Nucleus accumbens D2- and D1-receptor expressing medium spiny neurons are selectively activated by morphine withdrawal and acute morphine, respectively

Opioids are effective analgesic agents but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal involves numerous brain regions and includes suppression of dopamine release and activation of neurons in the ventral striatum. By contrast, acute opioids increase dopamine release. Like withdrawal, acute opioids also activate neurons in the ventral striatum, suggesting that different populations of ventral striatal neurons may be activated by withdrawal and acute opioid actions. Here, immunofluorescence for the activity-related immediate-early gene, c-Fos, was examined in transgenic reporter mouse lines by confocal microscopy to study the specific populations of ventral striatal neurons activated by morphine withdrawal and acute morphine. After chronic morphine, naloxone-precipitated withdrawal strongly increased expression of c-Fos immunoreactivity, predominantly in D2-receptor (D2R) medium-sized spiny neurons (MSNs) of the nucleus accumbens (NAc) core and shell regions. By contrast, a single injection of morphine exclusively activated c-Fos immunoreactivity in D1-receptor expressing (D1R) MSNs of the core and shell of the NAc. These results reveal a striking segregation of neuronal responses occurring in the two populations of MSNs of the NAc in response to morphine withdrawal and acute morphine.

► D2R and D1R-GFP transgenics can identify activated (c-Fos) nucleus accumbens neurons.
► Both opioid withdrawal and acute morphine induce c-Fos in nucleus accumbens.
► Morphine withdrawal selectively induces c-Fos in D2R neurons in nucleus accumbens.
► Acute morphine selectively induces c-Fos in D1R neurons in nucleus accumbens.