Concepts of entheseal pain.

Pain is the main symptom of entheseal diseases (enthesopathies) despite a paucity of nerve endings in the enthesis itself. Eicosanoids, cytokines, and neuropeptides released during inflammatory and repeated non-physiological mechanical challenge not only stimulate or sensitize primary afferent neurons present in structures adjacent to the enthesis or but also trigger a "neuro-vascular invasion" that allows spreading of nerves and blood vessels into the enthesis. Nociceptive pseudo-unipolar neurons support this process by releasing neurotransmitters from peripheral endings that induce neovascularization and peripheral pain sensitization. This process may explain the frequently observed dissociation between subjective symptoms, i.e. pain and the structural findings in imaging in entheseal disease.