*6.1. Purinergic Receptors*

In acute and chronic pain models, small- and medium-diameter sensory neurons, which express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors, are the important pain transducers of noxious stimuli [57]. In women with EM, TRPV1 receptor expression has been demonstrated to be elevated in endometriotic lesions and correlated with pain [36,37,57].

Purinergic receptors are ligand-gated ion channels that are expressed in sensory neurons which can be activated by adenosine triphosphate (ATP). P2X3 is one such purinergic receptor. In women with EM, ATP released during retrograde menstruation and due to mechanical stretch from endometriotic adhesions or fibrotic scar tissue could potentially activate P2X3 receptors, leading to neuronal hypersensitivity and pain [58]. Indeed, its expression in the endometrium of women with EM was significantly higher compared to control endometrium and interestingly was also correlated with the severity of pain reported [58,59]. Current interest in targeting P2X3 in EM is high, with multiple pharmaceutical companies having initiated drug programs, one of which has begun to enter Phase IIb clinical trials (NCT04614246).
