The ion channels open based on pain stimuli propagating action potentials in sensory neurons.In order for excitability and conduction to occur, voltage-gated sodium channels must be activated. Changes in sodium channel (NaCH)  expression occur after inflammatory lesions, which may generate different pain states seen when neuronal fibers are activated. Studies have been done on major NaCh isoforms to examine expression patterns. Nav1.6 nodal accumulations do not vary in size or immunofluorescence staining activity in typical or atypical nodal sites; however, the proportion of typical nodal sites decreases and increase in atypical nodes in painful tooth samples compared to normal tooth samples. Nav1.7 has an increased expression in typical and atypical nodal sites in painful samples. As a result, an increased co-expression of multiple isoforms at demyelinating nodal sites in painful dental pulp. This isoforms of sodium channels may be a main factor in pain sensations due to their production of axonal excitability properties.Neuropeptides are increasingly being researched for having a role in molecular mechanisms involved with pain, including ion channels and inflammation. Substance P (SP) is a neuropeptide produced by capsaicin neuron cell bodies (localized in trigeminal ganglia and dorsal root) and plays a major role in dental pain and inflammation. Other peptides include cGRP, galanin, somatostatin, and neurokinin A-B. The biological effects of SP are expressed by the binding of specific G protein-coupled NK receptors. Interaction with SP receptors induces vasodilation and allows for plasma extravasation and mastocyte degranulation. SP is highly expressed in dental pulp and dentin.
Mutations generally prevent the production of any functional VHL protein or result in a change of structure of VHL protein. This genetic disorder shows an autosomal dominant inheritance pattern, with about 20% of patients possessing a new mutation. There are usually several other tumors which are part of the syndrome, including tumors of the central nervous system, kidneys, pancreas, adrenal glands, epididymis, broad ligament, along with the endolymphatic sac. The vast majority of patients with an endolymphatic sac tumor have von Hippel-Lindau syndrome. Pathology findings
Tumors range from several millimeters up to 10 cm, with larger tumors more frequently seen in older patients. If the tumor is bilateral, it is almost always seen in a VHL patient. The tumor destroys the mastoid air spaces and extends into the middle ear and/or posterior cranial fossa. The microscopic appearance shows an unencapsulated, destructive growth, remodeling and invading bone. The tumor is arranged as simple, broad, non-complex papillary projections without large cystic spaces. The spaces are often fluid filled, have extravasated erythrocytes and/or inspissated material. The cells are cuboidal, usually single layered along the papillary structures, showing indistinct cell borders. The nuclei are round and hyperchromatic. Immunohistochemistry
The neoplastic cells are reactive with keratin, CK7, and Epithelial membrane antigen, but negative with TTF-1 and CK20. Cytogenetics
The germline mutations of VHL tumor suppressor gene will be found on 3p25-26 (short arm  of chromosome 3), usually between base pair 10,158,318 to 10,168,761. Differential diagnosis
The clinical and pathology differential are different.