Footshock stress enhances morphine-induced reward but attenuates aversion in behavior and neural mechanisms.

The impact of stress on the behaviors and neural substrates underlying opioid use disorder (OUD) remains unclear. To investigate this, we employed a footshock treatment before the pre- and post-conditioning procedures for conditioned taste aversion (CTA) and conditioned place preference (CPP) with morphine injections. In the experiment, all rats were subjected to 10-second footshock (3 mA) or no footshock treatments. Subsequently, CTA was established by allowing all rats to drink a 0.1 % saccharin solution for 15 min before intraperitoneal injection with normal saline or 20 mg/kg of morphine. Aftre that, rats were placed in a CPP compartment for 30 min to induce CPP learning. The results showed that footshock enhanced freezing time during the situational reminder. Morphine simultaneously induced aversion in the CTA and reward in the CPP. Footshock stress attenuated morphine-induced aversion in the CTA and facilitated morphine-induced reward in the CPP task. c-Fos expression was downregulated in the basolateral amygdala (BLA) under morphine administration and upregulated in the PrL and IL under footshock stress. Combined footshock stress and morphine injections increased c-Fos expression in the prelimbic cortex (PrL), infralimbic cortex (IL), and BLA. Footshock stress appeared to disrupt the neural connectivities among the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc), and basolateral amygdala (BLA). The network data indicated that footshock stress facilitated addiction-related neural pathways for the NAc and the PrL, IL, and BLA after morphine administration. The findings extend the paradoxical hypothesis of abused drugs and provide clinical contributions to the literature on OUD.