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

Abstract

Abstract 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.