Accepted

Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 selective inhibitors are the most widely used drugs to treat pain. Conventional NSAIDs and COX-2 selective inhibitors, however, cause several side effects such as gastric damage, kidney damage, and cardiovascular problems. Our previous study showed that 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid ie, flusalazine (also known as ND-07), which exerts dual actions by serving both as an anti-inflammatory agent and a free radical scavenger, is an effective and safe treatment for severe inflammatory diseases in mice. The goal of the present study was to examine the potential analgesic action and safety of flusalazine in mice models of pain.

Low intraneuronal chloride in spinal cord dorsal horn (SCDH) pain relay neurons is of critical relevance for physiological transmission of primary sensory afferents because low intraneuronal chloride dictates GABA-ergic and glycin-ergic neurotransmission to be inhibitory. If neuronal chloride rises to unphysiological levels, the primary sensory gate in the spinal cord dorsal horn becomes corrupted, with resulting behavioral hallmarks of hypersensitivity and allodynia, for example in pathological pain. Low chloride in spinal cord dorsal horn neurons relies on the robust gene expression of and sustained transporter function of the KCC2 chloride-extruding electroneutral transporter. Based on a recent report where we characterized the GSK3-inhibitory small molecule, kenpaullone, as a gene expression-enhancer that potently repaired diminished expression and KCC2 transporter function in SCDH pain relay neurons, we extend our recent findings by reporting (i) effective pain control in a preclinical model of taxol-induced painful peripheral neuropathy that was accomplished by topical application of a TRPV4/TRPA1 dual-inhibitory compound (compound 16-8), and was associated with the repair of diminished gene expression in the SCDH; and (ii) potent functioning of kenpaullone as an antipruritic in a DNFB contact dermatitis preclinical model. These observations suggest that effective peripheral treatment of chemotherapy-induced painful peripheral neuropathy impacts the pain-transmitting neural circuit in the SCDH in a beneficial manner by enhancing gene expression, and that chronic pruritus might be relayed in the primary sensory gate of the spinal cord, following similar principles as pathological pain, specifically relating to the critical functioning of gene expression and the KCC2 transporter function.

After peripheral nerve injury, pain signals are transmitted from primary sensory neurons in the dorsal root ganglion (DRG) to the central nervous system. Epigenetic modification affects neuropathic pain through alterations in the gene expression in pain-related areas and glial cell activation. Recent studies have shown that non-coding RNA and n6-methyladenosine (m6A) methylation modification play pivotal regulatory roles in the occurrence and maintenance of neuropathic pain. Dysregulation of the RNA m6A level dynamic changes in methyltransferase and demethylase after central or peripheral nerve injury commonly regulates pain-associated genes, contributing to the induction and maintenance of neuropathic pain. The dynamic process has significant implications for the development and maintenance of neuropathic pain. However, the underlying mechanisms by which non-coding RNA and m6A RNA modification regulate neuropathic pain are not well-characterized. This article elucidates the multiple mechanisms of non-coding RNA and m6A methylation in the context of neuropathic pain, and summarizes its potential functions as well as recent advances.

Temporomandibular joint osteoarthritis (TMJ OA) is a disease with a multifactorial etiology, involving many pathophysiological processes, and requiring comprehensive assessments to characterize progressive cartilage degradation, subchondral bone remodeling, and chronic pain. This study aimed to integrate quantitative biomarkers of bone texture and morphometry of the articular fossa and joint space to advance the role of imaging phenotypes for diagnosis of Temporomandibular Joint Osteoarthritis (TMJ OA) in early to moderate stages by improving the performance of machine-learning algorithms to detect TMJ OA status. Ninety-two patients were prospectively enrolled (184 h-CBCT scans of the right and left mandibular condyles), divided into two groups: 46 control and 46 TMJ OA subjects. No significant difference in the articular fossa radiomic biomarkers was found between TMJ OA and control patients. The superior condyle-to-fossa distance ( < 0.05) was significantly smaller in diseased patients. The interaction effects of the articular fossa radiomic biomarkers enhanced the performance of machine-learning algorithms to detect TMJ OA status. The LightGBM model achieved an AUC 0.842 to diagnose the TMJ OA status with Headaches and Range of Mouth Opening Without Pain ranked as top features, and top interactions of VE-cadherin in Serum and Angiogenin in Saliva, TGF-1 in Saliva and Headaches, Gender and Muscle Soreness, PA1 in Saliva and Range of Mouth Opening Without Pain, Lateral Condyle Grey Level Non-Uniformity and Lateral Fossa Short Run Emphasis, TGF-1 in Serum and Lateral Fossa Trabeculae number, MMP3 in Serum and VEGF in Serum, Headaches and Lateral Fossa Trabecular spacing, Headaches and PA1 in Saliva, and Headaches and BDNF in Saliva. Our preliminary results indicate that condyle imaging features may be more important in regards to main effects, but the fossa imaging features may have a larger contribution in terms of interaction effects. More studies are needed to optimize and further enhance machine-learning algorithms to detect early markers of disease, improve prediction of disease progression and severity to ultimately better serve clinical decision support systems in the treatment of patients with TMJ OA.

The sympathetic nervous system (SNS) is suggested to be involved in some forms of pain, but the mechanisms of which are incompletely known. Moreover, there is a lack of information on the regulatory role of the SNS on macrophages in sensory ganglion, which plays an important role in pain development. The present study aims to investigate the effects of the SNS on orofacial inflammatory pain and examine, if any, how the SNS influences trigeminal ganglion (TG) macrophage responses.