osmolar stimulus of a hypertonic saline infusion also were measured. NE concentrations in both CSF and plasma were significantly lower in the physostigmine than in the no drug condition. AVP concentrations did not differ between conditions in either compartment, nor did physostigmine affect the AVP response to hypertonic saline. Physostigmine appears to decrease both central and peripheral noradrenergic activity in AD.

Noradrenergic lesioning with an anti-dopamine β-hydroxylase immunotoxin

Sympathectomy has been achieved by a variety of methods but each has its limitations. These include lack of tissue specificity, incomplete lesioning, and the age range of susceptibility to the lesioning. To circumvent these drawbacks, an immunotoxin was constructed using a monoclonal antibody against the noradrenergic specific enzyme dopamine β-hydroxylase (DβH) coupled via a disulfide bond to saporin, a ribosomal inactivating protein. Three days after intravenous injection of the anti-DβH immunotoxin (50 μg) into adult Sprague-Dawley rats, 66% of neurons in the superior cervical ganglia were chromatolytic. Superior cervical ganglia neurons were poisoned in 1 day old and 1 week old (86% of neurons) neonatal rats following subcutaneous injection of 3.75 and 15 μg, respectively. The anti-DβH immunotoxin will be a useful tool in the study of the peripheral noradrenergic system in adult and neonatal animals.

Spatial Learning and Noradrenaline Content in the Brain and Periphery of Young and Aged Rats

The present experiment studied whether a dysfunction of the noradrenergic neurons is related to spatial learning impairment by investigating the levels of noradrenaline in the brain and periphery as well as the acquisition of water maze task in saline-pretreated young rats, in noradrenergic neurotoxin (DSP-4)-pretreated young rats and in saline-pretreated aged rats. Aged rats, which had an increased escape latency onto the hidden platform, revealed a decreased noradrenaline content in the heart, but not in the hippocampus, striatum, or hypothalamus, whereas DSP-4-pretreated rats had decreased noradrenaline content in the brain; the acquisition of water maze task was not impaired. These results suggest that the peripheral noradrenergic system can show age-related changes different from those in the central noradrenergic system, and they failed to provide support for the hypothesis that decreased activity of the central noradrenergic nerves is related to impairment in the acquisition of the water maze task.

Modulation of the migrating myoelectric complex by brain noradrenergic systems in rats

The respective role of central and peripheral noradrenergic systems in the control of migrating myoelectric complex (MMC) was investigated in rats following lesions with 6-hydroxydopamine (6-OHDA). 6-OHDA was injected via intraperitoneal (ip), intracisternal (icis), and intracerebroventricular (icv) routes in rats. Control animals received the vehicle alone. One month later, MMC was recorded in conscious rats chronically fitted with electrodes. The MMC period was significantly lengthened after 6-OHDA ip or icv injection, and slightly shortened after 6-OHDA icis injection. No disruption of central noradrenergic systems was detected after ip lesions. Norepinephrine content was reduced in the digestive tract after ip lesions, in the spinal cord after icis lesions, and in the cortex, the hypothalamus, pons-medulla, and the spinal cord after icv lesions. After icis lesions, noradrenergic perikarya were spared in pons-medulla, whereas only pons noradrenergic perikarya were lesioned after icv lesions. We conclude that lesions of brain noradrenergic systems modify MMC periodicity in rats. The rostral noradrenergic systems may play the major modulatory role.

Noradrenergic innervation of human pineal gland: abnormalities in aging and Alzheimer's disease

Using previously characterized polyclonal antibody directed against dopamine β-hydroxylase (DBH), immunoreactive fibers were demonstrable in pineals of 6 controls of various ages and of 3 individuals with Alzheimer's disease (AD). Abnormal, swollen axons were present in pineals from aged individuals and from individuals with AD. The pathology of noradrenergic axons in a structure innervated by the superior cervical ganglion suggests that peripheral noradrenergic systems may be affected in aging and in AD.

The central and peripheral renin-angiotensin and noradrenergic systems in the spontaneous hypertensive rats (SHR)

The aim of this study was to evaluate the components of the renin-angiotensin system in the periphery and in the central nervous system (CNS) of the spontaneous hypertensive rats (SHR). On the other hand, the norepinephrine (NE) content of the different areas and of the mesenteric artery were also measured. Sixteen SHR and 9 Wistar Kyoto (WKY) control animals were used at about 6 months of age. Blood and cerebrospinal fluid (CSF) samples were collected. The brain was dissected into several areas and the mesenteric artery was excised. Plasma renin activity (PRA), plasma angiotensinogen concentration (P1AoC), brain renin (RC) and angiotensinogen concentrations (AoC) were evaluated by radioimmunoassay. NE was determined in all the tissues by a fluorimetric technique. PRA, P1AoC and NE concentration in the mesenteric artery were similar in both groups. An increase in the NE content of the cerebellum was detected in the SHR without changes in the other areas of the CNS. AoC was decreased in the CSF and in the brain stem of the SHR animals. RC was evaluated in the hypothalamus, brain stem, cerebral cortex and cerebellum of the same strain of rats. These results seem to indicate the some alteration of the peptidergic system in the CNS is present in the hypertensive animals.

Chronic cocaine effects on peripheral biogenic amines: a long-term reduction in peripheral dopamine and phenylethylamine production

The short- (during 12 h after last treatment) and long- (6 weeks after last treatment) term effects of repeated administration of cocaine on the total output of norepinephrine (NE) and its metabolites (sum NE), dopamine (DA) and its metabolites (sum DA) as well as the excretion of 5-hydroxyindoleacetic acid (5-HIAA) and phenylethylamine were evaluated in rats. The concentration of NE, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the celiac ganglion after 1,2 and 3 weeks of repeated cocaine administration were also measured. Sum NE remained unchanged during the cocaine treatment but NE and normetanephrine excretions were significantly decreased and increased respectively. 5-HIAA excretion was significantly reduced only after 3 weeks cocaine treatment. In the celiac ganglion NE and DOPAC contents showed tendencies towards being increased and decreased respectively. DA content was not changed. The excretions of DA, DOPAC, homovanillic acid (HVA) and phenylethylamine were significantly reduced during chronic exposure to cocaine. The above short-term changes in DA and phenylethylamine persisted for periods as long as 6 weeks after 1 week repeated exposure to cocaine. It is concluded that chronic exposure to cocaine can produce preferential long term deficiencies in the production of DA and phenylethylamine in the periphery. Peripheral noradrenergic and serotonergic neuronal systems are apparently minimally affected. The close association between DA or sum DA and phenylethylamine excretion suggest these 2 amines may coexistin the same neuron.

5-HT agonist induced analgesia modulated by central but not peripheral noradrenaline depletion in rats.

The antinociceptive effect elicited by the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was reversed or blocked in animals which had previously sustained severe spinal noradrenaline (NA) depletion via either systemic N-2-chlorethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP 4), neonatal 6-hydroxydopamine (neon. 6-OHDA), or intrathecal 6-OHDA treatment. Biochemical analysis of the lumbar spinal cord samples confirmed severe central NA depletions. Animals were tested with nondamaging heat pain (tail-flick test, hot-plate test) and electric footshock titration to determine the amount of antinociception or nociception. Peripheral NA depletion following intravenous (i.v.) 6-OHDA injection to adult rats had no effect on the antinociception induced by 5-MeODMT, but did cause severe NA depletions in the left heart atrium. These results suggest a modulatory effect of central and not peripheral noradrenergic system upon 5-HT agonist induced analgesia, and also give evidence that this effect is spinally mediated.

The effect of peripheral noradrenaline depletion on responding on a schedule of differential reinforcement of low rates of response (DRL).

First, it was confirmed that systemic injection of the neurotoxin 6-hydroxydopamine HBr (30 mg/kg IP) depleted noradrenaline levels in rat heart, but not centrally. Losses averaged 90% of control 1 day after injection, and 50% at 42 days. The same drug and dose was then administered to 50% of a group of rats which had been trained to lever-press for food reward on continuous reinforcement (CRF). After further CRF sessions, the rats were changed to a schedule of Differential Reinforcement of Low Rates of Response with a 20-s criterion (DRL 20). The drugged rats earned fewer reinforcements during DRL than did controls, and made fewer responses. Temporal discrimination (shown by the IRT/Opp distribution) was disrupted. It is concluded that peripheral noradrenergic systems may be involved in the control over responding by temporal cues associated with reward and non-reward.

Autonomic dysfunction, peripheral neuropathy, and depression

A 15-year-old boy with diarrhea, dizziness, dysesthesias, and depression is described. On admission, his blood pressure was 110/84 reclining but < 40 systolic while standing. Vibratory sensation and nerve conduction velocities were decreased in his lower extremities. CSF protein concentration was normal but sural nerve biopsy demonstrated generalized demyelination. Extensive toxicologic and metabolic screening proved unremarkable. Norepinephrine concentrations in plasma and urine, and CSF concentration of 3-methoxy-4-hydroxy phenylglycol (MHPG) were markedly reduced. The patient demonstrates a combination of autonomic dysfunction, peripheral neuropathy, and affective disorder. This collection of clinical and neurochemical findings represents a previously unreported entity involving a defect of both central and peripheral noradrenergic systems.

Genetic variation, chronic stress, and the central and peripheral noradrenergic systems.

Male rats from two inbred strains genetically selected for variation in response to stress were exposed for 9 consecutive days to 50 min of intermittent foot shock and killed 24 h after the last stress session. Maudsley Nonreactive (MNRA/Har) rats, genetically selected for decreased reactivity to stress, exhibited a significantly greater elevation (114% above control levels) in tyrosine hydroxylase activity in the locus ceruleus after chronic stress than Maudsley Reactive (MR/Har) animals (63% above control levels), genetically selected for heightened reactivity to stress. In the peripheral noradrenergic system, chronic stress produced an increase in norepinephrine (NE) content of small intestine and submaxillary gland of MNRA/Har rats, whereas chronic stress had no effect on NE content of these same tissues in MR/Har animals. These results are consistent with the proposition that genetic selection for variation in susceptibility to stress has altered the capacity of the central and peripheral noradrenergic system to adapt to chronic stress.

Assessing the noradrenergic system in normal aging: a review of methodology.

Studies evaluating plasma norepinephrine in the normal elderly have found significant increases as compared to the young and middle-aged individuals. The increased plasma norepinephrine concentrations found during the normal aging process in man may be relevant to both the understanding of drug therapeutics and underlying mechanisms of the noradrenergic system in the elderly. The authors critically review the experimental design of studies that have evaluated plasma norepinephrine and age. The various conditions and methods for assessment of plasma norepinephrine concentrations, which may contribute to the finding of a hypernoradrenergic system in the aged, are examined. An attempt is made to collate the studies and develop a standardized methodology for studying the peripheral noradrenergic system in the elderly.