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

Abstract

Qiong Luo,1,* Jing Luo,1,* Xixi Wang,2 Sifei Gan3 1Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Department of Anesthesiology, The First Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sifei Gan, Department of Anesthesiology, The First Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China, Email [email protected]: 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

Keywords

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