Trim14-IκBα Signaling Regulates Chronic Inflammatory Pain in Rats and Osteoarthritis Patients.

Chronic inflammatory pain is the highest priority for people with osteoarthritis when seeking medical attention. Despite the availability of NSAIDs and glucocorticoids, central sensitization and peripheral sensitization make pain increasingly difficult to control. Previous studies have identified the ubiquitination system as an important role in the chronic inflammatory pain. Our study displayed that the E3 ubiquitin ligase tripartite motif-containing 14 (Trim14) was abnormally elevated in the serum of patients with osteoarthritis and pain, and the degree of pain was positively correlated with the degree of Trim14 elevation. Furthermore, CFA-induced inflammatory pain rat model showed that Trim14 was significantly increased in the L3-5 spinal dorsal horn (SDH) and dorsal root ganglion (DRG), and in turn the inhibitor of nuclear factor Kappa-B isoform α (IκBα) was decreased after Trim14 elevation. After intrathecal injection of Trim14 siRNA to inhibit Trim14 expression, IκBα expression was reversed and increased, and the pain behaviors and anxiety behaviors of rats were significantly relieved. Overall, these findings suggested that Trim14 may contribute to chronic inflammatory pain by degrading IκBα, and that Trim14 may become a novel therapeutic target for chronic inflammatory pain.

Thalamic Nucleus Reuniens Glutamatergic Neurons Mediate Colorectal Visceral Pain in Mice via 5-HT2B Receptors.

Irritable bowel syndrome (IBS) is a common functional bowel disorder characterized by abdominal pain and visceral hypersensitivity. Reducing visceral hypersensitivity is the key to effectively relieving abdominal pain in IBS. Increasing evidence has confirmed that the thalamic nucleus reuniens (Re) and 5-hydroxytryptamine (5-HT) neurotransmitter system play an important role in the development of colorectal visceral pain, whereas the exact mechanisms remain largely unclear. In this study, we found that high expression of the 5-HT2B receptors in the Re glutamatergic neurons promoted colorectal visceral pain. Specifically, we found that neonatal maternal deprivation (NMD) mice exhibited visceral hyperalgesia and enhanced spontaneous synaptic transmission in the Re brain region. Colorectal distension (CRD) stimulation induced a large amount of c-Fos expression in the Re brain region of NMD mice, predominantly in glutamatergic neurons. Furthermore, optogenetic manipulation of glutamatergic neuronal activity in the Re altered colorectal visceral pain responses in CON and NMD mice. In addition, we demonstrated that 5-HT2B receptor expression on the Re glutamatergic neurons was upregulated and ultimately promoted colorectal visceral pain in NMD mice. These findings suggest a critical role of the 5HT2B receptors on the Re glutamatergic neurons in the regulation of colorectal visceral pain.

Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice.

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA a useful model for autism. However, how MIA causes autistic behaviors in offspring is not fully understood. Here, we show that NKCC1 is critical for mediating autistic behaviors in MIA offspring. We confirmed that MIA induced by poly(I:C) infection during pregnancy leads to autistic behaviors in offspring. We further demonstrated that MIA offspring showed significant microglia activation, excessive dendritic spines, and narrow postsynaptic density (PSD) in their prefrontal cortex (PFC). Then, we discovered that these abnormalities may be caused by overexpression of NKCC1 in MIA offspring's PFCs. Finally, we ameliorated the autistic behaviors using PFC microinjection of NKCC1 inhibitor bumetanide (BTN) in MIA offspring. Our findings may shed new light on the pathological mechanisms for autism caused by pregnancy infection.