Accepted

Photobiomodulation therapy (PTB) is a therapeutic possibility for temporomandibular disorders (TMD), but its effectiveness and protocols for use remain controversial. This study is a RCT that compared the effectiveness of PTB on pain points of the masticatory muscles and TMJs, located through palpation versus application of pre-established points in women with painful TMD, diagnosis by DC/TMD (Diagnostic Criteria for Temporomandibular Disorders – Brazilian Portuguese version). Therefore, a total sample of 54 women, aged between 18 and 60 years, was investigated. Volunteers were randomly randomized and PTB was applied in four different groups with a dose of 4 J and 6 J divided into pre-established application points (PE – G1) and pain points (PD – G2) – Groups 4PE, 4PD, 6PE and 6PD. Four laser applications were performed with a wavelength of 780 nm, one session per week, totaling one month of therapy. The following assessments were performed: DC/TMD, Brief Pain Inventory (BPI), McGill Questionnaire – Short Version (SF-MPQ) and Pain Intensity, Visual Analogue Scale (VAS). Friedman's test was used for within-group comparisons, while the Mann-Whitney test was used for between-group comparisons (p < 0.05). According to the results, laser application on pain points (G2) was more effective. McGill's results showed that regardless of dose, the pain point application group had better outcomes (p = 0.004). Pain intensity evaluation (last days) also showed that application at the pain points was more effective regardless of dose (p = 0.0002). Medians and interquartile deviations showed overall that PTB was more effective at pain points, with a trend towards better outcomes at the 6 J dose. Therefore, it can be concluded that in women with chronic painful TMD, the application of PTB at pain points is more effective than the application at pre-established points. Therefore, individualized PTB protocols are proposed, based on examination palpation of the masticatory structures.

The amyloid precursor protein (APP) is critical for the pathogenesis of Alzheimer's disease (AD). The AD patients usually have lower pain sensitivity in addition to cognitive impairments. However, considerably less is known as yet about the role of APP and its two mammalian homologues, amyloid precursor-like protein 1 and 2 (APLP1, APLP2), in spinal processing of nociceptive information. Here we found that all APP family members were present in spinal cord dorsal horn of adult male C57BL/6J mice. Peripheral nerve injury specifically reduced the expression of spinal APLP2 that correlated with neuropathic mechanical allodynia. The loss of APLP2 was confined to inhibitory GABAergic interneurons. Targeted knockdown of APLP2 in GABAergic interneurons of GAD2-Cre mice evoked pain hypersensitivity by means of microglia activation. Our data showed that GABAergic terminals expressed APLP2, a putative cell adhesion protein that interacted with microglia-specific integrin molecule CD11b. Knocking down APLP2 in GAD2-positive neurons to disrupt the trans-cellular interaction led to microglia-dependent pain sensitization. Our data thus revealed an important role of APLP2 for GABAergic interneurons to control microglial activity and pain sensitivity.

Neuropathic pain is a growing concern in the medical community, and studies on new analgesic targets for neuropathic pain have become a new hot spot. Whether Connexin43 (Cx43) has a key role in neuropathic pain mediated by the purinergic 2X4 (P2X4) receptor in rats with chronic constriction injury (CCI) was explored in this study. Our experimental results show that blockade of Cx43 could attenuate neuropathic pain in rats suffering from CCI via the P2X4, p38, ERK, and NF-kB signalling pathways. These results suggest that Cx43 may be a promising therapeutic target for the development of novel pharmacological agents in the management of neuropathic pain.