Characterization of circular RNAs in dorsal root ganglia after central and peripheral axon injuries.

In central nervous system, axons fail to regenerate after injury while in peripheral nervous system, axons retain certain regenerative ability. Dorsal root ganglion (DRG) neuron has an ascending central axon branch and a descending peripheral axon branch stemming from one single axon and serves as a suitable model for the comparison of growth competence following central and peripheral axon injuries. Molecular alterations underpin different injury responses of DRG branches have been investigated from many aspects, such as coding gene expression, chromatin accessibility, and histone acetylation. However, changes of circular RNAs are poorly characterized. In the present study, we comprehensively investigate circular RNA expressions in DRGs after rat central and peripheral axon injuries using sequencing analysis and identify a total of 33 differentially expressed circular RNAs after central branch injury as well as 55 differentially expressed circular RNAs after peripheral branch injury. Functional enrichment of host genes of differentially expressed circular RNAs demonstrate the participation of Hippo signaling pathway and Notch signaling pathway after both central and peripheral axon injuries. Circular RNA changes after central axon injury are also linked with apoptosis and cellular junction while changes after peripheral axon injury are associated with metabolism and PTEN-related pathways. Altogether, the present study offers a systematic evaluation of alterations of circular RNAs in rat DRGs following injuries to the central and peripheral axon branches and contributes to the deciphering of essential biological activities and mechanisms behind successful nerve regeneration.

Adult Hippocampal Neurogenesis along the Dorsoventral Axis Contributes Differentially to Environmental Enrichment Combined with Voluntary Exercise in Alleviating Chronic Inflammatory Pain in Mice.

Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intraplantar injection of complete Freund's adjuvant, our results revealed that EE-VEx alleviated perceptual, affective, and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Overexpression of BDNF in the dentate gyrus mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain.SIGNIFICANCE STATEMENT Environmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.

Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.