Peripheral Nociceptors as Immune Sensors in the Development of Pain and Itch

The peripheral nervous system and the immune system perform a series of similar functionalities such as recognizing, responding, and adapting to external or internal stimuli despite significant morphological differences. The peripheral nervous system actively communicates and coordinates with the immune system to function as a unified defense system. The peripheral nervous system is highly regulated by the immune system, especially under inflammatory conditions. On the other hand, the nervous system can modulate the immune system via neurotransmitters and chemokines released by the peripheral nerve endings, particularly from nociceptors. In both physiological and pathological conditions, peripheral nociceptive (including pruriceptive) neurons may express a variety of immune-related receptors, such as chemokine receptors and immunoglobulin (Fc) receptors that are usually found on immune cells. Certain ligands such as chemokines and immune complexes may induce abnormal neuronal hyperexcitability and even ectopic action potential discharges, therefore producing the sensation of pain and/or itch in immune-related diseases. The immune-sensing mechanisms of peripheral nociceptors may play an important role in the development of chronic pain and pruritus and may indicate novel therapeutic strategies for these pathological conditions.