Preferential innervation of endometriosis by hyperexcitable Ret/GFRα1+ nociceptors associates with target GDNF and clinical pain

Endometriosis, a widespread condition marked by persistent pelvic pain that is often challenging to treat, has resisted clear understanding of its underlying mechanisms. Clinical observations suggest that the extent of lesion innervation, rather than the disease stage, correlates strongly with the severity of pain. However, the nature of the neurons that innervate these lesions remains unclear, presenting a potential avenue for the discovery of innovative, disease-modifying treatments.

To address this gap, researchers conducted a study involving functional assessments of lesion-innervating neurons in a mouse model alongside the simultaneous identification and analysis of such neurons in endometriosis patients experiencing pain. The confirmation of pain-like behaviors in the mouse model led to electrophysiological examinations revealing that the dorsal root ganglion (DRG) neurons innervating the lesions exhibited heightened excitability compared to control neurons.

These neurons were predominantly small in diameter and expressed Isolectin B4, a recognized marker for the GDNF Family Ligand receptor, Ret. It was found that GDNF accumulates within the stromal layer of both mouse and human lesions, in close proximity to axons expressing GFR1, another receptor crucial for GDNF signaling. Particularly noteworthy is the finding that clinical pain severity correlates directly with lesion GDNF levels, axonal density, and the expression of GFR1 in neurons.

These findings suggest that endometrial lesions may enlist the Ret-positive subset of nociceptors, which become sensitized and exacerbate patient pain. This research offers compelling evidence that targeting Ret-positive nociceptors could represent a novel strategy for mitigating pain associated with endometriosis.