Acute immobilization stress triggers skin mast cell
degranulation via corticotropin releasing hormone, neurotensin, and
substance P: A link to neurogenic skin disorders.
Singh LK, Pang X, Alexacos N, Letourneau R, Theoharides TC.
Department of Pharmacology and Experimental Therapeutics, Tufts University
School of Medicine, Boston, Massachusetts 02111, USA.
Many skin disorders, such as atopic dermatitis and psoriasis, worsen during
stress and are associated with increased numbers and activation of mast
cells which release vasoactive, nociceptive, and proinflammatory mediators.
Nontraumatic acute psychological stress by immobilization has
been shown to induce mast cell degranulation in the rat dura and colon.
Moreover, intradermal injection of corticotropin-releasing hormone (CRH) or
its analogue urocortin (10(-5)-10(-7) M) induced skin mast cell
degranulation and increased vascular permeability. Here, we investigated
the effect of acute immobilization stress on skin mast cell
degranulation by light microscopy and electron microscopy. Immobilization
for 30 min resulted (P < 0.05) in degranulation of 40.7 +/- 9.1% of skin
mast cells compared to 22.2 +/- 7.3% in controls killed by CO(2) or 17.8 +/-
2.4% in controls killed by pentobarbital. Pretreatment intraperitoneally (ip)
with antiserum to CRH for 60 min prior to stress reduced (P < 0.05) skin
mast cell degranulation to 21.0 +/- 3. 3%. Pretreatment with the neurotensin
(NT) receptor antagonist SR48692 reduced (P < 0.05) mast cell
degranulation to 12.5 +/- 3.4%, which was significantly (P < 0.05)
below control levels. In animals treated neonatally with capsaicin to
deplete their sensory neurons of their neuropeptides, such as substance
P (SP), mast cell degranulation due to immobilization stress was
reduced to about 15%. This is the first time that stress has
been shown to trigger skin mast cell degranulation, an action not only
dependent on CRH, but apparently also involving NT and SP. These
findings may have implications for the pathophysiology and possible
therapy of neuroinflammatory skin disorders such as atopic
dermatitis, neurogenic pruritus, or psoriasis, which are induced or
exacerbated by stress. Copyright 1999 Academic Press.
The role of psychoneuroimmunology in the pathogenesis
of psoriasis.
Farber EM, Lanigan SW, Rein G.
Department of Dermatology, Stanford University School of Medicine,
California.
Although it is well known that stress can trigger and exacerbate
psoriasis, the exact mechanism is unknown. An explanation is presented
based on recent findings in psychoneuroimmunology. The number of cutaneous
sensory nerves known to release neuropeptides, such as substance P,
is increased in patients with psoriasis. Preliminary data indicate
altered concentrations in psoriatic lesions of the same neuropeptides
known to be altered in the brain during stress. An anatomical pathway
is suggested to explain how descending information from the brain could
cause release of neuropeptides in the skin, which would then induce
psoriasis. Biochemical and clinical evidence is presented to support
the relationship between stress and psoriasis.
PMID: 2261789 [PubMed - indexed for MEDLINE]
MEDLINE Abstracts - Psychodermatology
- Dermatologic disorders may be significantly influenced by stress, stress-induced derangements in epidermal function as precipitators of inflammatory dermatoses. Yes there is an emerging field called psychodermatology &
neuroimmunoendocrinology.
Why doesn't everyone undergoing stress have the same symptoms? - Well besides stress
interpretation, coping mechanisms & environmental influences, genetic predispositions can
obviously effect us all differently. Is FB/FF/HH/Rosacea all psychosomatic
as some suggest?
Sympathetic nervous system activation in essential
hypertension, cardiac failure and psychosomatic heart disease.
Esler M, Kaye D.
Baker Medical Research Institute Melbourne, Australia.
Regional sympathetic activity can be studied in humans using
electrophysiological methods measuring sympathetic nerve firing rates and
neurochemical techniques providing quantification of noradrenaline spillover
to plasma from sympathetic nerves in individual organs. Essential
hypertension: Such measurements in patients with essential hypertension
disclose activation of the sympathetic outflows to skeletal muscle blood
vessels, the heart and kidneys, particularly in younger patients. This
sympathetic activation, in addition to underpinning the blood pressure
elevation, most likely also contributes to left ventricular hypertrophy, and
to the commonly associated metabolic abnormalities of insulin resistance and
hyperlipidaemia. Antihypertensive drugs, such as moxonidine, which act
primarily by inhibiting the sympathetic nervous system, should have
additional clinical benefits beyond those attributable to blood pressure
reduction, in protecting against hypertensive complications.
Obesity-related hypertension: Understanding the neural pathophysiology of
hypertension in the obese has been difficult. In normotensive obesity, renal
sympathetic tone is doubled, but cardiac noradrenaline spillover (a measure
of sympathetic activity in the heart) is only 50% of normal. In
obesity-related hypertension, there is a comparable elevation of renal
noradrenaline spillover, but without suppression of cardiac sympathetics
(cardiac sympathetic activity being more than double that of normotensive
obese and 25% higher than in healthy volunteers). Increased renal
sympathetic activity in obesity may be a 'necessary' cause for the
development of hypertension (and predisposes to hypertension development),
but apparently is not a 'sufficient' cause. The discriminating feature of
the obese who develop hypertension is the absence of the adaptive
suppression of cardiac sympathetic tone seen in the normotensive obese.
Heart failure: In cardiac failure, the sympathetic nerves of the heart are
preferentially stimulated. Noradrenaline release from the failing heart at
rest in untreated patients is increased as much as 50-fold, similar to the
level seen in the healthy heart during near-maximal exercise. Activation of
the cardiac sympathetic outflow provides adrenergic support to the failing
myocardium, but at a cost of arrhythmia development and progressive
myocardial deterioration. Psychosomatic heart disease: No more than 50% of
clinical coronary heart disease is explicable in terms of classical cardiac
risk factors. There is gathering evidence that psychological
abnormalities, particularly depressive illness, anxiety states, including
panic disorder and mental stress, are involved here, 'triggering' clinical
cardiovascular events, and possibly also contributing to atherosclerosis
development. The mechanisms of increased cardiac risk attributable to mental
stress and psychiatric illness are not entirely clear, but activation of the
sympathetic nervous system seems to be of prime importance.
Corticotropin-releasing hormone induces skin mast cell
degranulation and increased vascular permeability, a possible explanation
for its proinflammatory effects.
Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E,
Chrousos G.
Department of Pharmacology and Experimental Therapeutics, Tufts University
School of Medicine, Boston, Massachusetts 02111, USA. ttheoharides@infonet.tufts.edu
Mast cells are involved in atopic disorders, often exacerbated by stress,
and are located perivascularly close to sympathetic and sensory nerve
endings. Mast cells are activated by electrical nerve stimulation and
millimolar concentrations of neuropeptides, such as substance
P (SP). Moreover, acute psychological stress induces CRH-dependent
mast cell degranulation. Intradermal administration of rat/human CRH
(0.1-10 microM) in the rat induced mast cell degranulation and increased
capillary permeability in a dose-dependent fashion. The effect of CRH on
Evans blue extravasation was stronger than equimolar concentrations of the
mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH,
which does not interact with its receptors (CRHR), had no biological
activity. Moreover, systemic administration of antalarmin, a nonpeptide
CRHR1 antagonist, prevented vascular permeability only by CRH and not by
compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human
mast cells using RT-PCR. The stimulatory effect of CRH, like that of
compound 48/80 on skin vasodilation, could not be elicited in the mast cell
deficient W/Wv mice but was present in their +/+ controls, as well as in
C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice.
Treatment of rats neonatally with capsaicin had no effect on either Evans
blue extravasation or mast cell degranulation, indicating that the effect of
exogenous CRH in the skin was not secondary to or dependent on the release
of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue
extravasation and mast cell degranulation was inhibited by the mast cell
stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory
molecule somatostatin. To investigate which vasodilatory molecules might be
involved in the increase in vascular permeability, the CRH injection site
was pretreated with the H1-receptor antagonist diphenhydramine, which
largely inhibited the CRH effect, suggesting that histamine was involved in
the CRH-induced vasodilation. The possibility that nitric oxide
might also be involved was tested using pretreatment with a nitric
oxide synthase inhibitor that, however, increased the effect of
CRH. These findings indicate that CRH activates skin mast cells at
least via a CRHR1-dependent mechanism leading to vasodilation and increased
vascular permeability. The present results have implications for the pathophysiology
and possible therapy of skin disorders, such as atopic dermatitis, eczema,
psoriasis, and urticaria, which are exacerbated or precipitated by stress.
Servicio de Farmacia, Hospital de la Rioja, Logrono, Espana.
The presence of neuropeptides and their specific receptors has been
detected in the skin and the epithelial tissues. They are involved in
innervation, immunomodulation, glandular secretion, control of cellular
proliferation and regulation of blood flow. The fact that they act in so
many different ways means that neuropeptides and their agonists and
antagonists are now being regarded as potential therapeutic agents in
dermatologic diseases. Among the substances which act as antagonists,
particular attention should be paid to capsaicin, which has
therapeutic potential for three types of indication: peripheral neurologic
pain, affections with a neurogenic inflammatory component and pruriginous
dermatosis; peptide T with therapeutic potential for psoriasis; and spantide,
which might prove useful in dermatoses related to substance
P. The influence of topical corticosteroids on the mechanism of
action of neuropeptides can explain its efficacy in the treatment of many
dermatoses. Among the agonists, the possibility of taking advantage of the
vasodilatory activity of the calcitonin gene-related peptide is being
considered in Raynaud's disease and erectile disfunction of the penis; and
the immunomodulatory and anti-inflammatory action of the alpha-melanocyte
stimulating hormone is being studied as a potential means of controlling
inflammatory dermatoses of immunological origin.
Publication Types:
Review
Review, tutorial
PMID: 9273177 [PubMed - indexed for MEDLINE]
This study is still very preliminary (as SSRIs nearly try to prove they
are panaceas) but interesting nonetheless:
Short-term sertraline treatment suppresses sympathetic
nervous system activity in healthy human subjects.
Shores MM, Pascualy M, Lewis NL, Flatness D, Veith RC.
VA Puget Sound Health Care System (182B), 1660 S. Columbian Way, Seattle,
WA 98108, USA. mxs@u.washington.edu
Increased sympathetic nervous system (SNS) activity has been associated
with stress, major depression, aging, and several medical conditions.
This study assessed the effect of the selective serotonin reuptake
inhibitor (SSRI), sertraline, on sympathetic nervous system (SNS) activity
in healthy subjects. Twelve healthy volunteers participated in a
double-blind, placebo-controlled, norepinephrine (NE) kinetic
study, in which the effects of sertraline on SNS activity were ascertained
by determining NE plasma concentrations and NE plasma appearance rates and
clearance rates in sertraline or placebo conditions. Subjects received 50
mg of sertraline or placebo for two days and then one week later underwent
the same protocol with the other drug. By single compartmental analysis,
plasma NE appearance rates were significantly lower in the sertraline
compared to the placebo condition (0.26+/-0.10 vs 0.40+/-0.23 microg/m(2)/min;
P=0.04). Our study found that the net effect of short-term SSRI
treatment is an apparent suppression of SNS activity as indicated by a
decreased plasma NE appearance rate in the sertraline condition. If
this preliminary finding can be extended to long-term treatment of
patients, this could have significant therapeutic relevance for
treating depression in elderly patients or those with cardiac disease, in
which elevated SNS activity may exacerbate underlying medical conditions.
Drugs in development for social anxiety disorder: more
to social anxiety than meets the SSRI.
Ameringen MV, Mancini C, Farvolden P, Oakman J.
Anxiety Disorders Clinic, McMaster University Medical Centre, Hamilton
Health Sciences Corporation, 1200 Main Street West, Hamilton, ON, L8N 3Z5,
Canada. vanamer@fhs.mcmaster.ca
Individuals with social phobia (SP) fear and avoid a wide variety of
social and performance situations in which they are exposed to unfamiliar
persons or to possible scrutiny by others. The lifetime prevalence of
SP is estimated to be as high as 13%. It is frequently co-morbid with
and usually precedes the onset of other psychiatric illnesses and is
associated with significant occupational and social impairment, including
academic and vocational underachievement. Fortunately, there are
effective treatments for this common and debilitating condition. There is
currently considerable evidence for the efficacy of pharmacotherapy and
especially the monoamine oxidase inhibitors (MAOIs) and selective
serotonin re-uptake inhibitors (SSRIs) in the treatment of this disorder.
However, SSRIs are generally preferred as the first-line treatment of
choice due to the advantages of SSRIs over MAOIs in terms of safety and
tolerability. Despite encouraging results, current treatments most
often produce partial symptomatic improvement, rather than high end-state
functioning. While current first line treatments for social phobia
target the serotonergic system, it is important to remember that different
social fears are likely to have different developmental roots and may be
based on quite different neurobiological systems. In this article we
provide a review of current pharmacotherapeutic options for SP, current
knowledge of the neurobiology of SP, and a review of new and promising
directions in pharmacological research. It is increasingly clear that
serotonin (5-HT) is unlikely to be the whole story in SP and that other
brain chemical systems, especially the dopaminergic,
noradrenaline-corticotropin releasing hormone and gamma-aminobutyric acid
(GABA) dependent systems, most probably have an important role to play in
a substantial percentage of cases. A number of new and novel agents,
including the substance P antagonists,
GABA agonists and CRF antagonists show considerable promise in the
treatment of SP. However, in order to enhance the understanding of the
neurobiology and treatment response of SP, we need to develop more
sophisticated theory-driven typologies of SP.
