The sodium channel 1.7 (Nav1.7), which is encoded by SCN9A gene, is involved in neuropathic pain. As crucial regulators of gene expression, many miRNAs have already gained importance in neuropathic pain, including miR-182, which is predicted to regulate the SCN9A gene. Nav1.7 expression in L4-L6 dorsal root ganglions (DRGs) can be up regulated by spared nerve injury (SNI), while miR-182 expression was down regulated following SNI model. Exploring the connection between Nav1.7 and miR-182 may facilitate the development of a better-targeted therapy. In the current study, direct pairing of miR-182 with the SCN9A gene was verified using a luciferase assay in vitro. Over-expression of miR-182 via microinjection of miR-182 agomir reversed the abnormal increase of Nav1.7 at both mRNA and protein level in L4-6 DRGs of SNI rats, and significantly attenuated the hypersensitivity to mechanical stimulus in the rats. In contrast, administration of miR-182 antagomir enhanced the Nav1.7 expression at both mRNA and protein level in L4-6 DRGs, companied with the generation of mechanical hypersensitivity in naïve rats. Collectively, we concluded that miR-182 can alleviate SNI- induced neuropathic pain through regulating Nav1.7 in rats.

Central post-stroke pain (CPSP) is a chronic neuropathic condition driven by central sensitization, often resulting in poor clinical outcomes. Neural circuits play a critical role in modulating chronic pain. To elucidate the mechanisms underlying CPSP, we established a mouse model via intracranial injection of type IV collagenase. cFos immunofluorescence and in vivo calcium imaging identified pain-associated activated nuclei. Using viral tracing, optogenetics, chemogenetics, and behavioral assays, we mapped a neural circuit comprising the ventral posterolateral thalamic nucleus (VPL), the hindlimb primary somatosensory cortex (S1HL), and the anterior cingulate cortex (ACC). In CPSP mice, ipsilateral S1HL^CaMKIIα and ACC^CaMKIIα neurons exhibited robust activation. Chemogenetic manipulation further demonstrated that activation of these neurons induced pain behaviors, whereas their inhibition alleviated pain. Notably, specific activation of the S1HL^CaMKIIα-ACC^CaMKIIα circuit produced mechanical allodynia, and optogenetic stimulation of VPL^CaMKIIα projections to S1HL similarly evoked pain responses while enhancing ACC neuronal firing. These findings underscore the critical role of the VPL-S1HL-ACC circuit in pain abnormalities and provide novel insights into the central sensitization underlying CPSP, suggesting promising therapeutic strategies for its management.

Chemotherapy-induced neuropathic pain poses significant clinical challenges and severely impacts patient quality of life. Sodium ion channels are crucial in regulating neuronal excitability and pain. Our research indicates that the microRNA-30b (miR-30b) in rat dorsal root ganglia (DRG) contributes to chemotherapy-induced neuropathic pain by regulating the Nav1.6 protein. Additionally, ten-eleven translocation methylcytosine dioxygenase 1 (TET1) plays a crucial role in pain generation by altering gene expression. We established a chemotherapy-induced neuropathy model using intraperitoneal oxaliplatin (OXA) injections and measured TET1 and Nav1.6 protein in the DRG. Using lentivirus and Tet1^flox/flox mice, we modulated TET1 expression and assessed pain behaviors, DRG neuronal excitability, Nav1.6 currents, miR-30b-5p, and demethylation of the Mir30b promoter region. We employed chromatin immunoprecipitation to pinpoint TET1-binding sites on the Mir30b promoter. The impacts of miR-30b agomir or antagomir on Nav1.6 expression and pain responses were assessed postintrathecal injections. The results showed that OXA reduced TET1, increasing neuronal excitability, Nav1.6 currents, and miR-30b-5p in the DRG. TET1 knockdown exacerbated these effects and induced pain behaviors. Conversely, TET1 overexpression reversed these effects. TET1 also targeted and enhanced demethylation at the Mir30b promoter (-1103 bp to -1079 bp). miR-30b agomir reduces Nav1.6, whereas miR-30b antagomir reverses TET1's effects on Nav1.6 and pain. In OXA-induced neuropathy, decreased TET1 reduces miR-30b, elevating Nav1.6 expression and currents and contributing to pain. We hypothesize that TET1 mediates this process by regulating the demethylation of the Mir30b promoter.

The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson’s disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals’ pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD.