Dental pulp is a soft mesenchymal tissue densely innervated by afferent (sensory) fibers, sympathetic fibers, and parasympathetic fibers. This complexity in pulp innervation has motivated numerous investigations regarding how these 3 major neuronal systems regulate pulp physiology and pathology. Most of this research is focused on
neuropeptides and their role in regulating pulpal blood flow and the development of
neurogenic inflammation. These
neuropeptides include
substance P,
calcitonin gene-related peptide,
neurokinin A,
neuropeptide Y, and
vasoactive intestinal polypeptide among others. The purpose of this article is to review recent advances in
neuropeptide research on dental pulp, including their role in pulp physiology, their release in response to common dental procedures, and their plasticity in response to extensive pulp and dentin
injuries. Special attention will be given to
neuropeptide interactions with pulp and immune cells via receptors, including studies regarding receptor identification, characterization, mechanisms of action, and their effects in the development of
neurogenic inflammation leading to
pulp necrosis. Their role in the growth and expansion of periapical lesions will also be discussed. Because centrally released
neuropeptides are involved in the development of dental
pain, the
pain mechanisms of the pulpodentin complex and the effectiveness of present and future pharmacologic
therapies for the control of dental
pain will be reviewed, including receptor antagonists currently under research. Finally, potential clinical
therapies will be proposed, particularly aimed to manipulate
neuropeptide expression or blocking their receptors, to modulate a variety of
biologic mechanisms, which preliminary results have shown optimistic results.