The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines (original) (raw)

2008, Nature Reviews Drug Discovery

Histamine was first identified as a mediator of biological functions in the early 1900s and drugs targeting its recep tors have been in clinical use for more than 60 years. Histamine exerts a range of effects on many physiological and pathological processes and new roles are still being elucidated. The best characterized roles of histamine are those in inflammation, gastric acid secretion and as a neuro transmitter (FIG. 1). During inflammation, histamine is released from preformed stores in mast cells and basophils. Histamine acts on vascular smooth muscle cells and endothelial cells, leading to vasodilation and an increase in vascular permeability. In the skin, this results in the 'triple response' , which is an immediate local reddening due to vasodilation, a wheal due to increased vascular permea bility and a flare response due to indirect vasodilation via the stimulation of axonal reflexes 1. In the gastrointestinal system, histamine is essential for gastric acid secretion 2. Gastrin and vagal stimulation induce enterochromaffin like cells in the gut to release histamine. This histamine can then act on parietal cells to stimulate H + , K + ATPases, leading to the secretion of H + and subsequent acidifica tion that assists in digestive processes. Histamine is also a neurotransmitter in the CNS with a role in sleep-wake cycles, appetite, learning and memory 3. It is produced in a subset of neurons in the tuberomammillary nucleus of the hypothalamus and its effects are transmitted widely to other regions of the brain. These effects have led to the development of drug therapies for allergy, gastric ulcers, motion sickness and insomnia and have been so successful and widespread that the word antihistamine has entered the common lexi con. However, histamine has also been postulated to be involved in other conditions. For example, histamine is increased in bronchoalveolar lavage fluid from patients with allergic asthma and this increase negatively corre lates with airway function 4-9. An increase in histamine levels has been noted in the skin and plasma of patients with atopic dermatitis 10,11 and in chronic urticaria 12,13. Histamine levels are also increased in multiple sclerosis 14 and in psoriatic skin 15. Both plasma and synovial fluid of patients with rheumatoid arthritis and plasma of patients with psoriatic arthritis have increased hista mine levels 16,17. For all of these conditions, the traditional antihistamines are generally regarded to be ineffective, leading to the conclusion that histamine is not involved in their pathology. However, it is now known that the diverse biological effects of histamine are mediated through four different histamine receptors, including the most recently described histamine H 4 receptor. The antihistamines that are currently used in the clinic have little, if any, affinity for the H 4 receptor and, as outlined in this Review, this receptor has been shown to func tion in inflammatory responses in vitro and in vivo. This emerging role for the H 4 receptor and recent data on