Peripheral changes in endometriosis-associated pain

Abstract

Background: Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis.

Methods: We conducted a systematic search using several databases (PubMed, MEDLINE, EMBASE and CINAHL) of publications from January 1977 to October 2013 to evaluate the possible roles of the peripheral nervous system in endometriosis pathophysiology and how it can contribute to endometriosis-associated pain.

Results: Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins. In women suffering from deep infiltrating endometriosis and bowel endometriosis, in which the anatomical distribution of lesions is generally more closely related to pelvic pain symptoms, endometriotic lesions and surrounding tissues present higher nerve fibre densities compared with peritoneal lesions and endometriomas. More data are needed to fully confirm a direct correlation between fibre density in these locations and the amount of perceived pain. A better correlation between the presence of nerve fibres and pain symptoms seems to exist for eutopic endometrium. However, this appears not to be exclusive to endometriosis. No correlation between elevated neurotrophin levels and pain severity appears to exist, suggesting the involvement of other mediators in the modulation of pain.

Conclusions: The increased expression of neurotrophic factors and nerve fibres in endometriotic lesions, eutopic endometrium and the peritoneum imply a role of such peripheral changes in the pathogenesis of endometriosis-associated pain. However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated.

Keywords: Endometriosis; nerve fibres; neuroangiogenesis; neurotrophins; peripheral changes.

Figure 1. Pain Taxonomy

Figure 2. Complexity of endometriosis-associated pain

Schematic presentation of important factors in endometriosis-associated pain.

Figure 3. Common cues of nerve and blood vessels wiring

Abbreviations: BDNF, Brain-derived neurotrophic factor; CGRP, calcitonin gene-related peptide; CGRPR, calcitonin gene-related peptide type receptor; DCC, deleted in colorectal carcinoma; NGF, β-nerve growth factor; NK-1R, neurokinin-1 receptor; NRP1, Neuropillin-1; NT3, neurpthrophin 3; p75, Low-Affinity Nerve Growth Factor Receptor; Robo, Roundabouts; SP, substance P; Sema, Semaphorin; Trk-A, high-affinity nerve growth factor receptor; Trk-B, BDNF/NT3 growth factors receptor; Trk-C, NT3 growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2. Schematic representation of the different molecules involved in nerve and blood vessel remodelling. In general, VEGF and NGF stimulate neuronal migration, axonal growth and blood vessels growth. However, the filopodia of both endothelial cells and axons express several receptors that may account for the different roles of several molecules in nerve and blood vessel remodelling. The VEGF¹⁶⁴ throughout Nrp1 attracts the filopodia whereas Sema3A/F binding to plexins/Nrp1 repels the filopodia (Atwal et al., 2003). In blood vessels Sema3E might bind to Plexins-d directly, independently of Npn1, promoting angiogenesis, whereas Sema3A stimulation of VEGFR/Nrp-1 inhibits endothelial cell migration. Conversely, binding of NGF to p75 on endothelial cells might inhibit endothelial survival (by inducing apoptosis) and encourage vascular regression. BDNF-p75 signalling shows a repulsive role while BDNF-TrkB signalling accounts for survival of 30–35% of sensory neurons (Jones et al., 1994) The attractive effects of Netrins in nerves are mediated by receptors of the DCC family, whereas members of the UNC5 family mediate the repulsive effects. Slits are implicated in axonal repulsion through Robo receptors. Other molecules, such as substance P and CGRP which are more important in inflammation, can also have an angiogenic role.

Figure 4. Possible pathophysiologic alterations in the peritoneal cavity of women with endometriosis

Abbreviations: AKT, Protein kinase B; COX-2, Cyclooxyhenase-2; EP/IP, Prostaglandins receptors; ERK, Extracellular signal-regulated kinases; HR, histamine receptor; IL, Interleukin; IP3, Inositol trisphosphate; PDGF, platelet-derived growth factor; PK, Protein kinase; RANTES, regulated on activation, normal T cell expressed and secreted; TGF-β, Transforming growth factor beta; TRPV1, transient receptor potential cation channel subfamily V member 1 Several immune mediators (cytokines, interleukins, growth factors) are upregulated in peritoneal fluid of women with endometriosis. All these molecules can be secreted by different immune cells and mediate the release of each other, thus maintaining a vicious circle. NGF is markedly up-regulated in nerve fibers associated with the inflamed area. NGF is secreted by inflammatory and endometriotic cells and can stimulate the synthesis of SP and CGRP (that activate mast cells to release histamine). NGF and these molecules also sensitize (lower the threshold) or excite the terminals of sensory nerve fibres. Other neurotrophins also play a critical role in the bidirectional signaling mechanisms between immune cells and the neurosensory network structures in the peritoneal cavity. Hypothetical mechanisms of peripherally mediated cross-organ sensitization through the innervation of the visceral organs and endometriosis implants by a single sensory neuron. Schematic drawing of a sensory nociceptor ending in the tissue. This schematic depicts neuropeptides and their receptors on a sensory afferent nerve fibre ending. The list of receptors and their associated neuropeptides is not complete, but those that are most relevant to inflammation and most researched are shown. These receptors act on different second messenger systems, which can act on voltage-gated ion channels, responsible for the generation of action potentials.