**4. Neurogenic Inflammation**

The concept of neurogenic inflammation was first postulated by Bayliss (1901) [26] and stated that peripherally located nerve fibres caused vasodilation in the hind limbs of dogs when stimulated by mechanical, chemical or thermal stimuli. This suggests that afferent fibres could also fire in an antidromic direction. These local antidromic currents were termed the "axon reflex" which is responsible for the vascular flare observed following tissue injury. This activation of sensory neurones leads to an inflammatory response called neurogenic inflammation [26]. This phenomenon is very well investigated in other chronic pain conditions, such as asthma, rheumatoid arthritis, and inflammatory bowel disease, for example. Here, we would like to show the increasing evidence of neurogenically derived inflammatory mechanisms occurring in the EM.

In some EM patients, pain characterization shifts from the more cyclical into an acyclical pattern (see Section 3). In this case, the ongoing activation of sensory nerve fibres releases proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), both of which are found close to endometrial lesions [6,27]. Furthermore, activation of sensory afferent nerves might initiate the recruitment of mast cells and, subsequently, the release of proinflammatory cytokines as TNFα, NGF, PGE2 and a variety of interleukins, such as IL-1β [28,29]. This inflammation encourages further stimulation of locally circulating mast cells and Mϕ [30]. Different studies have shown a high number of these cells in endometriotic lesions as well as an increased amount of proinflammatory cytokines in the peritoneal fluid of EM patients [3,20,21,31–34]. This

contributes to a chronic state of neurogenic inflammation. Increased levels of TNFα and glycodelin correlate with central hyperexcitability in response to repeated electrical stimulation and altered pain response to nociceptive withdrawal reflex [6]. The nociceptive ion channel TRPV1 showed elevated expression on infiltrating adhesions in EM patients, the increase correlating with pain intensity [35–37].

Taken together, elevated expression and activation of nociceptors and elevated levels of neuropeptides, other proinflammatory chemicals and cytokines imply that neuroinflammatory processes are present in the central nervous system in EM.
