Patients with
neuropathic pain are usually accompanied by depression.
Chemokine-mediated
neuroinflammation is involved in a variety of diseases, including
neurodegenerative diseases, depression, and
chronic pain. The nucleus accumbens (NAc) is an important area in mediating
pain sensation and depression. Here we report that spinal nerve
ligation (SNL) induced upregulation of
chemokine CCL2 and its major
receptor CCR2 in both
dopamine D1 and D2 receptor (D1R and D2R)-containing neurons in the NAc. Inhibition of CCR2 by
shRNA lentivirus in the NAc shell attenuated SNL-induced
pain hypersensitivity and depressive behaviors. Conversely, intra-NAc injection of CCL2-expressing lentivirus-induced nociceptive and depressive behaviors in naïve mice. Whole-cell patch clamp recording of D1R-positive or D2R-positive medium spiny neurons (MSNs) showed that SNL increased
NMDA receptor (NMDAR)-mediated currents that are induced by stimulation of prefrontal cortical afferents to MSNs, which was inhibited by a CCR2 antagonist. Furthermore, Ccr2
shRNA also reduced NMDAR-mediated currents, and this reduction was mainly mediated via NR2B subunit. Consistently, NR2B, colocalized with CCR2 in the NAc, was phosphorylated after SNL and was inhibited by intra-NAc injection of Ccr2
shRNA. Furthermore, SNL or CCL2 induced ERK activation in the NAc. Inhibition of ERK by a
MEK inhibitor reduced NR2B phosphorylation induced by SNL or CCL2. Finally, intra-NAc injection of NR2B antagonist or
MEK inhibitor attenuated SNL-induced
pain hypersensitivity and depressive behaviors. Collectively, these results suggest that CCL2/CCR2 signaling in the NAc shell is important in mediating
neuropathic pain and depression via regulating NR2B-mediated NMDAR function in D1R- and D2R-containing neurons following
peripheral nerve injury.