Restoration of the Activity of the Prefrontal Cortex to the Nucleus Accumbens Core Pathway Relieves Fentanyl-Induced Hyperalgesia in Male Rats

Abstract

Purpose

Functional connectivity between the prelimbic medial prefrontal cortex (PL-mPFC) and the core of the nucleus accumbens (NAc core) predicts pain chronification. Inhibiting the apoptosis of oligodendrocytes in the PL-mPFC prevents fentanyl-induced hyperalgesia in rats. However, the role of prefrontal cortex (PFC)-NAc projections in opioid-induced hyperalgesia (OIH) remains unclear. Herein, we explored the role of the PL-NAc core circuit in fentanyl-induced hyperalgesia.

Methods

An OIH rat model was established, and patch-clamp recording, immunofluorescence, optogenetics, and chemogenetic methods were employed for neuron excitability detection and nociceptive behavioral assessment.

Results

Our results showed decreased activity of the right PL-mPFC layer V output neurons in rats with OIH. Similarly, the excitability of the NAc core neurons receiving glutamatergic projections from the PL-mPFC decreased in OIH rats, observed by the light-evoked excitatory postsynaptic currents/light-excited inhibitory postsynaptic currents ratio (eEPSC/eIPSC ratio). Fentanyl-induced hyperalgesia was reversed by optogenetic activation of the PL-NAc core pathway, and chemogenetic suppression of this pathway induced hyperalgesia in control (saline-treated) rats. However, behavioral hyperalgesia was not aggravated by this chemogenetic suppression in OIH (fentanyl-treated) rats.

Conclusion

Our findings indicate that inactivation of the PL-NAc core pathway may be a cause of OIH and restoring the activity of this pathway may provide a strategy for OIH treatment.

Keywords:

• fentanyl-induced hyperalgesia
• prelimbic medial prefrontal cortex
• nucleus accumbens core
• circuit

Data Sharing Statement

The data used to support the results of this study can be obtained from the corresponding author upon reasonable request.

Ethics Approval and Informed Consent

This study was performed in accordance with the ethical guidelines of the Laboratory Animal and Biomedical Ethics Committee of the South-Central University for Nationalities (Number: 2019- SCUEC-AEC-022).

Acknowledgments

The study was undertaken in the laboratory of Prof. Chenhong Li at the South-Central University for Nationalities. We sincerely appreciate the animal and electrophysiological experimental platform provided by the South-Central University for Nationalities. We thank the Editage (www.editage.cn) for English language editing.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China (grant number: 81974165); the Fundamental Research Funds for the Central Universities (grant number: 2042023kf0070).