Inhibition of Oligodendrocyte Apoptosis in the Prelimbic Medial Prefrontal Cortex Prevents Fentanyl-induced Hyperalgesia in Rats

Wang, Xixi; Cui, Lingling; Gan, Sifei; Zhang, Zeru; Xiao, Jing; Li, Chenhong; Luo, Fang

doi:10.1016/j.jpain.2021.12.012

Cited by 10 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, mechanical and thermal hyperalgesia reached their nadir at 6.5 h after fentanyl exposure, with hypersensitivity states gradually returning to basal levels by day 7. These results corroborate ndings from previous reports that rats exposed to opioids experience hyperre exia symptoms in a time-dependent manner [14,31,41].…”

Section: Resultssupporting

confidence: 92%

HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats

et al. 2023

Self Cite

View full text Add to dashboard Cite

Opioids are often rst-line analgesics in pain therapy. However, prolonged use of opioids causes paradoxical pain, termed "opioid-induced hyperalgesia (OIH)". The infralimbic medial prefrontal cortex (IL-mPFC) has been suggested to be critical in in ammatory and neuropathic pain processing through its dynamic output from Layer V pyramidal neurons. Whether OIH condition induces excitability changes of these output neurons and what mechanisms underlie these changes remains elusive. Here, with combination of patch-clamp recording, immunohistochemistry, as well as optogenetics, we revealed that IL-mPFC Layer V pyramidal neurons exhibited hyperexcitability together with higher input resistance. In line with this, optogenetic and chemogenetic activation of these neurons aggravate behavioral hyperalgesia in male OIH rats. Inhibition of these neurons alleviates hyperalgesia in male OIH rats but exerts an opposite effect in male control rats. Electrophysiological analysis of hyperpolarization-activated cation current (Ih) demonstrated that decreased Ih is a prerequisite for the hyperexcitability of IL-mPFC output neurons. This decreased Ih was accompanied by a decrease in HCN1, but not HCN2, immunolabeling, in these neurons. In contrast, the application of HCN channel blocker increased the hyperalgesia threshold of male OIH rats. Consequently, we identi ed an HCN-channel-dependent hyperexcitability of IL-mPFC output neurons, which governs the development and maintenance of OIH in male rats.

show abstract

Section: Resultssupporting

confidence: 92%

HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…As previously reported, the pain threshold reached the lowest at 6.5 h and last almost 3days after fentanyl administration, and thus this timepoint was chosen for most of the present study [44]. As one of the immediate early genes (IEG), c-Fos would respond to extrinsic cellular stimuli and induce action potential ring and was therefore chosen as an excitatory marker [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…Prelimbic medial cortex (PL), another subregion of the medial prefrontal cortex, is next to IL anatomically, displays close functional connections with IL and has been identi ed to play a crucial role in chronic pain [41,53]. Recently, we found that the oligodendrocyte decreased in the PL in OIH rats, which might affect the synaptic transmission between the PL and its projections [44]. However, there exists few projections from PL to CeLC [19].…”

Section: Discussionmentioning

confidence: 99%

“…Activating or silencing IL-CeLC circuit did not signi cantly affect mechanical pain thresholds in naive rats, indicating that this cortical gain might only launch in OIH rats. Previous studies have found that the state of hyperalgesia could last for about 3 days after fentanyl administration [9,10,44]. However, we only select the time point for electrophysiology when the rat was most sensitive to the stimuli.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Scaling up IL glutamatergic outputs to the amygdala alleviates opioid induced hyperalgesia in male rats

Cui

Wang

Zhu

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for sever pain. Although the cellular and molecular mechanisms for OIH have been tested at different level on the pain pathway, little is known about the neural circuits underlying OIH modulation. Previous studies suggest that laterocapsular division of the central nucleus of amygdala (CeLC) is critically involved in the regulation of OIH. The purpose of this study is to clarify the role of the projections from infralimbic medial cortex (IL) to CeLC in OIH modulation. OIH was produced by repeated fentanyl subcutaneous injection in male rats. Immunofluorescence staining revealed that c-Fos-positive neurons were significantly more in the right CeLC in OIH rats than untreated rats. Then, we reported that there were functional projections from glutamate pyramidal neurons in IL to the CeLC and found that IL glutamate release onto CeLC increased after fentanyl administration. However, optogenetic activation of this IL-CeLC circuit prevented OIH by inhibiting the CeLC, while silencing this circuit by chemogenetics exacerbated OIH through activating the CeLC. Combined with the electrophysiology results, the enhanced glutamate release from IL to CeLC was a protective response rather than a reason for OIH generation. We imply that increased glutamate release was a cortical gain of IL to relieve OIH, scaling up IL outputs to CeLC may be an effective neuromodulation strategy to inhibit OIH.

show abstract

“…Oligodendrocytes in the mPFC have also been reported to play an important role in pain management. Downregulation of myelin-related proteins and oligodendrocyte apoptosis were observed in rats with fentanyl-induced hyperalgesia, whereas prophylactic blockage of oligodendrocyte apoptosis in the mPFC prevented hyperalgesia to occur ( Wang et al, 2022 ). Together with these findings, our study suggests that restoring oligodendrocytes and myelin in the mPFC may be key to the treatment of comorbidity of pain and related depression.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Transcriptomic Signatures in Brain Regions Critical for Neuropathic Pain-Induced Depression

Dai

Huang

Luo

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces differential long-term structural, functional, and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results showed that the SNI-induced transcriptomic changes in female and male mice were largely distinct. Interestingly, the female mice exhibited more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurred in the mPFC. Cell type enrichment analyses revealed that the differentially expressed genes involved genes enriched in neurons, various types of glia and endothelial cells. We further performed gene set enrichment analysis (GSEA), which revealed significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization were enriched, and gene sets for extracellular matrix were de-enriched after SNI, while such signatures were absent in male ACC. Collectively, these findings revealed region-specific and sexual dimorphism at the transcriptional levels induced by neuropathic pain, and provided novel therapeutic targets for chronic pain and its associated affective disorders.

show abstract

Inhibition of Oligodendrocyte Apoptosis in the Prelimbic Medial Prefrontal Cortex Prevents Fentanyl-induced Hyperalgesia in Rats

Cited by 10 publications

References 61 publications

HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats

HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats

Scaling up IL glutamatergic outputs to the amygdala alleviates opioid induced hyperalgesia in male rats

Sex-Specific Transcriptomic Signatures in Brain Regions Critical for Neuropathic Pain-Induced Depression

Contact Info

Product

Resources

About