Persistent pain facilitates response to morphine reward by downregulation of central amygdala GABAergic function

Opioid-based analgesics are widely used for treating chronic pain, but opioids are highly addictive when repeatedly used because of their strong rewarding effects. In recent years, abuse of prescription opioids has dramatically increased, including incidences of misuse of opioid drugs prescribed for pain control. Despite this issue in current clinical pain management, it remains unknown how pain influences the abuse liability of prescription opioids. Pain as aversive experience may affect opioid reward of positive emotion through common brain sites involved in emotion processing. In this study, on a rat model of chronic pain, we determined how persistent pain altered behavioral responses to morphine reward measured by the paradigm of unbiased conditioned place preference (CPP), focusing on GABAergic synaptic activity in neurons of the central nucleus of the amygdala (CeA), an important brain region for emotional processing of both pain and reward. We found that pain reduced the minimum number of morphine-conditioning sessions required for inducing CPP behavior. Both pain and morphine conditioning that elicited CPP inhibited GABA synaptic transmission in CeA neurons. Pharmacological activation of CeA GABA A receptors reduced the pain and inhibited CPP induced both by an effective dose of morphine and by a sub-threshold dose of morphine under pain condition. Furthermore, inhibition of CeA GABA A receptors mimicked the pain effect, rendering the sub-threshold dose of morphine effective in CPP induction. These findings suggest that pain facilitates behavioral responses to morphine reward by predisposing the inhibitory GABA function in the CeA circuitry involved in the behavior of opioid reward.