Projections from IL glutamatergic outputs to amygdala mediates opioid induced hyperalgesia in male rats.

Repeated use of opioid analgesics may cause a paradoxically exacerbated pain known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for severe pain. Currently, 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. Our purpose is to clarify the role of the projections from infralimbic medial prefrontal cortex (IL) to CeLC in OIH. We first produced an OIH model by repeated fentanyl subcutaneous injection in male rats. Immunofluorescence staining revealed that c-Fos-positive neurons were significantly increased in the right CeLC in OIH rats than the saline controls. Then, we used calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) labeling and the patch-clamp recordings with ex vivo optogenetics to detect the functional projections from glutamate pyramidal neurons in IL to the CeLC. The synaptic transmission from IL to CeLC, shown in the excitatory postsynaptic currents (eEPSCs), inhibitory postsynaptic currents (eIPSCs) and paired-pulse ratio (PPR), was observably enhanced after fentanyl administration. Moreover, optogenetic activation of this IL-CeLC pathway decreased c-Fos expression in CeLC and ameliorated mechanical and thermal pain in OIH. On the contrary, silencing this pathway by chemogenetics exacerbated OIH by activating the CeLC. Combined with the electrophysiology results, the enhanced synaptic transmission from IL to CeLC might be a cortical gain of IL to relieve OIH rather than a reason for OIH generation. Scaling up IL outputs to CeLC may be an effective neuromodulation strategy to treat OIH.