A review.The contribution of sensory nerve fibers to inflammatory responses and immune regulation has been the subject of intense study for many years.Capsaicin has been particularly useful as a tool to probe this connection as it dissects a specific subset of sensory nerve fibers, namely those with unmyelinated fibers that carry polymodal nociceptors.These nerves are sites of release for various proinflammatory neuropeptides that initiate the cascade of neurogenic inflammation, and they convey pain to the central nervous system.The capsaicin receptor, also known as the vanilloid VR1 or TRPV1 receptor, plays a pivotal role in the hyperalgesic response that follows inflammatory challenge in rodent models of pain.TRPV1 is activated by noxious heat, and endogenous proinflammatory mols., such as arachidonic acid metabolites, nerve growth factor, bradykinin, and protons (tissue acidification), act in concert to reduce the heat activation threshold of this receptor below body temperatureTRPV1 protein levels are up-regulated in exptl. models of inflammatory hyperalgesia and in a number of human disorders (e.g., inflammatory bowel disease).Hence, the development of novel TRPV1 antagonists could bring about new therapies for the treatment of inflammatory diseases.The interaction between sensory nerves and immune cells is, however, even more complex than previously thought.For example, functional TRPV1 receptors are expressed on a broad array of cells (e.g., mast cells, lymphocytes, dendritic cells) involved in immune responses, and, in turn, mediators released from these cells (e.g., mast cell tryptase via proteinase-activated receptor 2 and protein kinase C) can activate TRPV1 in sensory nerves.A better understanding of the complex cross talk between sensory nerves and immune cells may identify novel indications for pharmacol. intervention.