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Transdermal Histamine in Multiple Sclerosis

Part Two:  A Proposed Theoretical Basis for Its Use

George Gillson, MD, PhD, Jonathan V. Wright, MD, Elaine DeLack, RN, and George Ballasiotes, BSc, Pharm

Histamine Neurophysiology and Neuroanatomy
There is considerable evidence in the literature that histamine is an ancient and pervasive regulator of physiologic processes. Histaminergic neural paths extend throughout the bodies of lower organisms, including insects⁴ and marine animals.⁵ Histaminergic fibers are found in the sympathetic chains of mice⁶ and higher mammals.

Histaminergic neural paths extend from the brain to synapses in the higher cervical spinal cord.⁷ In humans, histaminergic fibers project from a dense population of cell bodies in the hypothalamus to almost all areas of the brain, including the cerebellum.^8-10 The goat pineal gland contains a large amount of histamine.¹¹ This suggests a link between histamine and melatonin production, although similar data on humans has not been obtained. Histamine is synthesized within these neurons by decarboxylation of the amino acid histidine.

The hypothalamic histaminergic system modulates diverse and crucial aspects of physiology, including thirst, hunger, sex drive, circadian rhythm, arousal level,¹² urine output,^13,14 thermoregulation,¹⁵ nociception,12 and vestibular function.^16,17 Histamine also participates in other aspects of neuroendocrine function, including stress-induced secretion of such mediators as adrenocorticotropin (ACTH), beta endorphin, melatonin, prolactin, and peripheral catecholamines.^18,19

Three different receptor subtypes, denoted H1, H2, and H3, mediate these responses. Discussion of these receptors can be found in reference 20. Briefly, all the histamine receptors are thought to be G-protein coupled receptors. Stimulation of the H1 receptor is, in general, associated with an increase in intracellular Ca2+ and formation of inositol triphosphate and diacylglycerol. Stimulation of the H2 receptor results in an elevation of intracellular cyclic adenosine monophosphate (cAMP). The intracellular coupling of the H3 receptor is not well understood; possible mechanisms include coupling to calcium channels. On neurons, the H3 receptor is a presynaptic receptor that is inhibitory both for release of histamine (autoreceptor) and other neurotransmitters (heteroreceptor).

The interpretation of experimental findings pertaining to histamine is sometimes difficult due to the number of histamine receptors and their diverse actions. For a given phenomenon, the action of histamine at H1 receptors often opposes that seen at H2 receptors.²¹ Sometimes the effects of stimulation at both receptors are the same.¹⁸ Furthermore, H3 receptor stimulation inhibits the release of histamine from mast cells, including brain mast cells.²² The effect of histamine in any given situation may, therefore, be sensitive to the relative populations of the three receptor subtypes at a given location, as well as the concentration of histamine in the vicinity of the receptors.

The following examples illustrate the diversity of action of histamine in the brain. In rats, H1 stimulation decreases feeding,¹³ increases alertness, and increases nociception,¹² whereas H3 receptor stimulation provokes drinking.¹³ Both H1 and H2 stimulation (via intracerebroventricular histamine receptor agonist injection) elicited hypothermia in mice, whereas H3 stimulation prevented development of hypothermia.¹⁵ Intracerebroventricular injection of histamine also stimulates diuresis in rats via H2 receptors. Histamine also stimulates release of melanocyte stimulating hormone from the pituitary via both H1 and H2 receptor stimulation.¹⁸

Approximately one-half of the histamine in the mouse brain resides in mast cells, as shown by Maeyama, who studied mutant mice devoid of mast cells.²³ Outside the brain, considerable histamine is stored in the enterochromaffin-like (ECL) cells of the gastric mucosa, where histamine plays a critical role in acid secretion. Histamine is also found in circulating basophils, eosinophils and platelets, as well as mast cells in many tissues, including the skin, heart, lungs, liver, kidneys, spleen, bladder, ovaries, and testicles.^24-27 Further discussion of the role of histamine in these tissues is beyond the scope of this article.

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