Autonomic innervation of the heart and vasculature

As shown in the following table, activation of sympathetic efferent nerves to the heart increases heart rate (positive chronotropy), contractility (positive inotropy), rate of relaxation (increased lusitropy), and conduction velocity (positive dromotropy). Parasympathetic effects are opposite. Parasympathetic effects on inotropy are weak in the ventricle, but relatively strong in the atria. Physiologically, whenever the body activates the sympathetic system, it down regulates parasympathetic activity, and visa versa, so that the activities of these two branches of the autonomic nervous system respond reciprocally.

In blood vessels, sympathetic activation constricts arteries and arterioles (resistance vessels), which increases resistance and decreases distal blood flow. Sympathetic-induced constriction of veins (capacitance vessels) decreases venous compliance and blood volume, and thereby increases venous pressure. Most blood vessels in the body do not have parasympathetic innervation. However, parasympathetic nerves do innervate salivary glands, gastrointestinal glands, and genital erectile tissue where they cause vasodilation.

The overall effect of sympathetic activation is to increase cardiac output, systemic vascular resistance (both arteries and veins), and arterial blood pressure. Enhanced sympathetic activity is particularly important during exercise, emotional stress, and during hemorrhagic shock.

Cardiac function is altered by neural activation. Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects. Sympathetic and parasympathetic effects on heart function are mediated by beta-adrenoceptors and muscarinic receptors, respectively.

Sympathetic adrenergic nerves travel along arteries and nerves and are found in the adventitia (outer wall of a blood vessel). Varicosities, which are small enlargements along the nerve fibers, are the site of neurotransmitter release. Capillaries receive no innervation. Activation of vascular sympathetic nerves causes vasoconstriction of arteries and veins mediated by alpha-adrenoceptors.

Richard E. Klabunde, Ph.D.

loss of myocardial sympathetic-nerve terminals

"The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa–carbidopa (Sinemet)."

"The results of 6-[¹⁸F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa–carbidopa."

Sympathetic Cardioneuropathy in Dysautonomias

David S. Goldstein, M.D., Ph.D., Courtney Holmes, C.M.T., Richard O. Cannon, M.D., Graeme Eisenhofer, Ph.D., and Irwin J. Kopin, M.D.


The New England Journal of Medicine , March 6, 1997

Clinical Investigation

To validate the method, healthy volunteers underwent 6-¹⁸F-fluorodopamine scanning of the head, thorax, and abdomen, with or without treatment with desipramine to block sympathoneural uptake of catecholamines. ¹³N-Ammonia scanning was used to address possible group differences in 6-¹⁸F-fluorodopamine delivery by blood perfusion. Results: Desipramine treatment was associated with decreased 6-¹⁸F-fluorodopamine–derived radioactivity in the heart, renal cortex, and thyroid gland but not in the liver, spleen, renal pelvis, or salivary glands. Both the PD+OH group and the PAF group had decreased 6-¹⁸F-fluorodopamine–derived radioactivity in the heart (P <> (P = 0.02 and P = 0.005, respectively). The PD+OH group also had decreased radioactivity in the thyroid gland (P = 0.01). Neither group had decreased radioactivity in the other organs, after correction for ¹³N-ammonia–derived radioactivity. Conclusion: 6-¹⁸F-Fluorodopamine scanning visualizes sympathetic innervation in the heart, renal cortex, and thyroid gland. Both PD+OH and PAF involve decreased noradrenergic innervation that is most prominent in the heart but is also detectable in extracardiac organs.
Dnyanesh N. Tipre, MPharm, PhD and David S. Goldstein, MD, PhD

Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

JNM 2005 46

Heterogenous cardiac sympathetic innervation - cause of sudden cardiac death

Recently, a colony of German shepherd dogs with inherited spontaneous cardiac arrhythmias and associated sudden death has been developed and characterized. Due to the median age of onset of the arrhythmia (4.5 months), the tendency for the arrhythmia to occur during REM sleep or after exercise, and the absence of structural heart disease, we hypothesized a developmental abnormality of the sympathetic innervation to the heart. METHODS AND RESULTS: We studied 11 dogs from this colony, ranging in age from 6 months to 6 years, and four 7-month-old German shepherd dogs unrelated to the colony as controls. We imaged the distribution of functional myocardial sympathetic innervation and perfusion with [123I]metaiodobenzylguanidine (MIBG) and 201Tl, respectively. Sympathetic nerve distribution was evaluated morphologically by immunocytochemical localization of tyrosine hydroxylase. All of the hearts showed evidence of a regional decrease in MIBG uptake, ranging from 5.3% to 53.4% of the myocardium, whereas control dogs showed homogeneous MIBG uptake. Immunocytochemical studies on sections from regions with decreased MIBG uptake showed a striking paucity of nerves compared with regions with normal MIBG uptake, confirming denervation. When the dogs were grouped into those with (n=6) and without (n=5) evidence of ventricular tachycardia on ambulatory ECG, the group with ventricular tachycardia showed 35+/-16.5% denervation, whereas the group without ventricular tachycardia showed 12+/-5.6% denervation (P<.02). CONCLUSIONS: Abnormal heterogeneous sympathetic innervation exists in these dogs with inherited ventricular arrhythmia and sudden cardiac death. Mechanisms relating the presence and extent of regional denervation to the incidence of ventricular arrhythmia remain to be defined.

Loss of sympathetic innervation to the eye

Loss of sympathetic innervation caused a significant increase in steady state mRNA levels of fibronectin and a 15% increase in laminin-ß1 mRNA 3 weeks after surgical sympathectomy. Protein expression also increased at this point. In addition, capillary basement membrane thickness increased significantly. NG2 proteoglycan staining decreased significantly in pericytes in the sympathectomized rat retina. Steady state mRNA for PDGF-BB decreased significantly 6 weeks after surgery.
Sympathetic nerves may be compromised in diabetes, and these findings suggest that they may regulate some complications of diabetic retinopathy. Gene expression levels of fibronectin and laminin-ß1 changed between 1 and 3 weeks. These data are supported by electron microscopy, which showed the increase in basement membrane thickness in vivo. Loss of sympathetic innervation to the eye also caused a decrease in the number of pericytes. Steady state mRNA expression of PDGF-BB was reduced, suggesting a mechanism for the loss of pericytes in the sympathectomized retina. Overall, these results suggest that sympathetic nerve alterations may function in some complications observed in diabetic retinopathy, and this may be a suitable model to investigate therapies for this disorder.
(Investigative Ophthalmology and Visual Science. 2005;46:744-748.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI: 10.1167/iovs.04-1023

Coronary artery calcification

Ludman et al. have reported the prevalence of coronary artery calcification in heart transplant recipients and examined risk factors for calcifi- cation[1]. The authors noted that in some patients calcification was present despite angiographically trivial disease. One possible explanation to consider is that in cardiac transplant recipients, the usual close correlation between coronary artery calcification
and atheroma may not hold true.
Specifically, denervation might result in calcification of the media of coronary vessels. Medial calcification cannot easily be distinguished from intimal calcification with electron beam CT scanning.
Autopsy studies of unselected patients show that coronary calcification is atherosclerosis-related and intimal and this is the basis for using the calcification score as a proxy foratheroma burden. However, calcification of the media in in peripheral vessels is commonin diabetic patients in whom it is closely related to autonomic neuropathy and there are case reports of medial calcification in coronary vessels of diabetic patients.
Lumbar sympathectomy can also result in medial calcification
of peripheral vessels. Thus given that the transplanted heart is denervated
it is at least possible that some of the calcification detected
by Ludman et al is medial.
H.M. COLHOUN
Circ 1994; 90: 1786–93.

Clinical Lecturer in
Epidemiology and Public Health,
University College,
London, U.K.

Ablation of the sympathetic nervous system by sympathectomy is a standard model for the study of sympathetic nervous system regulation of immune function

Ablation of the sympathetic nervous system by chemical sympathectomy is a standard model for the study of sympathetic nervous system regulation of immune function. We have previously documented that chemical denervation results in enhanced antigen-specific, but suppressed mitogen-induced, cytokine production by spleen cells. In our investigation into the mechanisms of sympathectomy-induced immune alterations, we first evaluated the peritoneal environment into which the protein antigen keyhole limpet hemocyanin is administered. Denervation resulted in increased production of tumor necrosis factor- by peritoneal exudate cells and these cells appeared to have enhanced antigen presenting capability. We hypothesized that nerve terminal destruction may be inducing an inflammatory response by monocyte/macrophages and other cell types throughout the periphery that could differentially alter subsequent mitogen versus antigen-specific responses. However, no evidence of sympathectomy-induced systemic or local splenic inflammatory responses was observed, as indicated by measuring the proinflammatory cytokines tumor necrosis factor- and interleukin-1. These experiments indicate that an inflammatory response is not likely to be responsible for sympathectomy-induced immune alterations, eliminating a potential confounding factor in interpreting sympathectomy studies. Copyright 2001 Elsevier Science (USA).
Authors: Callahan T.A.^{1, 2}; Moynihan J.A.^{1, 2, 3, 4, 5}
Source: Brain, Behavior, and Immunity, Volume 16, Number 1, February 2002 , pp. 33-45(13)

Effects of antidepressants on cytokine production and actions

There are intriguing analogies between many features of depression and physiological and behavioral responses to infection, which are mediated by the brain effects of cytokines. These observations suggest that depression can be considered as a psychoneuroimmunological disorder where a central increase of pro-inflammatory cytokines, may have adverse consequences on the functional activity of the neurochemical and neuroendocrine systems implicated in the symptoms of the disorder. According to this hypothesis, the therapeutic effects of antidepressants should be at least partly exerted by attenuating the brain expression and/or actions of pro-inflammatory cytokines. Despite their inherent limitations, animal models of depression that are based on behavioral and pharmacological analogies with the symptoms observed in humans, represent the best available tool to test this hypothesis and to investigate the action mechanisms of the immune effects of antidepressants. Treatment with different classes of antidepressants indeed conferred protection against cytokine-induced depressive-like biological and behavioral changes. This ‘anti-inflammatory’ profile may be due to alterations of the pro-/anti-inflammatory cytokine balance. The mechanisms underlying these effects of antidepressants are presently unknown, but the available literature suggests several possibilities, including actions on different molecules representing potential mediators of mood disorders induced by cytokines. The studies summarized in this review have opened up new vistas in both the pathophysiology of depression and the pharmacology of antidepressants. Whether their demonstrated immune effects are a side effect or a significant part of their clinical activity still remains to be elucidated.

Nathalie Castanon^{, , a}, Brian E. Leonard^b, Pierre J. Neveu^a and Raz Yirmiya^c

^a INRA-INSERM U394, Neurobiologie Integrative, Institut François Magendie, Rue Camille Saint-Saëns, Bordeaux Cedex 33077, France

^b Pharmacology Department, National University of Ireland, Galway, Ireland

^c Department of Psychology, The Hebrew University, Mount Scopus, Jerusalem 91905, Israel

Received 9 July 2001.

Available online 1 October 2002.

In 1965, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression

In 1965, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. In favour of this hypothesis was the observation that the antihypertensive drug reserpine, which depletes central and peripheral vesicular stores of catecholamines such as noradrenaline, can precipitate depression in patients in remission. The experimental drug -methyl-paratyrosine that blocks the synthesis of noradrenaline and dopamine by inhibiting the rate-limiting enzyme tyrosine hydroxylase also precipitates depression in patients during remission. Such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression – more direct evidence is needed to substantiate the hypothesis.
In depression, it should be emphasised that the reduced growth hormone response to clonidine cannot be accounted for by the drug treatment, age or gender of the patient, which supports the view that the noradrenergic system is dysregulated. Lastly, determination of the urine or plasma concentrations of MHPG (an indicator of central noradrenergic activity), suggests that central noradrenergic function is sub-optimal in depression. Taken together, these results suggest that central noradrenergic function is decreased in depression, an event leading to an increase in the density of the post-synaptic ß-adrenoceptors (Leonard, 1986; Dinan, 1994).
The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in patients with depression. Whereas the overall psychophysiological effects of noradrenaline in the central nervous system appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood (see Charney et al, 1991). The main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), is reduced in the cerebrospinal fluid (CSF) of patients with severe depression, as are 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims (Agren, 1980). Serotonin receptor function is also abnormal in depression with an increase in the density of cortical 5-HT_2a receptors in the brains of suicide victims and also on the platelet membrane of patients with depression.
Dopaminergic function
Studies on platelets, lymphocytes, changes in cerebrospinal fluid metabolites of brain monoamines and post-mortem studies suggest that a major abnormality in both noradrenergic and serotonergic function occurs in depression, and that such changes could be causally related to the disease process.
Less attention has been paid to the possible involvement of dopamine in this disorder. However, anhedonia is a characteristic feature of major depression, and a defect in dopaminergic function is thought to be causally involved in this symptom (Willner, 1983). The concentration of the main dopamine metabolite, homovanillic acid (HVA), is decreased in the CSF of patients with depression, particularly those with psychomotor retardation.

Advances in Psychiatric Treatment (2000) 6: 178-186
© 2000 The Royal College of Psychiatrists

Clinical implications of mechanisms of action of antidepressants

Brian Leonard

Sympathetic innervation of white adipose tissue and its regulation of fat cell number

White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS), and the central origins of this innervation have been demonstrated for inguinal and epididymal WAT (iWAT and eWAT, respectively) using a viral transneuronal tract tracer, the pseudorabies virus (PRV). Although the more established role of this sympathetic innervation of WAT is as a major stimulator of lipid mobilization, this innervation also inhibits WAT fat cell number (FCN); thus, local denervation of WAT leads to marked increases in WAT mass and FCN. The purpose of this study was to extend our understanding of the SNS regulation of FCN using neuroanatomical and functional analyses. Therefore, we injected PRV into retroperitoneal WAT (rWAT) to compare the SNS outflow to this pad from what already is known for iWAT and eWAT. In addition, we tested the ability of local unilateral denervation of rWAT or iWAT to promote increases in WAT mass and FCN vs. their contralateral neurally intact counterparts. Although the overall pattern of innervation was more similar than different for rWAT vs. iWAT or eWAT, its SNS outflow appeared to involve more neurons in the suprachiasmatic and solitary tract nuclei. Denervation produced significant increases in WAT mass and FCN for both iWAT and rWAT, but FCN was increased significantly more in iWAT than in rWAT. These data suggest differences in origins of the sympathetic outflow to WAT and functional differences in the WAT SNS innervation that could contribute to the differential propensity for fat cell proliferation across WAT depots in vivo.
Robert R. Bowers,^1,* William T. L. Festuccia,^2,* C. Kay Song,³ Haifei Shi,³ Renato H. Migliorini,² and Timothy J. Bartness³

¹Molecular and Cellular Biology and Pathobiology Program, Medical University of South Carolina, Charleston, South Carolina 29425; ²Department of Physiology, School of Medicine, University of São Paulo, Ribeirão Preto-SP, 14049-900 Brazil; and ³Department of Biology and Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia 30303

Submitted 29 September 2003 ; accepted in final form 17 February 2004

Cross-talk between sympathetic neurons and adipocytes in coculture.

L C Turtzo, R Marx, M D Lane

Departments of Biological Chemistry and Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

White adipose tissue plays an integral role in energy metabolism and is governed by endocrine, autocrine, and neural signals. Neural control of adipose metabolism is mediated by sympathetic neurons that innervate the tissue. To investigate the effects of this innervation, an ex vivo system was developed in which 3T3-L1 adipocytes are cocultured with sympathetic neurons isolated from the superior cervical ganglia of newborn rats. In coculture, both adipocytes and neurons exhibit appropriate morphology, express cell-type-specific markers, and modulate key metabolic processes in one another. Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY). Secretion of NPY by neurons is up-regulated dramatically by the presence of adipocytes in coculture and appears to be mediated by an adipocyte-derived soluble factor. Insulin, an antilipolytic agent, down-regulates NPY secretion. Our findings suggest that an adipocyte-derived factor(s) up-regulates the secretion of NPY by sympathetic neurons, which, in turn, attenuates lipolytic energy mobilization by adipocytes.

Proc Natl Acad Sci U S A. 2001 Oct 23;98 (22):12385-90 11606782 (P,S,E,B) Cited:1

Completing the Loop: Neuron-Adipocyte Interactions and the Control of Energy Homeostasis

Control of energy homeostasis requires communication between the brain and adipose tissue. The sympathetic nervous system plays an integral role in relaying information during this process. Recent investigations indicate that the contributions of the sympathetic nervous system to the regulation of adipose tissue are greater than initially appreciated. A recently developed co-culture system provides evidence that a local feedback loop may exist between sympathetic neurons and adipose tissue. The co-culture approach may prove useful in further investigations of the interaction between sympathetic neurons and adipocytes, and might be adapted to study interactions between other types of neurons and adipose tissue.

L. C. Turtzo¹, M. D. Lane^{1 1} Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Horm Metab Res 2002; 34: 607-615
DOI: 10.1055/s-2002-38245

Limbic-cortical dysregulation: a proposed model of depression

J Neuropsychiatry Clin Neurosci 1997; 9:471-481
Copyright © 1997 by American Neuropsychiatric Association

REGULAR ARTICLES

HS Mayberg
Department of Medicine (Neurology), University of Texas Health Science Center at San Antonio 78284-6240, USA. mayberg@uthscsa.edu

A working model of depression implicating failure of the coordinated interactions of a distributed network of limbic-cortical pathways is proposed. Resting state patterns of regional glucose metabolism in idiopathic depressed patients, changes in metabolism with antidepressant treatment, and blood flow changes with induced sadness in healthy subjects were used to test and refine this hypothesis. Dorsal neocortical decreases and ventral paralimbic increases characterize both healthy sadness and depressive illness; concurrent inhibition of overactive paralimbic regions and normalization of hypofunctioning dorsal cortical sites characterize disease remission. Normal functioning of the rostral anterior cingulate, with its direct connections to these dorsal and ventral areas, is postulated to be additionally required for the observed reciprocal compensatory changes, since pretreatment metabolism in this region uniquely predicts antidepressant treatment response. This model is offered as an adaptable framework to facilitate continued integration of clinical imaging findings with complementary neuroanatomical, neurochemical, and electrophysiological studies in the investigation of the pathogenesis of affective disorders.

Causes of Changes in Brain Noradrenaline Systems and Later Effects on Responses to Social Stressors in Rhesus Monkeys: The Cascade Hypothesis

Disruption of social attachments in social primates produces a protest-despair response. In rhesus monkeys, the response is probably adaptive in the feral environment, although the despair stage resembles human depression in many respects. The severity of the response varies between individuals and is affected by deprivation of certain classes of social stimuli during development. Social deprivation is associated with differences in the concentrations of noradrenaline (NA) in cerebrospinal fluid and in responses to agents that affect catecholamine systems. Thus, early rearing conditions and pre-existing genetic or perinatal differences between monkeys can have long-term effects on the response to social separation, and NA system release and/or receptor mechanisms are involved.

NA systems appear to mediate adaptation to the environment from the level of perception to reorganization of neural tissue. Adaptation to the social environment may involve a cascade of changes that begins with behavioural coping attempts and terminates in structural reorganization of regions of the cerebral cortex. Processes at each level occur within environmentally appropriate but neurobiologically constrained time-frames. The cerebral NA system may be an adaptive mechanism that can fail or be damaged. Behavioural changes caused by such damage or failure would be manifested by inappropriate responses to environmental contingencies and inability to change behaviour to adapt to the prevailing environment. These features of NA system disorder could be common to depression and several other forms of human psychopathology.

Chapter Author: Gary W. Kraemer

Series: Novartis Foundation Symposia

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.
Leonard BE.
Department of Pharmacology, University College, Galway, Ireland.

Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons

Pieribone V A, Xu ZQ, Zhang X, Grillner S, Bartfei T and Hökfelt T (1995) Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons in the brainstem slice. Neuroscience 64, 861-874.

.

Serum dopamine-p-hydroxylase: Decrease after chemical sympathectomy

Drugs as Tools in Neurotransmitter Research

By Alan A.

Effects of locus coeruleus lesions on vigilance and attentive behaviour

Delagrange P, Canu MH, Rougeul A, Buser P, Bouyer JJ.

Département de Neurophysiologie comparée, CNRS-UPMC, Paris, France.

Previous data have suggested that in the cat, expectancy behaviour (waiting for a target to appear) and associated electrocortical, focal, synchronized activity ('mu' rhythms) are modulated by a noradrenergic system possibly originating from the locus coeruleus (LC). To test the latter hypothesis, we have examined the behavioural and ECoG changes induced after bilateral LC lesions. Our results demonstrated that destruction of the anterior 3/4th of the LC (A6 noradrenergic cell group) resulted in a considerable increase of mu rhythms and expectancy behaviour, without episodes of drowsiness that normally occur. Destruction of the posterior fourth of LC (A4 noradrenergic group) only increased the duration of slow sleep. Extending the A6 lesion to include the dorsal ascending noradrenergic bundle also increased the expectancy behaviour and mu rhythms. Finally, when the nucleus subcoeruleus was also involved, the duration of slow sleep and the frequency of paradoxical sleep episodes increased. These findings indicate that the LC exerts an inhibitory effect on structures involved in the induction and persistence of expectancy behaviour with accompanying mu rhythms.

Behav Brain Res. 1993 Feb 26;53(1-2):155-65.

Compensatory increase in tyrosine hydroxylase activity

.. INCREASE IN ACTIVITY AFTER CHEMICAL SYMPATHECTOMY, SCIENCE 163: 468 (1969). ... IN NEURONS OF NUCLEUS LOCUS COERULEUS DURING RETROGRADE REACTION, ...
www.sciencemag.org/cgi/content/refs/207/4430/537 -

Similar pages - Note this

Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: putative implications for psychiatry and psychopharmacology

the new data seem to allow a better understanding of how autonomic vulnerability or visceral dysfunction may precipitate or aggravate mental symptoms and disorder.

T. H. Svensson¹

(1)	Department of Pharmacology, Karolinska Institute, Box 60 400, S-104 01 Stockholm, Sweden

Received: 20 June 1986 Revised: 25 November 1986
Psychopharmacology

Sympathetic nervous system mediates cold stress-induced suppression of natural killer cytotoxicity

The aim of the present study is to investigate the mechanisms of suppression of splenic natural killer (NK) cytotoxicity caused by cold stress, using 6-hydroxydopamine (6-OHDA) as chemical sympathectomy. The NK activity was measured by ⁵¹chromium release assay. Central sympathectomy with intracerebroventricular injection of 6-OHDA significantly reduced the elevation of the plasma corticosterone level, the expression of Fos in hypothalamic paraventricular nucleus and in locus coeruleus, as well as the suppression of NK activity induced by cold stress at 4 °C for 4 h. Peripheral sympathectomy with intraperitoneal (i.p.) injection of 6-OHDA and blockade of β-adrenergic receptor with i.p. injection of propranolol also reversed the cold stress-induced suppression of NK cytotoxicity, but without significant effect on Fos expression in the brain. The results suggest that the activation of the hypothalamic-pituitary-adrenal axis induced by cold stress might be mediated, at least partially, by the central noradrenergic system, and that the cold stress-induced suppression of NK cytotoxicity might be mediated by the activation of the peripheral sympathetic nerve.

JIANG Xing-Hong ^{(1 2)} ; GUO Shi-Yu ^{(1 2)} ; SHUANG XU ^{(1 2)} ; YIN Qi-Zhang ⁽²⁾ ; OHSHITA Yusuke ⁽¹⁾ ; NAITOH Michiko ⁽¹⁾ ; HORIBE Yuzo ⁽¹⁾ ; HISAMITSU Tadashi ⁽¹⁾ ;
2004, vol. 358, n^o1, pp. 1-4 [ Neuroscience letters ISSN 0304-3940

Depletion of noradrenaline in the brain has been shown to cause a decrease in drive and motivation, and may be linked to depression.

A small area in the brainstem consisting of a pair of identical nuclei (clusters of neurons) in the pons from which all brain connections using noradrenaline arise. It appears to be involved in attention and mental focus.
A catecholamine neurotransmitter (catecholamine means that a substance belongs to a group of compounds containing ceratin structural characteristics, such as a catechol nucleus and an amine group), like dopamine. Cell bodies that contain noradrenaline are found in the pons and medulla, and these project neurons to the hypothalamus, thalamus, limbic system and cerebral cortex. These neurons are particularly important in controlling sleep patterns. Depletion of noradrenaline in the brain has been shown to cause a decrease in drive and motivation, and may be linked to depression.

locus coeruleus after guanethidine sympathectomy

Cytochemical study of the neurocytes of the rat locus coeruleus after guanethidine sympathectomy

Altan G, Iarygin VN, Grigor'eva AV.

The histone localization, template activity of chromatin and epinephrine fluorescence in L. Coeruleus (LC) neurons of normal a. guanethidine sympathectomized (GS) rats (15 mg/kg during 3, 8 or 14 days after birth) were studied. The absence of chromatin rearrangements connected with genome reprogramming under sympathectomy was documented by the fact that maximal doses of guanethidine gives no changes in ammoniacal silver staining pattern. However GS caused the decrease in nuclear and extranuclear template activity and in epinephrine fluorescence proportionally with GS. It is obvious that LC cells tend to form discrete classes according to their transcription levels.

Biull Eksp Biol Med. 1989 Feb;107(2):242-5.

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.