TABLE 2.

Pain mechanisms in endometriosis.

	Site	Mechanism	Key players in pain
Inflammation	Peritoneal fluid and endometrial lesions	Retrograde menstruation and cyclical bleeding at lesion sites	Activation of an innate immune response increases inflammatory and nociceptive cytokines/chemokines (TNFα interleukins IL-8 and IL-1β) (Barcz et al., 2000), ROS, growth factors (NGF and VEGF) (Donnez et al., 1998), neutrophils and prostaglandins (PGE2) (Sacco et al., 2012; Králíèková and Vetvicka, 2015)
Neurogenic inflammation	Sensory nerves	Build-up of pro-nociceptive environment can act directly on sensory nerve fibers	Degraded tissue by-products including ROS, PGE2 and acidification can activate sensory nerves (Reeh and Steen, 1996; Holzer, 2011). Positive feedback loop maintains inflammation by releasing further proinflammatory modulators including SP and CGRP (Tokushige et al., 2006b).
Peripheral Sensitization	Peripheral sensory nerves	Neuroplasticity of peripheral sensory nerves	Persistent inflammation can cause structural and synaptic changes occur to shift the neuronal function into a more sensitized state (Brierley and Linden, 2014). The abundance of inflammatory molecules in the peritoneal fluid, including glycodelin, ROS, TNFα, NGF, and PGE2 may contribute to this (Chiu et al., 2012).
Central Sensitization	Central nervous system (CNS)	Long term changes in CNS signaling	Persistent nociceptive barrage leads to a long-lasting central sensitization of sensory afferents, evoking long term changes in pain processing or ‘memory’ (Bajaj et al., 2003; Woolf, 2011).
Cross-organ Sensitization	Sensitized afferents across multiple organs	Sensitized afferents from one organ induce sensitization of the afferents innervating another organ	Visceral afferents converge into similar areas of the spinal cord providing opportunity for the sensitization of neighboring cells due to spatial location (Ge et al., 2019)