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

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.

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

Opioids are often first-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 inflammatory 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 aggravates 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 identified an HCN-channel-dependent hyperexcitability of IL-mPFC output neurons, which governs the development and maintenance of OIH in male rats.

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

Opioid-induced hyperalgesia (OIH) is a problem associated with prolonged use of opioids in chronic pain management, and its effective treatment has been hampered by lack of mechanistic evidence. Oligodendrocytes have recently been linked with several pain-related diseases; however, little is known its role in OIH. The prelimbic medial prefrontal cortex (PL-mPFC) has emerged as a significant center of pain regulation, and is rich in oligodendrocytes. Herein we explored the effect of oligodendrocyte apoptosis of PL-mPFC on OIH. Using a fentanyl-induced rat model of OIH and proteomics analysis of the PL-mPFC, we observed a downregulation in 5 types of myelin-related proteins originating from oligodendrocytes; this was further verified by western blotting. Meanwhile, cleaved-caspase 3 (an apoptosis marker) was increased, whereas the oligodendrocyte precursor cell (OPC) marker NG2 remained unchanged. These results suggest that downregulated myelin-related proteins may be associated with oligodendrocyte apoptosis rather than a reduction in their generating source, and immunohistochemistry confirmed this hypothesis. Behaviorally, prophylactic blockade of oligodendrocyte apoptosis by microinjection of z-DEVD-fmk into the PL-mPFC prevented fentanyl-induced mechanical and thermal hyperalgesia, but downregulated myelin basic protein (mbp) gradually recovered in 12 h. We suggest that OIH may be primed in part via oligodendrocyte apoptosis in the PL-mPFC. PERSPECTIVE: In this study we showed that oligodendrocyte apoptosis in the PL-mPFC is a key trigger for fentanyl-induced hyperalgesia. Targeting oligodendrocyte apoptosis in the PL-mPFC may prevented hyperalgesia priming induced by fentanyl.