Defining a role for kappa opioid system in affective behavior and drug escalation in pain

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Pain and reward are considered opponent processes but are processed within overlapping brain structures. It has been demonstrated that rewarding stimuli can decrease pain sensitivity, whereas pain can impair reward processing leading to an anhedonic state. However, it is not yet known how the presence of pain modifies the reinforcing properties of natural rewards and opioids. The mesolimbic pathway is a critical brain nuclei that is altered in opioid addiction making it an ideal neural circuit to investigate the mechanistic basis for opioid abuse in the presence of pain. Opioid-induced released of dopamine (DA) in the nucleus accumbens (NAc) contributes to their abuse potential, where an allostatic shift in reward signaling leads to the pathological state of addiction. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain the predominant opioids used for clinical and recreational-abuse purposes. In contrast, the activation of brain kappa opioid receptors (KOPR) causes dysphoria via suppression of mesolimbic DA and 5HT activity within the nucleus NAc reward circuitry. It is thought that these two opposing opioid-receptor systems work together to partially maintain the balance of affective state, however dysregulation of one or the other system can lead to dramatic changes in reward processing behaviors. We recently reported that persistent inflammatory pain negatively impacts function of MOPR in the ventral tegmental area (VTA) with a concomitant loss of mu-opioid-induced DA release in the NAc which may partially underlie the observed increase in the intake of very high doses of the opioid. Interestingly, our initial findings indicate that persistent inflammatory pain enhances KOPR function in the NAc, promoting negative affect states (i.e. decrease in the overall motivational state and enhanced aversive behavior) which may be crucially involved in driving increased opioid consumption when high doses are accessible, as recently proposed to maintain drug seeking and escalation of intake. Taken together, these preliminary findings strongly support the central hypothesis of this multidisplinary proposal that pain reduces the activity of the VTA-NAc dopamine reward circuit, via an enhancement of the dynorphin-KOPR system activity to decrease motivation and promote dysphoria. We hypothesize that this pain-induced KOPR-mediated negative affective state drives the intake of high dose opioids leading to misuse and drug escalation. Using a series of multidisplinary approaches including electrophysiology, microdialysis, voltammetry, optogenetics, chemogenetics, mouse genetics, and rodent PET imaging tools, we propose to determine whether in vivo manipulation of dynorphin-KOPR system in the VTA-NAc circuit prevents pain-induced negative affect which drives opioid dose escalation.