Kappa opioid receptors (KORs) in the anterior paraventricular nucleus of the thalamus (aPVT) mediate morphine withdrawal-, anxiety-, fear-, and KOR agonist-induced aversion-like behaviors in mice

PVT is involved in stress responses, fear, anxiety, arousal, aversion and reward. Anterior and posterior PVT (aPVT and pPVT) have different neuronal connections, molecular contents, and functional roles. PVT expressed a high level of KOR. Herein we mapped the projection targets of aPVT KOR(+) neurons and explored the behavioral significance of aPVT KOR. Using KOR-iCre mice and Cre-dependent anterograde tracer, we found that KOR(+) glutamatergic neurons in aPVT primarily projected to NAc, CeA, BNST, PFC, and reticular nucleus of the thalamus (RT). 3-D images showed the pathway emanating from aPVT to the ventral RT, through NAc, and out to the other regions, indicating widespread axonal collateralization. We conditionally knock-downed KOR (KOR cKD) in aPVT by injection of AAV-eGFP-Cre or AAV-eGFP (control) into aPVT of Oprk1lox/lox mice. [3H]U69,593 receptor autoradiography revealed substantial KOR cKD in aPVT. In both male and female mice, the KOR cKD in aPVT significantly reduced anxiety-like behaviors in the elevated plus-maze test, cue-induced freezing after fear conditioning and naloxone-precipitated morphine withdrawal-associated jumps. KOR cKD attenuated U50,488H-induced conditioned place aversion in males only, while having no effect on forced swim immobility or the U50,488H-induced visceral analgesic and antipruritic effects in either sex. Thus, our results reveal for the first time that KOR-mediated inhibition of aPVT neurons may mediate morphine withdrawal, anxiety, and cue-induced fear in both sexes but contribute to KOR agonist-induced aversion only in males. Notably, our findings reveal a previously unrecognized role for aPVT in regulating morphine withdrawal, acting in a manner distinct from pPVT.