Pain
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Temporomandibular disorders (TMDs), collectively representing one of the most common chronic pain conditions, have a substantial genetic component, but genetic variation alone has not fully explained the heritability of TMD risk. Reasoning that the unexplained heritability may be because of DNA methylation, an epigenetic phenomenon, we measured genome-wide DNA methylation using the Illumina MethylationEPIC platform with blood samples from participants in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Associations with chronic TMD used methylation data from 496 chronic painful TMD cases and 452 TMD-free controls. ⋯ Functional characterization of the identified regions found relationships between methylation at these loci and nearby genetic variation contributing to chronic painful TMD and with gene expression of proximal genes. These findings reveal epigenetic contributions to chronic painful TMD through methylation of the genes FMOD , PM20D1 , ZNF718 , ZFP57 , and RNF39 , following the development of acute painful TMD. Epigenetic regulation of these genes likely contributes to the trajectory of transcriptional events in affected tissues leading to resolution or chronicity of pain.
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Although the secondary somatosensory cortex (SII) is known to be involved in pain perception, its role in pain modulation and neuropathic pain is yet unknown. In this study, we found that glutamatergic neurons in deep layers of the SII (SII Glu ) responded to bilateral sensory inputs by changing their firing with most being inhibited by contralateral noxious stimulation. Optical inhibition and activation of unilateral SII Glu reduced and enhanced bilateral nociceptive sensitivity, respectively, without affecting mood status. ⋯ This study revealed that SII Glu and the circuits to the VPL and Po constitute a part of the endogenous pain modulatory network. These corticothalamic circuits became hyperactive after peripheral nerve injury, hence contributes to neuropathic pain. These results justify proper inhibition of SII Glu and associated neural circuits as a potential clinical strategy for neuropathic pain treatment.
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The potential role of gut microbiota in pain modulation is arousing an emerging interest since recent years. This study investigated neuromodulatory properties of gut microbiota to identify next-generation probiotics to propose alternative therapies for visceral pain management. Neuromodulation ability of 10 bacterial strains isolated from a healthy donor was assessed both on ND7/23 immortalized cell line and primary neuronal cells from rat dorsal root ganglia. ⋯ Antihyperalgesic effect unlikely involved modulation of inflammatory processes or restoration of intestinal barrier. Exploration of direct dialogue mechanisms between this strain and nervous system, assessed by calcium imaging experiments, revealed that F1-2 interacts directly with nociceptors by reducing activation level on capsaicin, inflammatory soup, and bradykinin stimulations. Our study provides new insights about bacteria-host interaction and places P distasonis as a potential therapeutic strategy in the treatment of visceral pain observed in leaky gut-associated pathologies.
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Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. Painful diabetic neuropathy is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, axonal degeneration, and changes in cutaneous innervation. However, the complete molecular profile underlying the hyperexcitable cellular phenotype of DRG nociceptors in PDN has not been elucidated. ⋯ Furthermore, in vivo calcium imaging allowed us to demonstrate that activation of Mrgprd-positive cutaneous afferents that persist in diabetic mice skin resulted in an increased intracellular calcium influx into DRG nociceptors that we assess in vivo as a readout of nociceptors hyperexcitability. Taken together, our data highlight a key role of Mrgprd-mediated DRG neuron excitability in the generation and maintenance of neuropathic pain in a mouse model of PDN. Hence, we propose Mrgprd as a promising and accessible target for developing effective therapeutics currently unavailable for treating neuropathic pain in PDN.