Although mast cells were discovered over 100 years ago, they still represent a “biological enigma” [1]. Mast cells possess a series of biochemical and functional properties that place them at the center of both the inflammatory and immune responses. Mast cells are activated by stimuli of “agonists” and released by means of degranulation, a wide array of biologically active mediators. These mediators can be synthesized at the time of the stimulus, or can be immediately released from storage vesicles called cytoplasmic granules [2, 3]. Mast cells are able to respond to a wide range of agonist stimuli, and to differentially release biochemical mediators [4]. It is this heterogeneity that enables mast cells to have a functional role in a wide range of problems including sexual pain disorders, ranging from inflammatory conditions (e.g., IC), to neuropathic pain syndromes (e.g., PVD), to fibrotic involutions (endometriosis) [5–8].

Mast cells contain, and selectively release, biochemicals that mediate the typical signs and symptoms of local inflammation including erythema, edema, increased local temperature, pain, and functional impairment as first described by ancient Roman physicians in “rubor, tumor, calor, dolor, functio laesa.” These changes can be seen during a cystoscopic examination of a woman with IC or vulvoscopic (see Chapter 7) examination of a woman with PVD. Mast cells also contain “neurotrophins” that activate the nerve endings of pain fibers, inducing proliferation and growth toward the epidermis of the nerve terminals in the inflamed mucosa. These changes are the morphological correlates, respectively, of hyperalgesia and allodynia. These alterations in pain perceptions are typical of sexual pain disorders including PVD, generalized vulvodynia (GVD), and IC.

Selye was the first to describe the human mast cell as rounded elements with an oval nucleus and cytoplasm filled with spherical metachromatic granules, located in the dermis, adjacent to blood vessels, nerve endings, glandular ducts, and hair follicles. Historically, Toluidine blue and Giemsa stains were used to visualize mast cells microscopically [9, 10]. Unfortunately, these stain techniques inadequately demonstrated the presence of mast cells in inflamed tissue, but with newer immunostaining techniques (immunotryptase), mast cells are more easily seen. This increased visualization has yielded evidence of mast cell proliferation in the initial stages of several sexual pain disorders including PVD, IC, irritable bowel syndrome (IBS), and endometriosis. In later stages of these diseases, when the chronic inflammation has led to fibrosis, mast cells may almost disappear from the functionally deserted tissue.

Mast cells are currently divided into three groups based on their immunocytochemical characteristics [11, 12]. Specifically, there are mucosal mast cells containing only tryptase (mast cell_T); connective tissue mast cells containing tryptase, chymase, carboxypeptidase, and cathepsin G (mast cell_TC); and mast cells that can be found in several different tissues containing chymase and carboxypeptidase (mast cells_C). Although dermal mast cells have traditionally been thought of as indigenous only to the dermis, mast cells have a migratory capacity and demonstrate extraordinary functional adaptation in response to disturbances of tissue homeostasis [2].

The density of mast cells in inflamed tissue changes over time. In tissue where there is an acute inflammatory response, the concentration of mast cells is high. As the inflammation becomes more chronic, the number of mast cells decreases and may even disappear late in the fibrotic process. However, as the density of mast cells decreases, there is an increase in neuronal proliferation. At this late stage of the inflammatory process, neuropathic symptoms, such as spontaneous hyperalgesia, become prominent.

Dermal mast cells, which are strategically located between vessels and nerves, are directly stimulated by immunological signals from cytokines, immunoglobulin E, complement fractions, and neuropeptides [2, 13–15]. These activated dermal mast cells play several crucial roles in mediating the inflammatory responses discussed below:

(a) Neurogenic inflammation: Neuropeptide nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), and somatostatin are released by stimulated or damaged dermo-epidermal nerve endings. These neu-ropeptides activate local mast cells, causing degranulation [14]. In addition, physical, chemical, or mechanical stimuli also act to trigger mast cell degranulation [16, 17]. Once released from the mast cells, cytokines, growth factors,vasoactive amines, and proteolytic enzymes influence the surrounding cellular elements, thereby coordinating the biological response to tissue injury with both defensive and reparative effects.

(b) The mast cell–mediated vascular response: