The Journal of Pain | 2019
(349) Pain-Induced Negative Affect is Mediated Via Recruitment of the Nucleus Accumben Kappa Opioid System
Abstract
Prolonged negative affect significantly impacts the quality of life for patients suffering from pain. These maladaptive emotional states can lead to severe depression, suicide, involuntary opioid overdose, and related neuropsychiatric comorbidities. The nucleus accumbens (NAc) shell, which integrates both the aversive and rewarding valence of stimuli, exhibits allostatic changes in the presence of pain. In discrete regions of this structure, activation of the kappa opioid receptor (KOR), either by dynorphin, its endogenous agonist, or pharmacological ligands, acutely decreases the reinforcing properties of rewards and induces dysphoria and aversive behaviors. Using a wide range of complementary techniques including pharmacology, optogenetics, chemogenetics, physiology, biochemistry and in vivo positron emission tomography (PET) imaging, our current findings demonstrate that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is both necessary and sufficient to drive pain-induced negative affective states. Furthermore, we reveal that inflammatory pain impacts patterns of consumption of fentanyl using an intra-venous self-administration paradigm. Those particular patterns, where rats in pain display bursts of consumption interrupted by periods of “rest”, could lead to the occurrence of respiratory depression and subsequent involuntary lethal overdose. Taken together, our results provide evidence that adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention in pain that could circumvent affective disorders and may prevent life-threatening episodes.