Role of noradrenaline in sustaining drive

In a placebo-controlled 8-week study comparing the selective noradrenaline re-uptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, in major depression, patient social motivation and behaviour were investigated through a newly developed 21-item self-rating scale, the Social Adaptation Self-evaluation Scale (SASS). At last assessment the mean SASS total score was significantly superior on both reboxetine (n = 103) and fluoxetine (n = 100) compared with on placebo (n = 99). In addition, the SASS total score in the reboxetine group was significantly higher compared with the fluoxetine group. At point-biserial correlation analysis, all but one item discriminated reboxetine from placebo, while only 12 items discriminated fluoxetine from placebo. In the reboxetine-fluoxetine comparison, nine items showed a positive association with reboxetine, while the opposite was never seen; the association was maximal in the area of negative self perception and lack of motivation towards action. These results support, at social functioning level, a differential effect of selective manipulation of the noradrenergic or serotonergic system in keeping with the long-debated hypothesis on the specific involvement of serotonin in regulating mood and of noradrenaline in sustaining drive.
Dubini A, Bosc M, Polin V.Eur Neuropsychopharmacol. 1997 Apr;7 Suppl 1:S49-55; discussion S71-3.
http://www.ncbi.nlm.nih.gov/pubmed/9169310

The importance of noradrenaline in depression is supported by its association with clinical parameters such as vigilance and drive

The need for new and better antidepressants: reboxetine a new option.

Neuropsychiatry Unit, Institute of Clinical Neurosciences, Sahlgrenska University Hospital, Goteborg, Sweden.

The selective serotonin reuptake inhibitors (SSRIs) have obtained global attention but have not demonstrated superior efficacy in major depression compared with older tricyclic antidepressants. From a pharmacological viewpoint the noradrenergic system in the brain appears to have a central role in neurotransmitter organization. The importance of noradrenaline in depression is supported by its association with clinical parameters such as vigilance and drive. Reboxetine is a selective noradrenaline reuptake inhibitor--the first in its class to be marketed. In both preclinical and clinical studies reboxetine has been found to be an effective and safe antidepressant. Furthermore, reboxetine restores a patients' social functioning, producing a better quality of remission than fluoxetine.

Acta Psychiatr Scand Suppl. 2000;402:6-11.

The role of noradrenaline and selective noradrenaline reuptake inhibition in depression.

Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy. brunello.nicoletta@unimo.it

Depression is a common disorder that impacts on all aspects of a person's life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.

Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J, Paykel E, Versiani M, Racagni G.

Noradrenaline in basic models of depression

This review reports anatomical studies evaluating central and peripheral alpha 2- and beta-adrenoceptors. The results suggest abnormalities exist in the noradrenergic system in depressed patients. Most animal models involve the use of stress to simulate depression in man. All models that have been developed lead to differential changes in noradrenergic function. We have assessed the effects of reboxetine, a novel, selective noradrenaline-reuptake inhibitor (NARI) in olfactory bulbectomised rats, a procedure that induces significant changes in amygdala function. Reboxetine is an effective antidepressant in the forced swim test and open field test in bulbectomised rats. Unlike the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is selective for the noradrenergic system. Owing to the abnormalities that occur in depression, it would seem sensible to target the noradrenergic system for treatment of this condition.
Eur Neuropsychopharmacol. 1997 Apr;7 Suppl 1:S11-6; discussion S71-3.

Psychopathology of depression

Brian E Leonard

This review assesses some of the important advances that have been made in our understanding of the psychopathology of depression. While the monoamine theory, that postulates dysfunctional noradrenergic and serotonergic systems as the underlying cause of depression, has been valuable in the development of conventional antidepressants that are thought to act by reversing these dysfunctional states, recent clinical and experimental studies have questioned this reductionist view of depression. This has led to an assessment of the role of dysfunctional endocrine and immune systems in the aetiology of depression. In addition to explaining the link between defective neurotransmitter function and the symptoms of depression, changes in the endocrine and immune axes also help to explain the link between major depression and physical ill health. In addition, experimental and clinical studies have extended the possible involvement of neurotransmitters to include the glutamate and GABA systems. Such approaches may stimulate the development of new types of antidepressants that hopefully will combine increased efficacy with shorter speed of onset and improved side effect profiles.

Drugs Today (Barc). 2007 Oct ;43 (10):705-16 17987223 (P,S,E,B,D)

Stress, norepinephrine and depression

Acta Neuropsychiatrica. 14(4):173-180, August 2002.
Leonard, Brian E.

Abstract:
Experimental and clinical evidence implicates stress as a major predisposing factor in depression and other severe psychiatric disorders. In this review, evidence is presented to show how the impact of stress on the central sympathetic system leads to changes in the endocrine, immune and neurotransmitter axes which underlie the main clinical symptoms of depression. Thus it can be shown that the noradrenergic system is dysfunctional in depression, a situation which reflects the chronic hypersecretion of glucocorticoids and inflammatory mediators within the brain in addition to an enhanced activity of the locus ceruleus. With regard to the actions of antidepressants in modulating the stress response and alleviating depression it is now evident that, irrespective of the presumed specificity of the antidepressants for the noradrenergic or serotonergic systems, they all normalize noradrenergic function. This action is due partly to the regulation of tyrosine hydroxylase activity in the locus ceruleus but also enhances neuronal sprouting which counteracts the neurodegenerative effects of chronic stress.

THE PREFRONTAL CORTEX is considered to be a key cortical substrate of the highest-level mental processes

THE PREFRONTAL CORTEX is considered to be a key cortical substrate of the highest-level mental processes. Yet, despite the bewildering gamut and complexity of cognitive processes that depend on the prefrontal cortex, over the last decades significant progress has been made in linking the prefrontal function with its cellular and circuit mechanisms in a field at the interface between cognitive sciences and cellular electrophysiology. A landmark paper that helped usher prefrontal research into neurophysiology is Funahashi, Bruce, and Goldman-Rakic's article published in 1989 in the Journal of Neurophysiology (3).

Funahashi S, Bruce CJ, and Goldman-Rakic PS. Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 61: 331–349, 1989 (http://jn.physiology.org/cgi/reprint/61/2/331).

Reserpine impairs spatial working memory performance

Repeated daily treatment with the catecholamine-depleting agent, reserpine, dramatically reduced performance on the delayed response task, a test of spatial working memory that depends upon the integrity of the prefrontal cortex. Delayed response performance fell from an average of 27.2/30 trials correct before reserpine treatment to an average of 20.4/30 trials correct after repeated reserpine administration. Injection of the alpha 2-adrenergic agonist, clonidine (0.0001-0.05 mg/kg), to chronic reserpine-treated monkeys significantly restored performance on the delayed response task; performance after an optimal dose averaged 27.8/30 trials correct. Clonidine's beneficial effects on delayed response performance were longlasting; monkeys remained improved for more than 24 h after a single clonidine injection. The finding that clonidine is efficacious in reserpinized animals supports the hypothesis that alpha 2-adrenergic agonists improve cognitive function through actions at postsynaptic, alpha 2-adrenergic receptors on non-adrenergic cells. In contrast to the delayed response task, reserpine had little effect on performance of a visual discrimination task, a reference memory task which does not depend on the prefrontal cortex. These results emphasize the importance of postsynaptic, alpha 2-adrenergic mechanisms in the regulation of working memory.

Cai JX, Ma YY, Xu L, Hu XT
Brain Res 1993; 614:191-6.

Role of Myocardial Catecholamines in Cardiac Contractility

Science 10 April 1959: Vol. 129. no. 3354, pp. 967 - 968 DOI: 10.1126/science.129.3354.967

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WOO CHOO LEE ¹ and F. E. SHIDEMAN ¹

¹ Department of Pharmacology and Toxicology, University of Wisconsin, Madison

In cats bilateral sympathectomy or administration of reserpine results in a marked reduction in concentration of myocardial catecholamines. The contractility of papillary muscles from such animals is significantly less than that of muscles from untreated animals. These findings demonstrate the importance of normal levels of myocardial catecholamines in the maintenance of normal cardiac contractility.

The increase after sympathectomy is blocked by adrenal denervation.

Neuromethods

By Ralph N. Adams, Glen B. Baker, Judith M. Baker, Alan N. Bateson, Donald P. J. Boisvert,

Adrenal PNMT is also under neuronal control (Ciaranello, 1978, Molinoff and Axelrod, 1971). Its activity increases markedly following catecholamine depletion with reserpine (Molinoff, et al., 1970,) and after chemical sympathectomy with 6-hydroxydopamine (Thoenen at al., 1970). The increase after sympathectomy is blocked by adrenal denervation.
ISBN:0896030792
1986 - 619 pages

The antihypertensive effect of the drug may be enhanced in the post-sympathectomy patient.

PROTENSIN-M tablets

COMPOSITION:
Each tablet contains 50 mg hydroflumethiazide and 0,125 mg reserpine.
Protensin-M is contra-indicated in patients with a history of mental depression because of the possibility that it will potentiate depression and increase the possibility of suicide.
The antihypertensive effect of the drug may be enhanced in the post-sympathectomy patient.

Marked depletion of cardiac catecholamines (80 to 90%) following denervation

Can. J. Physiol. Pharmacol. 48(3): 182–184 (1970) | doi:10.1139/y70-031 | © 1970 NRC Canada

Effect of cardiac sympathectomy, reserpine, and environmental temperatures on the catecholamine levels in the chicken heart

Y. C. Lin, P. D. Sturkie, and J. Tummons

Abstract: Cardiac catecholamine levels were spectrofluorometrically determined in adult male chickens following two treatments: (1) denervation of the cardioaccelerator nerves or (2) reserpine administration after acclimatization of the birds to low, intermediate, or high ambient temperatures. Marked depletion of cardiac catecholamines (80 to 90%) was found 2 weeks after denervation and 24 h after injection of reserpine. Acclimatization did not alter the response to reserpine.

depression of myocardial norepinephrine content following sympathectomy

Am J Physiol Heart Circ Physiol 270: H1078-H1084, 1996;
0363-6135/96 $5.00

Endogenous myocardial norepinephrine is not essential for ischemic preconditioning in rabbit heart

Right ventricular norepinephrine content (pmol/mg protein), 51.4 +/- 11.1 in untreated rabbits, was reduced to 0.6 +/- 0.2 and 1.8 +/- 0.5 by surgical sympathectomy and reserpine, respectively.

Role of Myocardial Catecholamines in Cardiac Contractility

Role of Myocardial Catecholamines in Cardiac Contractility

LEE and SHIDEMAN
Science 10 April 1959: 967-968
DOI: 10.1126/science.129.3354.967

the role of central NO mechanisms in the altered sympathetic outflow in disease states

Role of Nitric Oxide in Central Sympathetic Outflow

Kaushik P. Patel^*,1, Yi-Fan Li^* and Yoshitaka Hirooka

^* Department of Physiology and Biophysics, University of Nebraska Medical Center, 984575 Nebraska Medical Center, Omaha, Nebraska 68198-4545; and
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan

The gaseous molecule nitric oxide (NO) plays an important role in cardiovascular homeostasis. It plays this role by its action on both the central and peripheral autonomic nervous systems. In this review, the central role of NO in the regulation of sympathetic outflow and subsequent cardiovascular control is examined. After a brief introduction concerning the location of NO synthase (NOS) containing neurons in the central nervous system (CNS), studies that demonstrate the central effect of NO by systemic administration of NO modulators will be presented. The central effects of NO as assessed by intracerebroventricular, intracisternal, or direct injection within the specific central areas is also discussed. Our studies demonstrating specific medullary and hypothalamic sites involved in sympathetic outflow are summarized. The review will be concluded with a discussion of the role of central NO mechanisms in the altered sympathetic outflow in disease states such as hypertension and heart failure.

Renal function following sympathectomy

Acute renal function in chronically sympathectomized deoxycorticosterone acetate-treated miniature swine

GD Thomas and EJ Zambraski
Department of Biology-Physiology Section, Rutgers University, New Brunswick, New Jersey 08903.

We recently validated a swine model in which chronic treatment with 6- hydroxydopamine (6-OHDA) produced an effective sympathectomy. These sympathectomized swine demonstrated a significantly attenuated hypertensive response when treated with deoxycorticosterone acetate (DOCA). Because renal nerve activity is elevated and important in controlling renal function and blood pressure in the DOCA swine model, we wanted to study the effect of chronic sympathectomy on acute renal hemodynamics and tubular function. Kidney function was assessed in 14 DOCA-treated miniature swine, 8 of which were sympathectomized by chronic treatment with 6-OHDA, while 6 served as controls. Effective renal sympathectomy in this model has been previously confirmed by a significant reduction (97%) of norepinephrine in renal cortical tissue. When anesthetized, mean arterial pressure and renal blood flow were similar between the two groups. Glomerular filtration rate was lower by 43%, urine flow rate by 71%, sodium excretion by 66%, and potassium excretion by 48% in the 6-OHDA DOCA animals. All of these parameters were significantly different from the intact DOCA controls. These results indicate that anesthetized, chronically sympathectomized swine exhibit decreased renal excretory function. The changes in renal function may have been due to the development of a tubular or glomerular supersensitivity to circulating antinatriuretic factors, since the 6-OHDA group had a 28% greater pressor response to the alpha- agonist phenylephrine and a significantly greater fall in mean arterial pressure in response to alpha-blockade with prazosin when compared with the controls. These changes in renal function may also explain why the 6-OHDA animals demonstrated a slight increase in mean arterial pressure in response to DOCA. Because acute renal denervation in DOCA-treated swine produces a diuresis and natriuresis, this study affirms that there may be important functional differences in acutely versus chronically denervated kidneys for which the implications under normal physiologic conditions are unknown.

Proceedings of the Society for Experimental Biology and Medicine, Vol 197, 331-336, Copyright © 1991 by Society for Experimental Biology and Medicine

Comparison of effects of surgical and chemical sympathectomy

Comparison of effects of surgical and chemical sympathectomy on beta adrenergic and muscarinic receptors of parotid gland of young and adult rats

CA Schneyer, M Humphreys-Beher and HD Hall
Department of Physiology and Biophysics, University of Alabama, Birmingham 35294

QNB binding was decreased with surgical sympathectomy as well as reserpine-induced sympathectomy of adult parotid gland; norepinephrine concentration was decreased to levels of a few percent of innervated glands. The relation between development of glandular supersensitivity and increase in beta adrenoceptors is discussed.

Proceedings of the Society for Experimental Biology and Medicine, Vol 188, 420-426, Copyright © 1988 by Society for Experimental Biology and Medicine

Calcium in Salivary Glands

Calcium in Salivary Glands of the Rat After
Autonomic Denervation
PABLO M. BAZERQUE,* CARLOS J. PEREC,* and SILVIA E. TERRADASt
Department of Physiology, Faculty of Odontology,
University of Buenos Aires, Buenos Aires, Argentina
Experientia 25:1327-1328, 1969.

Differences in the norepinephrine system are implicated in depression

Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors are antidepressants that treat depression by increasing the amount of serotonin and norepinephrine available to postsynaptic cells in the brain. There is some recent evidence, implying that SNRIs may also increase dopamine transmission.^{[citation needed]} This is because SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex).

Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin activity, but tend to have side effects due to the nonspecific activation of histamine and acetylcholine receptors. Side effects include tiredness, increased hunger, dry mouth, and blurred vision. For this reason, they have largely been replaced by newer selective reuptake drugs such as Prozac.

Reserpine depletion of monoamine neurotransmitters in the synapses is often cited as evidence to the theory that depletion of the neurotransmitters causes subsequent depression in humans.

Norepinephrine

As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle.

Norepinephrine is also released from postganglionic neurons of the sympathetic nervous system, to transmit the fight-or-flight response in each tissue respectively. The adrenal medulla can also be counted to such postganglionic nerve cells, although they release norepinephrine into the blood.

By indication

Norepinephrine may be used for the indications attention-deficit/hyperactivity disorder, depression and hypotension. Norepinephrine , as with other catecholamines, itself cannot cross the blood-brain barrier , so drugs such as amphetamines are necessary to increase brain levels.

Attention-deficit/hyperactivity disorder

Norepinephrine, along with dopamine, has come to be recognized as playing a large role in attention and focus.

Severe post- sympathectomy neuralgia can be devastating

Minimal Access Therapy for Vascular Disease

by Austin L. Leahy, Peter R F Bell, Barry T. Katzen - 2002 - Medical - 288 pages

Severe post- sympathectomy neuralgia can be devastating, requiring brachial plexus nerve blocks and transcutaneous nerve stimulation. ...
books.google.com.au/books?isbn=1901865274...

Peripheral Neurons in Nociception: Physio-Pharmacological Aspects

by Jean-Marie R. Besson, G. Guilbaud, H. Ollat - 1994 - Neurons - 270 pages

This has not directly been tested, but pain may develop in about 10% to 20% of the patients after surgical sympathectomy

Post-sympathectomy neuralgia

Copyright © 1996 Published by Elsevier Science B.V.

Clinical review

Post-sympathectomy neuralgia: hypotheses on peripheral and central neuronal mechanisms

Ronald C. Kramis^a, , William J. Roberts^{b, a} and Richard G. Gillette^c

^a Legacy / Good Samaritan Hospital, Portland, OR 97209, USA

^b R. S. Dow Neurological Sciences Institute, Portland, OR 97209, USA

^c Western States Chiropractic College, Portland, OR 97209, USA

Received 2 February 1995.

Available online 2 March 1999.

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Post-sympathectomy neuralgia is proposed here to be a complex neuropathic and central deafferentation/reafferentation syndrome dependent on: (a) the transection, during sympathectomy, of paraspinal somatic and visceral afferent axons within the sympathetic trunk; (b) the subsequent cell death of many of the axotomized afferent neurons, resulting in central deafferentation; and (c) the persistent sensitization of spinal nociceptive neurons by painful conditions present prior to sympathectomy. Viscerosomatic convergence, collateral sprouting of afferents, and mechanisms associated with sympathetically maintained pain are all proposed to be important to the development of the syndrome.

The most common complication is post-sympathectomy neuralgia

Neural Blockade in Clinical Anesthesia and Management of Pain

By Michael J. Cousins, Phillip

"The most common complication is post-sympathectomy neuralgia.... The reported incidence has varied widely between studies, from around 30% to 50%. Whether the sympathectomy is achived by open surgical resection or percutaneous techniques does not seem to influence the incidence."

Vascular Surgery: Principles and Practice

by Robert W. Hobson, Samuel E. Wilson, Frank J. Veith - 2004 - Medical - 1600 pages
Postsympathectomy neuralgia is a constant and annoying feature of sympathectomy, and the patient should be forewarned.

sensitization that lead to a major physiological change of the autonomic, pain and motor systems

Expert Review of Neurotherapeutics

May 2006, Vol. 6, No. 5, Pages 669-681

(doi:10.1586/14737175.6.5.669)

Pathophysiology of complex regional pain syndrome

Robert J Schwartzman, Guillermo M Alexander & John Grothusen

† Author for correspondence

Complex regional pain syndrome (CRPS) most often follows injury to peripheral nerves or their endings in soft tissue. A combination of prostanoids, kinins and cytokines cause peripheral nociceptive sensitization. In time, the Mg²⁺ block of the N-methyl-D-aspartate receptor is removed, pain transmission neurons (PTN) are altered by an influx of Ca²⁺ that activates kinases for excitation and phosphatases for depression, activity-dependent plasticity that alters the firing of PTN. In time, these neurons undergo central sensitization that lead to a major physiological change of the autonomic, pain and motor systems. The role of the immune system and the sickness response is becoming clearer as microglia are activated following injury and can induce central sensitization while astrocytes may maintain the process.

Loss of vasoconstrictor reflexes/exacerbate pain

COPYRIGHT 2004 British Medical Association

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Publication Date: 01-JAN-04

Author: Drummond, P.D. ; Finch, P.M.

Background: Stimuli arousing sympathetic activity can increase ratings of clinical pain in patients with complex regional pain syndrome (CRPS).

Objective: To determine whether the increase in pain is mediated by peripheral sympathetic activity.

Methods: The effect of sympathetic ganglion blockade on pain evoked by a startle stimulus and cooling the forehead was investigated in 36 CRPS patients.

Results: Loss of vasoconstrictor reflexes and warming of the limb indicated that sympathetic blockade was effective in 26 cases. Before sympathetic blockade, pain increased in 12 of these 26 patients when they were startled. Pain increased in seven of the 12 patients and in another five cases when their forehead was cooled. As expected, pain that increased during sympathetic arousal generally subsided in patients with signs of sympathetic blockade. However, pain still increased in three of 12 of patients after the startle stimulus and in six of 12 of patients during forehead cooling, despite indisputable sympathetic blockade.

Conclusions: These findings suggest that stimuli arousing sympathetic activity act by a central process to exacerbate pain in some patients, independent of the peripheral sympathetic nervous system. This may account for the lack of effect of peripheral sympathetic blockade on pain in some CRPS patients.

The effect of noradrenaline, angiotensin II and vasopressin on blood flow and sensitivity to heat in capsaicin-treated skin

Peter D. Drummond¹

(1)	Psychology Department, Murdoch University, 6150, Western Australia, Australia

Received: 10 June 1997 Accepted: 16 October 1997

Abstract The effect of iontophoretically applied noradrenaline, angiotensin II and vasopressin on blood flow and sensitivity to heat was investigated in the capsaicin-treated forearms of 52 healthy volunteers. Non-specific effects of a 4-min saline iontophoresis were investigated in another 19 subjects. Pretreatment with phentolamine inhibited vasoconstriction and thermal hyperalgesia to noradrenaline, indicating that -adrenoceptors mediated these responses. The intensity of thermal hyperalgesia differed significantly across the following treatments: saline (heat pain threshold 1.1°C lower than at control sites), angiotensin II (3.4°C), noradrenaline (6.4°C), and vasopressin (9.0°C). Decreases in skin blood flow were significantly greater after the iontophoresis of noradrenaline (65% reduction from baseline) and vasopressin (68%) than after the iontophoresis of angiotensin II (45%). In contrast to the other two drugs, angiotensin II induced thermal hyperalgesia in proportion to the intensity of vasoconstriction. The findings suggest that iontophoretic currents induce minor non-specific thermal hyperalgesia. Angiotensin II appears to increase sensitivity to heat by an ischaemic mechanism, whereas an additional non-vascular influence contributes to thermal hyperalgesia induced by noradrenalinge and vasopressin. These mechanisms could contribute to hyperalgesia in chronic inflammatory or neuropathic pain syndromes. Clin Auton Res 8:87–93 © 1998 Lippincott-Raven Publishers

Adrenergic receptors in the forehead microcirculation

P. D. Drummond¹

(1)	Division of Psychology, Murdoch University, 6156, Western Australia

Received: 7 August 1995 Accepted: 26 October 1995

The presence of - and -adrenoceptors in the forehead microcirculation was investigated in 49 healthy subjects. Local vascular responses to noradrenaline, isoprenaline and adrenergic antagonists, administered transcutaneously by iontophoresis, were monitored via laser Doppler flowmetry. Iontophoresis of the -adrenergic antagonist phentolamine induced a persistent increase in skin blood flow, whereas iontophoresis of saline induced a minor increase in skin blood flow which subsided rapidly. Skin blood flow increased moderately after the iontophoresis of the -adrenergic antagonist propranolol.

The insular cortex is involved in cardiac regulation

S. M. Oppenheimer¹ , G. Kedem¹ and W. M. Martin¹

(1)	Laboratory of Neurocardiology, Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21287-7585 Baltimore, Maryland, USA

Received: 18 December 1995 Accepted: 20 December 1995

Abstract The insular cortex is involved in cardiac regulation. The left insula is predominantly responsible for parasympathetic cardiovascular effects. Damage to this area could shift cardiovascular balance towards increased basal sympathetic tone (a proarrhythmic condition) and contribute to the excess cardiac mortality following stroke. Acute left insular stroke increased basal cardiac sympathetic tone and was associated with a decrease in randomness of heart rate variability. In addition, phase relationships between heart rate and blood pressure were disturbed, implying a disruption of oscillators involved in cardiovascular control. The insula appears to be involved in human heart rate regulation and damage to it may encourage a pro-arrhythmic state.

yawning is associated with a sympathetic suppression

We conclude that yawning is associated with a sympathetic suppression that favours a parasympathetic dominance, as indicated by the MSNA and the decrease in blood pressure. The slow expiration following a yawn is associated with a sympathetic activation marked by an MSNA discharge and an increase in blood pressure.

J. J. M. Askenasy¹ and N. Askenasy²

(1)	Sleep Medicine Institute, Sheba Medical Centre (affiliated to Sackler School of Medicine, Tel Aviv University), Israel

(2)	Department of Internal Medicine E, Asaf Harofeh Medical Centre, Israel

(3)	Sleep Medicine Institute, Sheba Medical Centre, 52621 Tel Hashomer, Israel

Received: 15 November 1995 Accepted: 26 April 1996

Pattern of plasma levels of catecholamines in familial dysautonomia

F. B. Axelrod¹ , D. S. Goldstein², C. Holmes², D. Berlin³ and I. J. Kopin²

(1)	Departments of Pediatrics and Neurology, New York University Medical Center, 530 First Avenue, Suite 3A, 10016 New York, NY, USA

(2)	Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 20892 Bethesda, MD, USA

(3)	Department of Pediatrics, New York University Medical Center, 10016 New York, NY, USA

Received: 20 November 1995 Accepted: 12 April 1996

Abstract This report extends previous investigations of endogenous catecholamine levels in patients with orthostatic hypotension due to familial dysautonomia (FD), to define better the neurochemical phenotype and elucidate possible pathophysiological mechanisms. Ten FD patients (age 26.1±2.6 (SEM) years) and eight control subjects (age 29.5±3.7 years) were studied. Heart rate, blood pressure and venous blood samples were obtained while supine and after 5 min in the upright position. Plasma levels of dihydroxyphenylalanine (DOPA), noradrenaline (NA), adrenaline (A), dopamine (DA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) were measured. When supine, the FD group had greater NA and DOPA levels, and lower DHPG levels. Plasma NA did not increase with erect posture in FD patients. Individual FD mean blood pressures were correlated positively with plasma NA levels when supine and with plasma DA and DOPAC when upright. In FD, DOPA:DHPG ratios were above the range found in normal subjects or that reported in patients with acquired forms of dysautonomia regardless of posture, whereas DOPAC:DHPG ratios remained normal. Thus FD patients have a characteristic neurochemical pattern which probably reflects either decreased vesicular storage of catecholamines or limited oxidative deamination despite normal or increased tyrosine hydroxylation.

Parallels between patients post-sympathectomy and patients with MS

Neuropeptide Y plasma levels and serum dopamine-beta-hydroxylase activity in MS patients with and without abnormal cardiovascular reflexes.

1994, N° 1 (Vol. 94/1)

Gallai V, Sarchielli P, Firenze C, Trequattrini A, Paciaroni M, Usai F, Franceschini M, Palumbo R

Abstract:

An impairment in the autonomic function has been demonstrated in patients with multiple sclerosis (MS) using electrophysiological, pupillary and biochemical tests. Particularly evident were alterations in the cardiovascular reflexes, cutaneous sympathetic response and lymphomonocyte adrenergic binding. Electrophysiological and biochemical findings in MS patients have only occasionally been compared. Among the peripheral markers of the autonomic system, Neuropeptide Y (NPY) and dopamine-beta-hydroxylase (DBH) have been singled out as reliable indices of sympathetic function. The former is a peptide with a strong vasoconstrictive action, which is released from adrenergic endings together with noradrenaline following sympathetic activation. The latter is the enzyme which catalyses the conversion of dopamine to norepinephrine. It is located both in sympathetic endings and the chromaffin granules of adrenal medulla. To verify a failure in autonomic function in the course of MS, a battery of cardiovascular tests (assessing sympathetic and parasympathetic functions) was performed on 25 MS patients. The results were compared with a group of 20 age- and sex-matched control individuals. The plasma levels of NPY and the serum DBH activity were also determined in both groups. 52% of patients showed an impairment in sympathetic function in one or more tests (sustained handgrip, postural hypotension, cold face test). 48% of the patients had abnormal values in deep breathing test, indicating a failure of the parasympathetic function. 44% of patients showed also a paroxysmal tachycardia after cold face test, indicating an abnormal function of the vagal-cardiac and sympathetic-vascular smooth muscle pathways of the trigeminal nerve.

heart rate variability and body size are are correlated

R. Freeman^{1, 2, 8} , S. T. Weiss^{4, 5, 8}, M. Roberts^{3, 7}, S. M. Zbikowski⁴ and D. Sparrow^{6, 8}

(1)	The Division of Neurology, Deaconess Hospital, Suite 7H, 110 Francis Street, 02215 Boston, MA, USA

(2)	The Department of Neurology, Beth Israel Hospital, Boston, MA, USA

(3)	The Department of Medicine, Shadyside Hospital, Boston, MA, USA

(4)	The Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA

(5)	The Department of Medicine, Pulmonary and Critical Care Division, Beth Israel Hospital, Boston, MA, USA

(6)	The Department of Veterans Affairs Outpatient Clinic, Normative Aging Study, Boston, MA, USA

(7)	University of Pittsburgh, Pennsylvania, USA

(8)	Harvard Medical School, Boston, MA, USA

Received: 8 March 1995 Accepted: 19 July 1995

Abstract There is a well-recognized relationship between autonomic nervous system function and body habitus although few studies have addressed the role of the parasympathetic nervous system. A decrease in parasympathetic nervous-system-mediated heart rate variability in obesity may in part explain the mortality and morbidity that are associated with the obese state. We used multiple linear regression techniques to explore the relationship between measures of heart rate variability and anthropometric indices in 597 male participants in the Normative Aging Study. After adjustment for age and log₁₀ heart rate, weight and body mass index were significant predictors of both the expiratory to inspiratory ratio (E/I ratio) and the difference between maximum and minimum heart rate (HR_Max-Min). The abdomen-to-hip ratio and percentage body fat were not significant predictors of measures of heart rate variability. A one standard deviation change in the anthropometric index (weight, body mass index) resulted in a decrease in the E/I ratio of 0.010–0.014 and a decrease in the HR_Max-Min of 0.486–0.715 beats/min. A change in the anthropometric index across the distribution (5–95 percentile) resulted in a decrease in the E/I ratio of 0.032–0.037 and a decrease in the HR_Max-Min of 1.56–2.39 beats/min. These results indicate that heart rate variability and overall body size are correlated. This association could in part explain the mortality and morbidity that is associated with the obese state.

Parallels between patients post-sympathectomy and patients with spinal cord injury:

The amount of compensatory sweating depends on the patient, the damage that the white rami communicans incurs, and the amount of cell body reorganization in the spinal cord after surgery.

www.ubcmj.com/pdf/ubcmj_2_1_2010_24-29.pdf
After severing the cervical sympathetic trunk, the cells of the cervical sympathetic ganglion undergo transneuronic degeneration
After severing the sympathetic trunk, the cells of its origin undergo complete disintegration within a year.
http://www.date.hu/acta-agraria/2002-08i/welento.pdf

sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain

Blocking sympathetic function, whether by surgical sympathectomy, systemic phentolamine, or systemic guanethidine, relieves partial nerve injury-induced neuropathic pain in laboratory animal models as well as humans (8, 35, 146, 239, 278). Indeed, sympathectomy does not just relieve pathological pain in the body region ipsilateral to the CRPS-initiating event; rather, it also relieves pain arising from anatomically impossible mirror-image sites, that is, the identical body region contralateral to the initiating event (278). Thus sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain. 

Alterations in sympathetic fibers rapidly follow peripheral nerve injury. This occurs as sprouting of sympathetic fibers, creating aberrant communication pathways from the new sympathetic terminals to sensory neurons (35). Sympathetic sprouting has been documented in the region of peripheral terminal fields of sensory neurons (262), at the site of nerve trauma (57), and within the dorsal root ganglia (DRG) containing cell bodies of sensory neurons (248, 343). Each of these sites develops spontaneous activity and sensitivity for catecholamines and sympathetic activation (8, 53). 

The clearest evidence that immune activation participates in sympathetic sprouting comes from studies of the DRG. DRG cells receive signals that peripheral nerve injury has occurred via retrograde axonal transport from the trauma site. These retrogradely transported signals trigger sympathetic nerve sprouting into DRG (205, 308). As a result of nerve damage-induced retrogradely transported signals, glial cells within the DRG (called satellite cells) proliferate (248) and become activated (343); macrophages are recruited to the DRG as well (63, 176). In turn, the activated satellite glial cells (and, presumably, the macrophages) release proinflammatory cytokines and a variety of growth factors into the extracellular fluid of the DRG (206, 246 –248, 258, 277, 308, 358). These substances stimulate and direct the growth of sympathetic fibers, which form basket-like terminals around the satellite cells that, in turn, surround neuronal cell bodies (247, 248, 343). 

Until recently, the sympathetic sprouting, rather than the glial (satellite cell) activation, has attracted the attention of pain researchers. The satellite cells were ignored as they were thought to be irrelevant to the creation of exaggerated pain states. However, it may be speculated that the satellite cells, rather than the sympathetic sprouts, have the most impact on pain.

Physiol Rev • VOL 82 • OCTOBER 2002 • www.prv.org

Beyond Neurons: Evidence That Immune and Glial Cells 

Contribute to Pathological Pain States 

LINDA R. WATKINS AND STEVEN F. MAIER 

Department of Psychology and the Center for Neuroscience, 

University of Colorado at Boulder, Boulder, Colorado

 

"-Adrenoceptor responsiveness in dorsal foot veins is increased in patients with tetraplegia. Hypersensitivity of vascular -adrenoceptors may contribute to autonomic dysreflexia in patients with high spinal cord injury."

J. M. O. Arnold¹ , Q. -P. Feng¹, G. A. Delaney² and R. W. Teasell³

(1)	Victoria Hospital, University of Western Ontario, 375 South Street, N6A 4G5 London, Ontario, Canada

(2)	Parkwood Hospital, University of Western Ontario, London, Ontario, Canada

(3)	University Hospital, University of Western Ontario, London, Ontario, Canada

Received: 5 September 1994 Accepted: 20 July 1995

nausea and vomiting are commonly associated with sympathetic withdrawal

F. Costa¹, P. Lavin¹, D. Robertson¹ and I. Biaggioni¹

(1)	Division of Clinical Pharmacology, the Clinical Research Center, and the Center for Space Physiology and Medicine, Departments of Pharmacology, Medicine, Neurology and Ophthalmology, Vanderbilt University, Nashville, TN, USA

(2)	Clinical Research Center, Room AA3228 Medical Center North, Vanderbilt University, 37232-2195 Nashville, TN, USA

Received: 6 July 1995

Abstract Conditions associated with nausea and vomiting, such as motion sickness or side effects of medications, are commonly associated with a clinical picture consistent with parasympathetic activation and sympathetic withdrawal.

The autonomic nervous system and the regulation of arterial tone in migraine

L. L. Thomsen¹ and J. Olesen¹

(1)	Department of Neurology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, DK-2600 Glostrup, Denmark Clinical Autonomic Research

Received: 17 March 1995 Accepted: 24 July 1995

Abnormal regulation of the large cranial arteries seems to play a significant role in the mechanisms of migraine pain. Thus, vasodilatation of extra- and intracranial conductance arteries has been described both during spontaneous migraine attacks and during experimentally provoked vascular headaches. The regulation of the diameter of these arteries is complex and involves autonomic, trigeminovascular, endothelial and humoral mechanisms. Studies concerned with the function of the autonomic nervous system in migraine suggest that a mild parasympathetic dysfunction may be present.

Neural Regulation of Pineal Serotonin

Melatonin Metabolism: Neural Regulation of Pineal Serotonin: Acetyl Coenzyme A N-Acetyltransferase Activity

David C. Klein,^* Joan L. Weller,^* and Robert Y. Moore^†

Proc Natl Acad Sci U S A. 1971 December; 68(12): 3107–3110.

Influence of sympathectomy in humans on the rhythmicity of 6-sulphatoxymelatonin urinary excretion

MOLLER Morten ; OSGAARD Ole ; GRONBECH-JENSEN Michael ;

The amount of 6-sulphatoxymelatonin, the chief metabolite of melatonin, in the urine was measured in nine patients, who were subjected to bilateral sympathectomy at the second thoracic ganglionic level for treatment of hyperhidrosis of the palms. All patients showed before surgery a normal 6-sulphatoxymelatonin excretion with a peak in the excretion during the night time. After the sympathectomy, the high night time excretion was clearly abolished in five patients but remained high in four patients. This indicates that the segmental locations of the preganglionic sympathetic perikarya in the spinal cord, stimulating the melatonin secretion in the pineal gland in humans, vary between individuals. An increase in daytime melatonin excretion was observed in the patients responding to the sympathectomy with an abolished 6-sulphatoxymelatonin rhythm. This increase could indicate that the final sympathetic neurons innervating the pineal gland might have a both stimulatory and inhibitory function.
Molecular and cellular endocrinology ISSN 0303-7207 CODEN MCEND6

Source / Source

2006, vol. 252, n^o1-2, pp. 40-45 [6 page(s)

Editeur / Publisher

Elsevier, Shannon, IRLANDE (1974)

The Pineal Gland and Sympathectomy

H. J. Romijn¹

(1)	Present address: Department of Electron Microscopy, Netherlands Central Institute for Brain Research, Amsterdam, The Netherlands

Received: 3 March 1975

Summary The ultrastructure of the rabbit pineal gland was investigated after sympathectomy (extirpation or decentralization of the superior cervical ganglia), parasympathectomy, continuous illumination and continuous darkness. The similarity of the ultrastructural changes in the light pinealocytes occurring after sympathectomy and after continuous illumination was striking. It is supposed that these changes have a common cause,viz. the lack of free noradrenaline, the pinealotropic neurotransmitter.

The smooth endoplasmic reticulum present in the terminals of the offshoots of the light pinealocytes is possibly involved in pineal indoleamine synthesis.

Pineal Gland - function

The pineal gland was originally believed to be a "vestigial remnant" of a larger organ (much as the appendix was thought to be a vestigial digestive organ). Aaron Lerner and colleagues at Yale University discovered that melatonin, the most potent compound then known to lighten frog skin, was present in the highest concentrations in the pineal.^[8] Melatonin is a derivative of the amino acid tryptophan, which also has other functions in the central nervous system. The production of melatonin by the pineal gland is stimulated by darkness and inhibited by light.^[9] Photosensitive cells in the retina detect light and directly signal the suprachiasmatic nucleus (SCN), entraining it to the 24 hour clock. Fibers project from the SCN to the paraventricular nuclei (PVN), which relay the circadian signals to the spinal cord and out via the sympathetic system to superior cervical ganglia (SCG), and from there into the pineal gland. The function(s) of melatonin in humans is not clear; it is commonly prescribed for the treatment of circadian rhythm sleep disorders.

In his book DMT: The Spirit Molecule, Dr. Rick Strassman hypothesized that the pineal gland produces the psychedelic chemical DMT,^[10] but there is no data to support this speculation.

The pineal gland is large in children, but shrinks at puberty. It appears to play a major role in sexual development, hibernation in animals, metabolism, and seasonal breeding. The abundant melatonin levels in children is believed to inhibit sexual development, and pineal tumors have been linked with precocious puberty. When puberty arrives, melatonin production is reduced. Calcification of the pineal gland is typical in adults.

Studies suggest that in rodents the pineal gland may influence the actions of recreational drugs, such as cocaine,^[13] and antidepressants, such as fluoxetine (Prozac),^[14] and its hormone melatonin can protect against neurodegeneration.^[15]

Cultures, philosophies and mythologies

The secretory activity of the pineal gland has only relatively recently become understood. Historically, its location deep in the brain suggested to philosophers that it possessed particular importance. This combination led to its being a "mystery" gland with myth, superstition and metaphysical theories surrounding its perceived function.

René Descartes, who dedicated much time to the study of the pineal gland,^[16] called it the "seat of the soul".^[17] He believed that it was the point of connection between the intellect and the body.^[18] This was in part because of his belief that it is unique in the anatomy of the human brain in being a structure not duplicated on the right and left sides. This observation is not true, however; under a microscope one finds the pineal gland is divided into two fine hemispheres. Another theory was that the pineal operated as a valve releasing fluids, thus the position taken during deep thought, with the head slightly down meeting the hand, was an allowance for the opening of these 'valves'.

The pineal gland is occasionally associated with the sixth chakra (also called Ajna or the third eye chakra in yoga) or sometimes the Seventh (Crown) chakra. It is believed by some to be a dormant organ that can be awakened to enable telepathic communication.^{[citation needed]}

procedures that interrupt the only source of central neural input to the pineal gland

PNAS | December 1, 1971 | vol. 68 | no. 12 | 3107-3110
Copyright © 1971 by the National Academy of Sciences

Melatonin Metabolism: Neural Regulation of Pineal Serotonin: Acetyl Coenzyme A N-acetyltransferase Activity

David C. Klein, Joan L. Weller, and Robert Y. Moore

There is a diurnal rhythm in the activity of serotonin N-acetyltransferase in the rat pineal gland. In the normal rat, the nocturnal enzyme activities are 15- to 30-fold greater than are daytime activities. This rhythm is abolished by decentralization or removal of the superior cervical ganglia, procedures that interrupt the only source of central neural input to the pineal gland. This effect of superior cervical sympathectomy on the N-acetyltransferase rhythm cannot be attributed to changes occurring in the denervated pineal parenchymal cells. When chronically denervated glands are placed in organ culture with norepinephrine, the neurotransmitter normally located in sympathetic terminals in the gland, N-acetyltransferase activity increases 10- to 20-fold. These data indicate that superior cervical sympathectomy abolishes the N-acetyl-transferase rhythm by elimination of the input of central signals to the gland. These signals appear to regulate the N-acetyltransferase rhythm in the normal rat by regulation of the release of norepinephrine from the sympathetic terminals within the pineal gland.

Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors

Neurobiology

Laura Calzà^*,,, Luciana Giardino^,, Alessandro Giuliani, Luigi Aloe^§, and Rita Levi-Montalcini^§

Department of Veterinary Morphophysiology and Animal Production, University of Bologna, 40064 Ozzano Emilia, Bologna, Italy; Pathophysiology Center for the Nervous System, Hesperia Hospital, 41100 Modena, Italy; and ^§ Institute of Neurobiology, Consiglio Nazionale delle Ricerche, 00137 Rome, Italy

Contributed by Rita Levi-Montalcini, December 29, 2000

In postnatal tissues, angiogenesis occurs in nontumoral conditions on appropriate stimuli. In the nervous tissue, hypoxia, neural graft, increased neural function, and synaptic activity are associated with neoangiogenesis. We have investigated the occurrence of neoangiogenesis in the superior cervical ganglia (scg) of newborn rats treated for 8-21 days with 6-hydroxy-dopamine (6-OHDA), nerve growth factor (NGF), or 6-OHDA + NGF. The two latter treatments induced a significant increase in scg size. However, the increase after combined treatment far exceeded that of NGF alone. Similarly, histological and histochemical analysis revealed neuronal hypertrophy and endothelial cell hyperplasia associated with stromal hypertrophy (as described by laminin immunostaining) and increased vascular bed (as revealed by platelet/endothelial cell adhesion molecule-1 immunostaining) in 6-OHDA + NGF-treated pups. NGF, either alone or associated with 6-OHDA, also induced a significant up-regulation of NADPH diaphorase, neuronal nitric oxide synthase, and vascular endothelial growth factor expression in scg neurons. The present investigation suggests that the increase of scg size induced by NGF and 6-OHDA + NGF is associated with neoangiogenesis, and that the induction of vasoactive and angiogenic factors in neurons represents a further and previously undisclosed effect of NGF.

Rapid Increase in Enzyme and Peptide mRNA in Sympathetic Ganglia after Electrical Stimulation In Humans

PNAS | June 1, 1989 | vol. 86 | no. 11 | 4302-4305
Copyright © 1989 by the National Academy of Sciences

Martin Schalling, Philip E. Stieg, Christer Lindquist, Menek Goldstein, and Tomas Hokfelt

Thoracic ganglia in humans were studied after electrical, preganglionic stimulation using in situ hybridization with synthetic oligonucleotide probes against the catecholamine-synthesizing enzymes tyrosine hydroxylase (EC 1.14.16.2) and dopamine ß -hydroxylase (EC 1.14.17.1) and neuropeptide tyrosine. Immunohistochemical analysis was also performed. Following short peroperative stimulation a severalfold increase in all three mRNAs was found in principal ganglion cells, whereas no definite changes could be detected in enzyme or peptide levels with immunohistochemistry. The results suggest a very rapid and sensitive regulation of genes involved in signal transmission in the sympathetic nervous system of humans. Moreover, they indicate that electrical stimulation of neurons and/or pathways combined with in situ hybridization may be used as a method to define neuronal projections by visualizing increases in mRNAs for transmitter enzymes and/or peptide in target cells.