Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

Abstract

The Ca2+-binding protein Kv channel interacting protein 3 (KChIP3) or downstream regulatory element antagonist modulator (DREAM), a member of the neuronal calcium sensor (NCS) family, shows remarkable multifunctional properties. It acts as a transcriptional repressor in the nucleus and a modulator of ion channels or receptors, such as Kv4, NMDA receptors and TRPV1 channels on the cytomembrane. Previous studies of Kcnip3-/- mice have indicated that KChIP3 facilitates pain hypersensitivity by repressing Pdyn expression in the spinal cord. Conversely, studies from transgenic daDREAM (dominant active DREAM) mice indicated that KChIP3 contributes to analgesia by repressing Bdnf expression and attenuating the development of central sensitization. To further determine the role of KChIP3 in pain transmission and its possible involvement in emotional processing, we assessed the pain sensitivity and negative emotional behaviors of Kcnip3-/- rats. The knockout rats showed higher pain sensitivity compared to the wild-type rats both in the acute nociceptive pain model and in the late phase (i.e., 2, 4 and 6 days post complete Freund’s adjuvant injection) of the chronic inflammatory pain model. Importantly, Kcnip3-/- rats displayed stronger aversion to the pain-associated compartment, higher anxiety level and aggravated depression-like behavior. Furthermore, RNA-Seq transcriptional profiling of the forebrain cortex were compared between wild-type and Kcnip3-/- rats. Among the 68 upregulated genes, 19 genes (including Nr4a2, Ret, Cplx3, Rgs9, and Itgad) are associated with neural development or synaptic transmission, particularly dopamine neurotransmission. Among the 79 downregulated genes, 16 genes (including Col3a1, Itm2a, Pcdhb3, Pcdhb22, Pcdhb20, Ddc, and Sncaip) are associated with neural development or dopaminergic transmission. Transcriptional upregulation of Nr4a2, Ret, Cplx3 and Rgs9, and downregulation of Col3a1, Itm2a, Pcdhb3 and Ddc, were validated by qPCR analysis. In summary, our studies showed that Kcnip3-/- rats displayed higher pain sensitivity and stronger negative emotions, suggesting an involvement of KChIP3 in negative emotions and possible role in central nociceptive processing.

The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes

“…Furthermore, Tian et al found that DREAM (N-terminal 31–50 fragment) interacts with transient receptor potential ion channel V1 (TRPV1) and exogeneous DREAM or N-terminal 31–50 fragment peptide alleviated CFA-induced thermal hyperalgesia behavior [ 65 ]. On the other hand, the genetic loss of DREAM in rats showed enhanced pain sensitivity in the CFA-induced pain model, along with increased anxiety/depression-like behavior [ 64 , 65 ]. Consistent with our findings, the alleviated morphine tolerance in melatonin-cotreated rats may be attributed to the increased Kcnip3 expression.…”

Association Between NR4A2 Gene Polymorphism and Depressive Symptoms and Antidepressant Effect

“… 31 The study by Le-Niculescu et al provided evidence for the involvement of NR4A2 gene in hippocampal anxiety. 32 Guo et al 6 evaluated pain sensitivity and negative emotional behavior in KCNIP3 -/- rats. It was confirmed that KCNIP3 -/- rats showed higher pain sensitivity, higher anxiety levels and aggravated depression-like behavior than wild-type rats.…”

“…Thus, it protects against inflammatory-mediated dopamine neuronal death. [5][6][7] The expression of NURR1 mRNA in adult mice was detected by in situ hybridization. After 30 min and 3 h of forced swimming experiment, the expression of NURR1 mRNA was increased not only in the whole cerebral cortex but also in the dopamine cell body region.…”

Comprehensive Analysis of Differentially Expressed Genes and Key Pathways in Neuropathic Pain by Spinal Nerve Ligation

“…For example, Kcnip3, a DEG not identi ed as a hub gene, is a voltage-gated potassium channel gene. Its expression level decreased in the SNL group, which would reduce the potassium current causing neurons to remain in a high potential state for a longer time, thus promoting neuropathic pain [36].…”