Effects of a Post-Shock Injection of the Kappa Opioid Receptor Antagonist Norbinaltorphimine (norBNI) on Fear and Anxiety in Rats

Abstract

Exposure of rats to footshocks leads to an enduring behavioral state involving generalized fear responses and avoidance. Recent evidence suggests that the expression of negative emotional behaviors produced by a stressor is in part mediated by dynorphin and its main receptor, the kappa opioid receptor (KOR). The purpose of this study was to determine if a subcutaneous injection of the long-acting KOR antagonist norbinaltorphimine (norBNI; 15.0 and 30.0 mg/kg) given 2 days after an acute exposure of rats to footshooks (5×2 s episodes of 1.5 mA delivered over 5 min) attenuates the expression of lasting fear and anxiety. We report that exposure of rats to acute footshock produced long-lasting (>4 weeks) fear (freezing) and anxiety (avoidance of an open area in the defensive withdrawal test). The 30 mg dose of norBNI attenuated the fear expressed when shock rats were placed in the shock context at Day 9 but not Day 27 post-shock. The same dose of norBNI had no effect on the expression of generalized fear produced when shock rats were placed in a novel chamber at Days 8 and 24. In contrast, the 30 mg dose of norBNI produced consistent anxiolytic effects in shock and nonshock rats. First, the 30 mg dose was found to decrease the latency to enter the open field in the defensive withdrawal test done 30 days after the shock exposure. Second, the same high dose also had anxiolytic effects in both nonshock and shock rats as evidence by a decrease in the mean time spent in the withdrawal box. The present study shows that systemic injection of the KOR antagonist norBNI had mixed effect on fear. In contrast, norBNI had an anxiolytic effect which included the attenuation of the enhanced avoidance of a novel area produced by a prior shock experience.

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

“…The strategy of restricting data analysis to later portions of a test period is common in these types of screening procedures, especially in tests such as the forced swim test (Porsolt et al, 1977) Effects of kappa receptor ablation in dopamine systems A Van't Veer et al 2007). Elevated Center Time in the KOR mutants is also broadly consistent with previous work indicating that KOR antagonists have anxiolytic-like effects in rodents (Knoll et al, 2007;Carr and Lucki, 2010;Rogala et al, 2012). To further assess the possibility that increased Center Time in the DAT-KOR lox/lox mice reflects an anxiolytic-like phenotype, we tested additional (naive) cohorts of mice in the light/dark box test.…”

Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A/cAMP-response element binding protein signaling via a Gαs-mediated mechanism

“…Furthermore, decreased OX1R activity aggravated depression in a chronic unpredictable mild stress (CUMS) mouse model [27]. By contrast, activation of KOR induces anxious and fearful behavior in both humans and rodents [28].These findings support the hypothesis that OX1R and KOR may orchestrate their functions through dimerization, which could coordinate their responsiveness to the coreleased peptides and play an important role in hypothalamus and dopaminergic reward system. The present study aimed to examine this possibility and investigate novel heterodimerization-mediated signal transduction in depression, especially the effects of heterodimerization on the transcription factor CREB, which has been implicated in signalling pathways relevant for pathogenesis and therapy of depression.…”

“…Furthermore, decreased OX1R activity aggravated depression in a chronic unpredictable mild stress (CUMS) mouse model [27]. By contrast, activation of KOR induces anxious and fearful behavior in both humans and rodents [28].…”

The role of the dynorphin/κ opioid receptor system in anxiety

“…Although κ opioid receptor agonists present conflicting profiles in mood disorders, the administration of κ opioid receptor antagonists have been shown to exert consistent anxiolytic effects in different animal models [34,[37][38][39][53][54][55][56][57][58][59][60] (see Table 2 for a summary of the current literature). The κ opioid receptor antagonists nor-BNI and JDTic increased open arm exploration in EPM tests and decreased conditioned fear in the fearpotentiated startle paradigm [55,60] .…”