Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2B-mediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell
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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.
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Ccl2 reduction with short hairpin RNA restores sucrose preference and increases swimming in the forced-swim test.
“Ccl2 reduction with short hairpin RNA restores sucrose preference and increases swimming in the forced-swim test [192].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [192]
In a spinal nerve ligation model of anhedonia, cytokine CCL2 is upregulated in both NAc D1- and D2-MSNs.
“Cytokines can also be released by neurons and in a spinal nerve ligation model of anhedonia, cytokine CCL2 is upregulated in both NAc D1-and D2-MSNs.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [192]
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References 59 · Cited by 68
- Authors
- Wu, X.-B., Jing, P.-B., Zhang, Z.-J., Cao, D.-L., Gao, M.-H., Jiang, B.-C., & Gao, Y.-J.
- Affiliations
- Nantong University (CN)
- Corresponding author
- Gao, Yong-Jing
- Venue
- Neuropsychopharmacology
- Published
- 2018-06-11
- Volume
- 43
- Issue
- 11
- Pages
- 2320-2330
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6135748
- OpenAlex
- W2807281752
- Cited by
- 68
- References
- 59
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 9 · 2023: 12 · 2022: 6 · 2021: 14 · 2020: 7 · 2019: 5
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81571070, 31700899, 81771197, 31671091)
- Natural Science Foundation of Jiangsu Province (BK20171255)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- CCR2, MCP-1, neuropathic pain, depression, nucleus accumbens shell, medium spiny neurons, dopamine D1 receptor, dopamine D2 receptor, NR2B subunit, NMDA receptor currents, ERK signaling, MEK inhibition, spinal nerve ligation, hyperalgesia
- MeSH terms
- Animals, Depression, Male, Mice, Inbred ICR, Neuralgia, Neurons, Nucleus Accumbens, Organ Culture Techniques, Receptors, N-Methyl-D-Aspartate, Receptors, Dopamine D1, Receptors, Dopamine D2, Excitatory Amino Acid Antagonists, Mice, Receptors, CCR2
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