The neurotransmitter hypothesis of urticaria

Medical Hypotheses 9: 617-634, 1982

THE NEUROTRANSMITTER HYPOTHESIS OF URTICARIA

John Charles NEWMAN : c/- the Clinical School, The Royal Prince Alfred Hospital, Camperdown. N.S.W. 2050, Sydney, Australia.

SUMMARY

The role of the CN S in the pathophysiology of urticaria has, historically, been almost totally neglected. The concept of the urticarias as “neurovascular disorders” is not a new one, and was first proposed at the turn of the century.

Recent advances in the understanding of the physiology of histamine (particularly in the CNS) permit an extension of the old “neurovascular hypothesis”. In this paper, evidence is presented to support the propositions that (i) dis- ordered histamine metabolism and/or release is common to all forms of urticaria, and (ii) that such peripheral upsets alter the hypothalamic functions of the histaminergic, serotoninergic and other amine neurotransmitter systems. Such hypothalamic upsets may disorder peripheral vascular function, thus amplifying or perpetuating the initial antigenic insult.

Thus, stress (by acting via the hypothalamic-vascular axis) may be part of the initiating event. Further, since the central histaminergic system is an ascending one, certain behavioural associations of urticaria (such as anxiety and depression) may have a physiological basis.

While the physical urticarias (cold, cholinergic and solar types) have been shown to be useful models of mast-cell histamine release, behavioural sequelae of such release should be assessed: recently, cholinergic urticaria was shown to result in alterations in lung-function, so other systemic effects are likely. Mastocytosis and urticaria pigmentosa (as extreme examples of conditions with excess plasma histamine release) have been associated with gross changes in CNS function.

While this paper argues the case for an intimate, two-way interplay between CNS and peripheral histamine in urticaria, it is suggested that the study of “food urticaria” might provide valuable insights into the effects of other mediators (such as prostaglandins) on CNS functioning; the effects of absorbed peptide fragments on CNS functioning provide yet another interactive pathway between the brain and peripheral vasculature.

Thus, it is suggested here that the CNS plays an important role in the pathogenesis of the urticarias, and that future research should not be restricted to the skin or the mastcell.

617

INTRODUCTION

Those clinical conditions known collectively as the “urticarias” are an heterogeneous group of disorders when one considers the immunology and the mediators involved (1); and their treatment is often unsatisfactory, as would be expected from a group of conditions whose pathophysiology is so poorly under stood.

The physical urticarias, in particular cold urticaria (21, offer the best starting-points for the development of the “neurotransmitter hypothesis” since they have been well-characterised now in terms of mediators, and reactions can be elicited reliably and reproducibly to various physical stimuli (such as cold, exercise and sunlight).

This paper proposes a new approach to the understanding of the pathophysiology of this group of diseases, and to their treatment. However, the foundations for this hypothesis were laid as long ago as 1903, by H. Radcliffe Cracker, of the University College Hospital, London, who regarded urticaria as “primarily a vasomotor disturbance” and also, by the great American allergist, W. W . Duke, who enunciated his “neurovascular hypothesis ” of cold urticaria in 1924 (3,4>.

* 2% * *

Any general hypothesis of urticaria must explain the following clinical observations:-

(a>

(b)

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(d)

(e>

The significance of the strong and repeated associations of stress with the onset of urticaria (6,7).

The frequent observation that emotional upsets, such as anxiety and depression, appear to be more strongly associated with urticaria than with other skin conditions (7,8> - and see Table 1.

Why certain drugs with central properties (such as cyproheptadine, hydroxyzine and the antidepressants appear to be more effective than conventional antihistamines (g-11).

How urticarias can arise following fevers and infection, chemical insults (including foods) and hormonal upsets, like pregnancy and thyroid dysfunction (5).

The observations of a “circadian pattern” of maximal whealing (in the mornings and evenings), (5).

Table 1 - Psychological Distress: mean scores per patient for Sheffield Rating Table subscales (after Fava, 1979).

Urticaria Fungal Dermatoses pa

Anxiety 0.91 0.48 pco.05 Depression 0.72 0.28 p co.01 Inadequacy 0.65 0.32 p co.01

618

In a previous review of cold urticaria (21, the essentials of the current hypothesis were outlined; the key concepts presented here are as follows:-

1. Urticaria is conceived of as a defect in the neuronai controls of microvessels, as well as of abnormal mast cell reactivity, or of deficiencies in various protease inhibitors, or of prostaglandin metabolism. (The subject of the relationship of histamine, prosto- glandins and the CNS is not considered in this paper).

2. There is a dynamic interaction between the skin, the mucosae (microvessels, mast cells and other mediator systems) and the CNS in terms of several important amine neurotransmitter systems.

3. While kinins, the leukctrienes and protease inhibitors have been implicated to varying degrees in individual cases of urticaria, histamine disturbances, both centrally and peripherally, probably contribute to the pathyphysiology of all types of urticaria (15,16,17).

4. Behavioural upsets are conceived of as incidental to disturbances in central histaminergic systems, which, in animals, appear to be ascending systems, passing through limbic brain structures, (58).

Histamine and Urticaria

The Harvard team of Soter, Wasserman et al. have lately demonstrated that cholinergic urticaria and a subtype of solar urticaria resemble cold urticaria in that histamine is released into the plasma of such patients, (12-140 This same group has nominated the physical urticarias as models of in vivo mast cells activation (15). Figure 1 illustrates the time-course of histamine release for these conditions; two peptides, ECF and NCF are also released from mast cells, and with a similar time-course.

While dermatologists have shown that histamine release from mast cells can be suppressed by steroids or doxantrazole, without abolishing the clinical signs (74,751, such a dissociation raises the question of “compartmentation” and whether local (or vessel) histamine concentrations are of more importance than plasma histamine levels. Of course, it is entirely possible that histamine release is an ‘epiphenomenon’ associated with vascular responses to other mediators (such as kinins or prostaglandins). If histamine release is indeed coincidental to some other process, then such drugs would permit a comparison of the effects of the urticarial response minus that due to histamine on CNS function. (Table 2 summarises drugs used for cold urticaria).

However, it has recently been demonstrated that intradermal histamine levels are elevated in patients with chronic idiopathic urticaria (161, and it was earlier recognised that the blood basophils of such patients exhibited a deficient histamine release (17). Thus, abnormalities of peripheral histamine metabolism appear to be associated with most types of urticaria. In the case of food-aggravated types, it has been suggested that substances absorbed across an abnormal mucosa might act as direct histamine releasers, (181, or that mast-cell bound IgE is somehow generated in the absence of circulating antibody, (81).

619

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FIGUREI. - Physical Urticarias Histamine release k

620

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Histamine Physiology and the CNS

It is perhaps not generally recognised that the physiology of histamine is still so poorly understood, although many workers have acknowledged this fact (19, 20).

For most medical graduates, the history of the physiology of histamine (and microvessels) begins with the brilliant empirical work of Sir Thomas Lewis in 1927, (21). However, while physiology texts maintain that the “flare” (spreading red reaction) of the Lewis “triple response” is not mediated by the CNS, a major neurology text states that the flare is modulated by the CNS - (22,23).

A series of clinical neurologists have challenged the view of the physiologists and have observed differences in responses to intradermal injections of histamine among patients with spinal cord and brain-damage (24-26).

This apparent discrepancy between the teachings of physiology and the findings of clinical neurology is no fault of Lewis, though; he did not exclude the influence of higher centres on the microvessels, merely demonstrating that such was not a necessary condition for the triple response. Further, Lewis did not claim to understand the pathophysiology of urticaria (21).

Closer scrutiny of the work of the neurologi sts confirms the concept of modern physiology, that microvessels are, in fact, modulated by various ascending and descending pathways from the cortex (patterned responses), through the hypothalamus and to the cord (which is concerned with local reflexes determ- ining vessel reactivity). Such concepts have been detailed in recent physiological reviews (27-29).

The mechanism whereby nervous factors can affect urticaria has been discussed by a number of authors (30-32). The cutaneous vascular reactions of patients with urticaria were studied, and correlated with stressful interviews. Vascular changes were measured by observing flushing and a raised skin temperature; there was also an effect on wheal production. This connection between the limbic system and the urticarial response is also illustrated by work in hypnosis: Kanako has reported the induction of urticarial attacks following the hypnotic suggestion of conflicts based on repressed aggression (33).

A “limbic connection” is strengthened by the many behavioural studies of urticaria patients. Shoemaker, for instance, reported that such patients often had an ‘unconscious conflict’ and were often frustrated at being unable to resolve their difficulties (loss of love), and that their anger occurred in a state of helplessness, (34). Reinhold (35) found that 18 of 27 patients im- proved markedly following discussions of life situations and psychotherapy. However, none of the behavioural work has attempted to correlate one specific type of urticaria (and mediators) with this “limbic connection”.

Once again, many dermatologists have referred to urticaria as “an exaggerated triple response”. While this may be descriptively useful, it may al so reflect the belief that urticarial effects are restricted to the skin, and responses being simply due to mast cell dysfunction.

622

It is increasingly clear that this view is a restrictive one, and the Harvard team has recently commented that, (with regard to the lung-function changes associated with cholinergic urticaria), “these observations extend to the lungs the manifestations of a condition thought to be restricted to the skin” (13).

To fully consider the pathophysiology of urticaria, then, concepts like the “triple response” and the “vasomotor centre” of the medulla must be updated in terms of modern physiology (29). Another concept which must be re-thought is that of the traditional ‘blood brain barrier’.

Histamine, the CNS and Neurotransmitters -

While it is commonly held that histamine does not cross this barrier, Synder & Axelrod showed that there was in fact measurable labelled histamine in rat brain following physiological doses (36); and there is evidence that histamine crosses more freely in pathological states, or in high doses (37). And while there is an anatomical barrier at the level of the capillaries, the ventricles are ‘leaky’ and the diencephalon and the hypothalamus both possess regions with amine-dependent transport vesicles (39). (Could these vesicles serve a “sensor function” for peripheral amine upsets?). In short then, the extent to which histamine affects the permeability and the function of the ‘blood brain barrier’ remains unsettled, and this is recognised in reviews (38) and by other investigators (53).

Similarities of structure between the skin and the brain are less improbable when one remembers their common embryological origins. Like the skin, brain microvessels possess histamine receptors, and mast-cells occur in various brain regiors (38,391. There are also some functional correlations. Stimulation of peripheral nerves can alter brain function. In sympathectomised monkeys, stimulation of the VII nerve nucleus near the medulla oblongata resulted in flow changes to the parietal lobe, while, in intact animals, the stimulation of sympathetics altered water permeability (40, 41) of whole brain.

CNS vessels possess both adrenergic and cholinergic nerve fibres in close association with small vessels, and the adjacent mast cells (38); so the CNS vessels (like peripheral vessels) are modulated by the autonomic (sympathetic) system. While “autoregulation” of brain vessels is the major physiological mechanism, the sympathetic system may over-ride this in certain pathological states. In the case of urticaria pigmentosa, for instance, diminished consciousness, fecal and urinary incontinence, flushing and thirst have been reported to be associated with high plasma histamine levels (86).

Therefore, CNS vessels share some similarities with the peripheral vascular system ; and while there is a high degree of compartmentation between the two systems, there is also a high level of functional interaction. For instance, synaptosomal levels of serotonin, the catecholamines and of acetylcholine are indirectly influenced by plasma concentrations of precursors (tryptophan, phenylalanine and choline), (42). The amino acid, histidine, is the direct precursor of histamine, both in the mast cell and in the synaptosome. As for the kidney (431, there are two transport systems into brain synaptosomes also. Similarly, in mammalian tissues , at least two isoenzymes are able to de- carboxylate histamine. One of these, (EC4.1.1.22) is specific for histidine has a high affinity for the aminoacid, and seems primarily responsible for the in vivo synthesis of histamine. The other is a low-affinity decarboxylase, and distinguishable from the former by pH optimum, and the effects of inhibitors (44).

623

As for other amines and their precursors, it has been demonstrated that changes in plasma histidine may affect levels of CNS histamine, and of various associated functions (45,461. Some of the biochemical interactions between peripheral histamine, histidine and other CNS amines were discussed in an earlier review (2).

“Histaminergic” Nerves

Many studies have demonstrated that peripheral histamine exerts an inhibitory effect (via HZ receptors) on presynaptic, adrenergic nerve terminals (47). What is less clear, however, is the issue of a peripheral “histaminergic” system.

This question has often been raised historically (481, and a consideration of a study by Ehinger (1974) offers some direct evidence. (Given the common embryology of brain and skin, and in view of many structural and functional similarities, plus the demonstration of a central histaminergic system, it might be supposed that histamine has a more direct input to the CNS than simply via amine precursors).

Ehinger (19) used rabbit iris preparations (which do not contain mast cells). He demonstrated that, using labelled precursors and autoradiography, there appears to be a histaminergic system closely applied to the adrenergic system. He further pointed out that, certain fine fibres, running in the cervical sympathetic ganglion to higher centres had not been rigorously identified as cholinergic, and could thus be of a histaminergic type.

Several pharmacological studies appear to support the existence of a peripheral histaminergic system (49~511, and the presence of histamine in sympathetic nerves adds to the controversy. Further, the presence of chemo- sensitive C-fibre pathways in the heart and great vessels reviewed recently (52), poses two questions: first, what happens to CNS function (in terms of amines concerned with neurovascular regulation) when there is a pathological whole-body release of histamine (short of anaphylaxis) in a physical urticaria? Secondly, what is the effect (via C-fibre afferents in the dermis and epidermis) on the CNS when there are very high local concentrations of histamine (and other mediators) in chronic idiopathic urticaria? The question, put simply, is “what are the effects cf histamine on the CNS - in particular, on the aminergic systems?”

Peripheral Histamine: CNS Effects

There has been surprisingly little work done to study the effects of histamine on the CNS; however, Mazurkiewicz-Kwilecki (53) did demonstrate changes in brain, heart and adrenal catecholamines following five weeks of histamine treatment in rats. Further, it has recently been reported that hypothalamic histamine levels are altered by the ip injection of Hl and H2 antagonists (54) and that intraventricular histamine injection alters the arousal state (behaviour) and the blood-pressure of goats in vivo, (55). Interestingly, peripheral histamine injections iv altered blood-pressure in a direction opposite to the intraventricular doses.

624

In a case-report of neurological effects of histamine release in mastocytosis, the rise in plasma histamine demonstrated was associated with some depression of the conscious state while blood-pressure was seen to drop only slightly. The author concluded that, “this may reflect a primary CNS effect of histamine on conscious state rather than one mediated via decreased cerebral perfusion associated with extreme hypotension” (86).

CN S Histamine

Currently, histamine appears to meet all the criteria for central neuro- transmission (56,571 and in rats, the predominant histaminergic system appears to bean ascending one, passing through the limbic system, and projecting to the cortex (58). This system appears to be closely related to the control of thermoregulation, other vascular functions, arousal, and to the production of certain pituitary hormones such as prolactin (59). It has previously been mentioned that chronic treatment with histamine (in rats) upsets catecholamine levels in the CNS; and it has been lately demonstrated that 4-methyl histamine and histamine itself can alter hypothalamic serotonin and 5-HIAA levels, and thus, by inference, the turnover of serotonin itself (61).

There has been much effort devoted to an understanding of the serotoninergic sys tern, and it appears to be intimately involved with the control of circadian rhythm, sleep, feeding, pain sensitivity, locomotor activity, aggression and thermoregulation (62).

Thus, at least two biogenic amines, histamine and serotonin, have been shown to be intimately concerned with the hypothalamic control of temperature. Very recently, Illig (87) has shown that the clinical onset of symptoms for two of the physical urticarias, generalised cold and cholinergic types, seems to be a function of the weighted average of skin plus core temperatures.

Thus, Illig believes that the initiating event in the onset of these urticarias must be concerned with thermoregulatory processes. His major concern is with peripheral mechanisms, but his work is also consistent with hypothalamic upsets: and it is worth noting that Duke, six decades ago, firmly maintained that cold urticarias were the result of some “hypothalamic dysfunction,” (4). Further, Kaplan, (891, reasoned that there must be some central component to cholinergic urticaria (from tourniquet tests), and felt that the efficacy of hydroxyzine in the treatment of this disease was due to some form of central antagonism.

However, single amines of the CNS must not be considered in isolation (as some psychiatrists did when framing the “amine hypothesis of urticaria”, (60). The various neurotransmitter systems interact, as Figure 2 attempts to illustrate. Indeed, prostaglandins may be the “final common denominator” of amine transmitter changes in the CNS (901, but the subject of prostaglandins, histamine and CNS function is too complex to be more than mentioned in passing here.

Clinical Implications of the Neurotransmitter Hypothesis

If the CNS is shown to be concerned with the pathogenesis of the urticarias, then new approaches to the management of these conditions would follow. For instance, patients with symptoms of anxiety and depression could be re-

625

CORTEX - behaviour b

LIMBIC - emotion \

P,T -, 1 , HYPOTHALAMUS

*Serotonin modulates AChE.

* Histamine modulates serotonin

HI strongly.NAd weakly.

l Serotonin modulates tyrosine

H2 hydroxylase.

(82-84).

on presynapt

Transmitter

-food additives, preservatives.

FIGURE2 - INTERACTING AMINE SYSTEMS.

626

assured that their emotional status was part of their “allergic“ diathesis, and not a separate problem: and the hoary old belief that urticaria is “psychosomatic” (implying moral responsibility on the part of the patient) could be Iaid to rest forever.

The circadian pattern of whealing would be explained on the basis of hypothalamic neurotransmitter rhythms (affecting peripheral vascular status and mast cell reactivity). In the case of generalised cold and cholinergic urticarias, such a phenomenon might simply be associated with signals of reduced temperatures in the morning and evenings (skin) plus reduced physical activity (core temperature) to the hypothalamus.

Further, the “neurotransmitter hypothesis” would relate both the antiserotonin and the antihistamine properties of such drugs as cyproheptadine, hydroxyzine and amitriptyline to their actions on specific central amine systems.

The concept that the antidepressant drugs may act on histamine receptors in the CNS to achieve some clinical actions is an interesting one, first proposed in 1978 and repeated more recently (67,68). It has been argued that antihistamine effects are the common property shared by these (diverse) classes of drugs; such an idea is clearly an oversimplification, but it does highlight the increasing importance being attached to histaminergic functions. However, tricyclics such as amitriptyline , for instance, have many effects: this drug has recently been shown to be implicated in the slow shift of serotonin receptor-populations, thus suggesting a possible mechanism for its (ten day) delayed onset in the depressions (69).

The three drugs, amitriptyline, hydroxyzine and cyproheptadine cross the blood brain barrier ’ ; amitriptyline and hydroxyzine possess potent anti- cholinergic properties in terms of metabolites (631, while drugs with a tricyclic structure (and various antipsychotic drugs) possess potent anti- kinin properties (64). (It should be remarked here that the role of the kinins in urticarias requires more critical assessment, in the light of work by Michaelsson with chronic urticaria (651, and of DeLaus and Winkelmann with cold urticaria (66).

Therefore, such drugs mentioned above are probably useful in the treatment of the urticarias precisely because they possess such a multiplicity of actions, both cent rally and peripherally.

While the initiating event may be any one of a number of events (immune complexes with SLE urticaria, CNS upsets with cold and cholinergic urticarias), the final common pathway for all urticarias would appear to involve histamine upsets: the value of this hopothesis is that it predicts behavioural sequelae which can be minimised by counselling and judicious use of low doses of tricyclic antidepressants: such practice has already been reported to be successful by two Australian dermatologists (881, but controlled trials clearly need to be undertaken. Low doses of antidepressants would be re - commended in such trials (lo-50 mg/day), since these drugs are being used as central/peripheral antihistamine and antiserotonin agents.

627

CONCLUSIONS

Urticaria was believed to be a “neurovascular disorder” at the turn of the century, but it has only been relatively recently that enough knowledge has accumulated to begin to detail the pathogenesis of this group of disorders.

The physiology of histamine is still poorly understood, but over the past few years, some significant advances have been made: histamine is associated with certain vascular and arousal mechanisms (as a neurotransmitter), and the hypothalamic system has been shown to be affected by peripheral histamine antagonists. Whether such effects occur directly (via leakage across regions of the cerebral circulation) or by means of direct nervous inputs, is still unclear.

Urticaria is a complex problem; the roles of other mediators (the kinins and prostaglandins) need to be better understood, as do effects of protease in- hibitor deficiencies, and agents which affect calcium metabolism. Neverthe- less, there is a strong case to be made for histamine upsets being associated with most forms of urticaria; and since histamine is the best-known of the mediators, it is logical to frame a general hypothesis of urticaria in terms of its physiology: and there is now good evidence for an interaction between peripheral histamine release and upsets of CNS function.

In a recent paper by Juhlin on recurrent urticaria (711, 16% of patients presented with severe psychiatric problems, while more than one third felt that their urticaria was aggravated by food substances.

It has been demonstrated that chronic urticariants have a reduced intestinal capacity for proteolysis (18)) and the possible role of altered peptides, absorbed through a defective GIT mucosa and affecting peptide neurotransmitter systems has been mentioned by Klee (72).

The validity of the “neurotransmitter hypothesis of urticaria will probably be extended in the near future, as relations between the other mediators, peptides and CNS function are better understood.

The clinical significance of the hypothesis is clear: if it is correct, then practitioners can explain clearly to their patients with mood-problems that there is probably a physiological basis underlying their irritability, anxiety or depression; further, if it is correct, then consideration must be given to the development of more specific central amine-antagonists (and to double- blind trials using the tricyclic antidepressants) in an effort to improve the treatment of the urticarias.

**********

626

1.

2.

3.

4.

5.

6.

7.

8.

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LO .

11.

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13.

14 *

15.

16.

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