Increasing evidence suggests that neuro-immune and neuro-glial interactions are critically involved in chronic pain sensitization. It is well studied how immune/glial mediators sensitize pain, but how sensory neurons control neuroinflammation remains unclear. We employed Myd88 conditional knockout (CKO) mice, in which Myd88 was deleted in sodium channel subunit Nav1.8-expressing primary sensory neurons, to examine the unique role of neuronal MyD88 in regulating acute and chronic pain, and possible underlying mechanisms. We found that baseline pain and the formalin induced acute inflammatory pain were intact in CKO mice. However, the late phase inflammatory pain following complete Freund’s adjuvant injection and the late phase neuropathic pain following chronic constriction injury (CCI), were reduced in CKO mice. CCI induced up-regulation of MyD88 and chemokine C-C motif ligand 2 expression in DRG neurons and macrophage infiltration into DRGs, and microglia activation in spinal dorsal horns in wild-type mice, but all these changes were compromised in CKO mice. Finally, the pain hypersensitivity induced by intraplantar IL-1β was reduced in CKO mice. Our findings suggest that MyD88 in primary sensory neurons plays an active role in regulating IL-1β signaling and neuroinflammation in the peripheral and the central nervous systems, and contributes to the maintenance of persistent pain.

As the sole cell type responsible for bone resorption, osteoclasts play a pivotal role in a variety of lytic bone diseases. Suppression of osteoclast formation and activation has been proposed as an effective protective therapy for new bone. In this study, we reported for the first time that phillyrin (Phil), an active ingredient extracted from forsythia, significantly inhibited RANKL-induced osteoclastogenesis and bone resorption in vitro and protected against lipopolysaccharide-induced osteolysis in vivo. Further molecular investigations demonstrated that Phil effectively blocked RANKL-induced activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase, which suppressed the expression of c-Fos and nuclear factor of activated T-cells cytoplasmic 1. Taken together, these data suggested that Phil might be a potential antiosteoclastogenesis agent for treating osteoclast-related bone lytic diseases.

No abstract

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays important roles in the nervous system. Increasing evidence supports that IGF-1 contributes to pain hypersensitivity through its insulin-like growth factor-1 receptor (IGF-1R) by activating IGF-1R/Akt or MAPK signaling pathways, whereas T-type Cav3.2 channel can facilitate and amplify pain signals originating from the sensory periphery. A recent study showed that activated IGF-1R can increase T-type Cav3.2 channel currents and further activate the G protein-dependent PKCα pathway to contribute to inflammatory pain sensitivity. However, the colocalization of IGF-1R and Cav3.2 in mouse dorsal root ganglion (DRG) under chronic inflammatory pain conditions remains elusive. In this study, we investigated changes in the expression of IGF-1R and the Cav3.2 channel, and their colocalization in mouse DRGs in chronic inflammatory pain condition (induced by complete Freund's adjuvant intraplanter injection) using real-time RT-PCR and immunohistochemistry approaches to confirm that Cav3.2 channel can mediate pain facilitation following IGF-1/IGF-1R signaling. We found that IGF-1R was expressed extensively in DRG neurons including small-, medium-, and large-sized neurons, whereas Cav3.2 channel was expressed exclusively in small-sized DRG neurons of naive mice. Expression of Cav3.2, but not IGF-1R, and colocalization of Cav3.2 and IGF-1R were increased in lumbar (L)4-L6 primary sensory neurons in DRGs of mice in chronic inflammatory pain. Moreover, the increased colocalization of IGF-1R and Cav3.2 is exclusively localized in small- and medium-sized primary sensory neurons. Our findings provided morphological evidence that T-type Cav3.2 channel, at least partially, mediates the pain facilitation of IGF-1/IGF-1R signaling in chronic inflammatory pain condition.