Hypothetical scenario that could potentially involve most of the proposed and interrelated causes in chronic prostatitis/chronic pelvic pain syndrome.

Hypothetical model of chronic pelvic pain syndrome. Intercellular homeostatic signaling demonstrating differentiation of CD4 T-cells in a context-dependent manner, regulation of mast cell activation by direct interaction (for example, through OX40 receptor), and activation of mast cells and subsequent deactivation, as well as how these signaling cascades interact to stimulate neurons. Reproduced from the article of Murphy et al. Nat Rev Urol 2014;11:259-69 [62] with permission. T_reg: regulatory T, ERK: extracellular signal-regulated kinases, JNK: c-Jun N-terminal kinase, NFB: nuclear factor kappa B, IFN: interferon gamma, IL: interleukin, TGF: transforming growth factor beta.

Hypothetical schematic representation of a modulated immune system in chronic prostatitis/chronic pelvic pain syndrome. An initiating event, such as bacterial infection, drives prostatic epithelial cell damage (1) and promotes the secretion and activation of proinflammatory cytokines, chemokines and presentation of antigens via antigen-presenting cells (APCs) (2). These signaling cascades result in CD4 T-cell activation, which is initially of Th1-type (interferon gamma, IFN) but Th17 activation is also implicated in the pathway, possibly at later stages of chronic pain development (3), followed by a loss of interleukin (IL)10-secreting suppressive regulatory T (T_reg) cells and a skewing towards Th1/17 responses (4). The loss of suppression of mast cells as a result of unchecked T-cell activation then results in a positive feedback loop in the mast cell (5, 6), resulting in degranulation and release of proteases such as tryptase, chymase, and allergy mediators such as histamine (7), and secretion of cytokines (such as IL6, IL17, tumor necrosis factor-, and IL6), resulting in the recruitment of inflammatory cells (8) and potentially disrupting the blood–brain barrier (9) and demyelinating neurons (10). Taken together, these processes result in neuronal activation and sensitization (11). The mast cell mediates these events and positive feedback loops enhance these processes. Further epithelial cell damage is one consequence of such increased mast cell activity (12). Prostate antigens generated from damage to the epithelium in the presence of an activated CD4 T-cell response, with unchecked mast cell degranulation and increased numbers of CD8 T-cells can result in the development of autoimmunity, which further exacerbates these mechanisms (13). Reproduced from the article of Murphy et al. Nat Rev Urol 2014;11:259-69 [62] with permission. TGF: transforming growth factor beta, ERK: extracellular signal-regulated kinases, JNK: c-Jun N-terminal kinase, NFB: nuclear factor kappa B.

The gate control theory of pain. This theory is based on the following propositions. (1) The transmission of nerve impulses from afferent fibers to spinal cord transmission (T) cells is modulated by a spinal mechanism. Gating mechanism in the dorsal horn. (2) The spinal gating mechanism is influenced by the relative amount of activity in large-diameter (L) and small-diameter (S) fibers: activity in large fibers tends to inhibit transmission (close the gate) while small-fiber activity tends to facilitate transmission (open the gate). (3) The spinal gating mechanism is influenced by nerve impulses that descend from the brain. (4) A specialized system of large-diameter, rapidly conducting fibers (the central control trigger) activates selective cognitive processes that then influence, by way of descending fibers, the modulating properties of the spinal gating mechanism. (5) When the output of the spinal cord transmission (T) cells exceeds a critical level, it activates the action system-those neural areas that underlie the complex, sequential patterns of behavior and experience characteristic of pain.