Unmyelinated nerve fibers in the human dental pulp express markers for myelinated fibers and show sodium channel accumulations

Abstract

Background The dental pulp is a common source of pain and is used to study peripheral inflammatory pain mechanisms. Results show most fibers are unmyelinated, yet recent findings in experimental animals suggest many pulpal afferents originate from fibers that are myelinated at more proximal locations. Here we use the human dental pulp and confocal microscopy to examine the staining relationships of neurofilament heavy (NFH), a protein commonly expressed in myelinated afferents, with other markers to test the possibility that unmyelinated pulpal afferents originate from myelinated axons. Other staining relationships studied included myelin basic protein (MBP), protein gene product (PGP) 9.5 to identify all nerve fibers, tyrosine hydroxylase (TH) to identify sympathetic fibers, contactin-associated protein (caspr) to identify nodal sites, S-100 to identify Schwann cells and sodium channels (NaChs). Results Results show NFH expression in most PGP9.5 fibers except those with TH and include the broad expression of NFH in axons lacking MBP. Fibers with NFH and MBP show NaCh clusters at nodal sites as expected, but surprisingly, NaCh accumulations are also seen in unmyelinated fibers with NFH, and in fibers with NFH that lack Schwann cell associations. Conclusions The expression of NFH in most axons suggests a myelinated origin for many pulpal afferents, while the presence of NaCh clusters in unmyelinated fibers suggests an inherent capacity for the unmyelinated segments of myelinated fibers to form NaCh accumulations. These findings have broad implications on the use of dental pulp to study pain mechanisms and suggest possible novel mechanisms responsible for NaCh cluster formation and neuronal excitability.

Nociceptive and sympathetic innervations in the abaxial part of the cranial horn of the equine medial meniscus: an immunohistochemical approach

“…Regarding the size of SP+ axons, even if estimations of axons' size is fairly unreliable due to the overlapping between A and C fibres (Bear et al 2007;Ruscheweyh et al 2007), the presence of axons of 0.6 and 5 lm in equine menisci suggest the presence of C and A fibres, respectively. Furthermore, our results are mostly in accord with Henry et al (2012), who reported that Schwann's cell nuclei with a more rounded appearance surrounded A myelinated fibres while elongated nuclei were associated with C unmyelinated fibres. Indeed, we found these two different shapes of nuclei, which correlates with the presence of two types of fibres, with the exception of Fig.…”

Ranolazine attenuates mechanical allodynia associated with demyelination injury

“…Without myelin, excitable membranes are found in close proximity, allowing for the establishment of ephaptic connections and cross-talk between neurons, which compromises the integrity of a transmitted signal and makes it possible for dispersion and amplification of signals that enter the central nervous system [65]. Additionally, the number of sodium channels increases dramatically and is inserted into the exposed membranes [16,25,62,64,[66][67][68][69][70], resulting in the generation of ectopic discharges. The resulting increase in regional excitability is thought to be associated with the perception of tingling, burning, sharp, and shocking pain [71].…”

Paradoxical surrogate markers of dental injury-induced pain in the mouse

“…Activation of pulpal fibers by thermal, mechanical or electrical stimuli almost always results in a sensation of pain [42; 49]. Interestingly, the majority of pulpal neurons are, in fact, low threshold mechanosensitive fibers rather than classical nociceptors [24; 29]. Outside of the tooth the axons of these neurons are myelinated, but they become unmyelinated upon entering the tooth, where the fibers branch extensively [9; 23; 26; 63].…”