Expression of 5-HT3 receptors and TTX resistant sodium channels (NaV1.8) on muscle nerve fibers in pain-free humans and patients with chronic myofascial temporomandibular disorders

Abstract

BackgroundPrevious studies have shown that 5-HT3-antagonists reduce muscle pain, but there are no studies that have investigated the expression of 5-HT3-receptors in human muscles. Also, tetrodotoxin resistant voltage gated sodium-channels (NaV) are involved in peripheral sensitization and found in trigeminal ganglion neurons innervating the rat masseter muscle. This study aimed to investigate the frequency of nerve fibers that express 5-HT3A-receptors alone and in combination with NaV1.8 sodium-channels in human muscles and to compare it between healthy pain-free men and women, the pain-free masseter and tibialis anterior muscles, and patients with myofascial temporomandibular disorders (TMD) and pain-free controls.MethodsThree microbiopsies were obtained from the most bulky part of the tibialis and masseter muscles of seven and six healthy men and seven and six age-matched healthy women, respectively, while traditional open biopsies were obtained from the most painful spot of the masseter of five female patients and from a similar region of the masseter muscle of five healthy, age-matched women. The biopsies were processed by routine immunohistochemical methods. The biopsy sections were incubated with monoclonal antibodies against the specific axonal marker PGP 9.5, and polyclonal antibodies against the 5-HT3A-receptors and NaV1.8 sodium-channels.ResultsA similar percentage of nerve fibers in the healthy masseter (85.2%) and tibialis (88.7%) muscles expressed 5-HT3A-receptors. The expression of NaV1.8 by 5-HT3A positive nerve fibers associated with connective tissue was significantly higher than nerve fibers associated with myocytes (P < .001). In the patients, significantly more fibers per section were found with an average of 3.8 ± 3 fibers per section in the masseter muscle compared to 2.7 ± 0.2 in the healthy controls (P = .024). Further, the frequency of nerve fibers that co-expressed NaV1.8 and 5-HT3A receptors was significantly higher in patients (42.6%) compared to healthy controls (12.0%) (P < .001).ConclusionsThis study showed that the 5-HT3A-receptor is highly expressed in human masseter and tibialis muscles and that there are more nerve fibers that express 5-HT3A-receptors in the masseter of women with myofascial TMD compared to healthy women. These findings indicate that 5-HT3-receptors might be up-regulated in myofascial TMD and could serve as potential biomarkers of chronic muscle pain.

Gender Difference in Associations between Chronic Temporomandibular Disorders and General Quality of Life in Koreans: A Cross-Sectional Study

“…Several studies have been conducted to determine the principle and mechanism through which TMD physically and psychologically affects patients. Christidis et al discovered that 5-HT3A(serotonin)-receptor, an important pain transmitter, exists in high levels in the masseter and tibialis muscles, and women with TMD possess more nerve fibers releasing 5-HT3A-receptors [ 58 ]. Also, Ojima et al revealed that genetic factors involved in serotonin transport modulate serotonin secretion, with consequent potential to act as a catalyst in pathological expression of TMD [ 59 ].…”

Repeated tender point injections of granisetron alleviate chronic myofascial pain - a randomized, controlled, double-blinded trial

“…Evidence suggests that 5-HT activates the 5-HT 3 -receptor to mediate muscle pain and mechanical sensitivity [ 13 – 15 ]. In a recent study it was shown that the 5-HT 3A -receptor is highly expressed in human masseter muscles and that more nerve fibers express 5-HT 3A -receptors in women with M-TMD compared to healthy women [ 16 ]. Therefore, targeting peripheral 5-HT 3 -receptors with drugs that block these receptors could be an interesting therapeutic approach for chronic muscle pain.…”

The Effect of Granisetron on Sensory Detection and Pain Thresholds in Facial Skin of Healthy Young Males

“…5-HT exerts its effect by activating different receptors, grouped into 5-HT 1 -to 5-HT 7 -receptors (1). The 5-HT 3 -receptor is widely distributed on neurons both in the brain and peripherally and participates in nociception supraspinally, spinally, and in the periphery (2)(3)(4). 5-HT 3 -antagonists, such as granisetron, ondansetron, and tropisetron, are commonly used treat radiotherapy-and chemotherapy-induced vomiting and nausea (5).…”