Abstract
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.
Highlights
Accumulating evidence suggests that neuro-immune and neuro-glial interactions play a critical role in chronic pain sensitization[1,2]
We first examined the expression of myeloid differentiation factor-88 adaptor protein (MyD88) in DRG neurons of littermate mice (WT) and MyD88 conditional knockout (CKO) mice, in which Myd[88] protein was deleted in Nav1.8-expressing primary sensory neurons, as described in our previous study[19]
Increasing evidence suggests that neurons expecially primary sensory neurons express Toll-like receptors (TLRs), including TLR3, TLR4, TLR5, TLR710,12–16
Summary
Accumulating evidence suggests that neuro-immune and neuro-glial interactions play a critical role in chronic pain sensitization[1,2]. Functional TLRs are expressed in microglia and astrocytes that modulate glial activation in persistent pain and itch conditions[8,9,10] While it is well known how immune/glial mediators sensitize pain, little is known as to how sensory neurons control inflammation and neuroinflammation[11]. Research on sensory neuron-specific role of TLR signaling is hampered by the lack of tissue (e.g., sensory neuron) specific knockout mice To this end, we generated MyD88 conditional knockout (CKO) mice by deleting MyD88 selectively in sodium channel Nav1.8-expressing nociceptive neurons[19]. We show that selective deletion of Myd[88] in Nav1.8-expressing primary sensory neurons in CKO mice leads to reductions in complete Freund’s adjuvant (CFA) induced inflammatory and chronic constriction injury (CCI) induced neuropathic pain in the maintenance phase, without affecting basal pain and acute inflammatory pain. Macrophage infiltration in DRGs and microglia activation in spinal dorsal horns after CCI are reduced in CKO mice
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