Scholarlink

Background <p>Chronic neuropathic pain is frequently accompanied by anxiety and depression, yet the cortical circuit mechanisms underlying this comorbidity remain unclear. The medial orbitofrontal cortex (mOFC) is a key cortical region involved in emotional regulation and valuation, and clinical imaging studies have reported altered mOFC activity in patients with chronic pain. However, it remains unclear how mOFC neuronal activity contributes to both the pain hypersensitivity and anxiodepressive-like behaviors associated with neuropathic pain. This study aimed to determine the pathway-specific roles of mOFC glutamatergic neurons in chronic pain and comorbid affective disturbances.</p> Methods <p>Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain sensitivity and anxiodepressive-like behaviors were assessed using von Frey, Hargreaves, open field, elevated plus maze, tail suspension, and forced swim tests. Electrophysiological recording and fiber photometry were used to monitor neuronal activity. Neuronal projection tracing identified projection patterns of mOFC glutamatergic neurons to mediodorsal thalamus (MD) and basolateral amygdala (BLA). Chemogenetic and optogenetic manipulations were applied to selectively modulate the mOFC<sup>CaMKIIα</sup>-MD and mOFC<sup>CaMKIIα</sup>-BLA pathways.</p> Results <p>The mOFC glutamatergic neurons are activated in neuropathic pain mice accompanied by anxiodepressive-like phenotypes. Chemogenetic and optogenetic inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. Retrograde labeling result revealed two non-overlapping mOFC<sup>CaMKIIα</sup> neurons projecting to the MD and BLA, respectively. Selective inhibition of mOFC<sup>CaMKIIα</sup>-MD pathway leads to amelioration of CCI-induced pain hypersensitivity. While selective inhibition of mOFC<sup>CaMKIIα</sup>-BLA pathway leads to amelioration of CCI-induced anxiodepressive-like behaviors.</p> Conclusions <p>The present study has revealed that the critical involvement of mOFC glutamatergic neurons in the comorbidity of chronic pain and affective disturbances. Inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. The discrete mOFC<sup>CaMKIIα</sup>-MD and mOFC<sup>CaMKIIα</sup>-BLA pathway independently control the sensory and affective components of neuropathic pain.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The medial orbitofrontal cortex mediates neuropathic pain and anxiodepressive-like behaviors via two distinct pathways

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月18日

查看全文
  • Zhixiao Li,
  • Tianen Si,
  • Liangliang Gao,
  • Yijie Meng,
  • Xinyu Su,
  • Liang Tao,
  • Jingjing Zhang,
  • Zhonghui Hu,
  • Yao Ge,
  • Xianglei Meng,
  • Jing Cao

摘要

Background

Chronic neuropathic pain is frequently accompanied by anxiety and depression, yet the cortical circuit mechanisms underlying this comorbidity remain unclear. The medial orbitofrontal cortex (mOFC) is a key cortical region involved in emotional regulation and valuation, and clinical imaging studies have reported altered mOFC activity in patients with chronic pain. However, it remains unclear how mOFC neuronal activity contributes to both the pain hypersensitivity and anxiodepressive-like behaviors associated with neuropathic pain. This study aimed to determine the pathway-specific roles of mOFC glutamatergic neurons in chronic pain and comorbid affective disturbances.

Methods

Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain sensitivity and anxiodepressive-like behaviors were assessed using von Frey, Hargreaves, open field, elevated plus maze, tail suspension, and forced swim tests. Electrophysiological recording and fiber photometry were used to monitor neuronal activity. Neuronal projection tracing identified projection patterns of mOFC glutamatergic neurons to mediodorsal thalamus (MD) and basolateral amygdala (BLA). Chemogenetic and optogenetic manipulations were applied to selectively modulate the mOFCCaMKIIα-MD and mOFCCaMKIIα-BLA pathways.

Results

The mOFC glutamatergic neurons are activated in neuropathic pain mice accompanied by anxiodepressive-like phenotypes. Chemogenetic and optogenetic inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. Retrograde labeling result revealed two non-overlapping mOFCCaMKIIα neurons projecting to the MD and BLA, respectively. Selective inhibition of mOFCCaMKIIα-MD pathway leads to amelioration of CCI-induced pain hypersensitivity. While selective inhibition of mOFCCaMKIIα-BLA pathway leads to amelioration of CCI-induced anxiodepressive-like behaviors.

Conclusions

The present study has revealed that the critical involvement of mOFC glutamatergic neurons in the comorbidity of chronic pain and affective disturbances. Inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. The discrete mOFCCaMKIIα-MD and mOFCCaMKIIα-BLA pathway independently control the sensory and affective components of neuropathic pain.

Graphical Abstract