κ Opioid Receptor Antagonism and Prodynorphin Gene Disruption Block Stress-Induced Behavioral Responses

Abstract

Previous studies have demonstrated that stress may increase prodynorphin gene expression, and kappa opioid agonists suppress drug reward. Therefore, we tested the hypothesis that stress-induced release of endogenous dynorphin may mediate behavioral responses to stress and oppose the rewarding effects of cocaine. C57Bl/6 mice subjected to repeated forced swim testing (FST) using a modified Porsolt procedure at 30 degrees C showed a characteristic stress-induced immobility response and a stress-induced analgesia observed with a tail withdrawal latency assay. Pretreatment with the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI; 10 mg/kg, i.p.) blocked the stress-induced analgesia and significantly reduced the stress-induced immobility. The nor-BNI sensitivity of the behavioral responses suggests an activation of the kappa opioid receptor by a stress-induced release of dynorphin peptides. Supporting this hypothesis, transgenic mice possessing a disrupted prodynorphin gene showed no increase in immobility or stress-induced analgesia after exposure to repeated FST. Because both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of forced swim stress on cocaine-conditioned place preference (CPP). FST-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place preference for the drug-paired chamber over the responses of unstressed mice. Surprisingly, nor-BNI pretreatment blocked stress-induced potentiation of cocaine CPP. Consistent with this result, mice lacking the prodynorphin gene did not show a stress-induced potentiation of cocaine CPP, whereas wild-type littermates did. The findings suggest that chronic swim stress may activate the kappa opioid system to produce analgesia, immobility, and potentiation of the acute rewarding properties of cocaine in C57Bl/6 mice.

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…Breeding and genotyping of KOR (−/−) and Dyn (−/−) (backcrossed onto on C57Bl/6 backgrounds) and their corresponding wild-type littermate (+/+) controls were generated by crossing heterozygotic parents as previously described (McLaughlin et al 2003(McLaughlin et al , 2006a. Mice were housed three to four per cage in self-standing plastic cages (28 cm L × 16 cm W × 13 cm H) lined with "Bedo'Cobs" and habituated to isolated decentralized housing 1 week before the start of the study.…”

“…The CPP apparatus consisted of two large Plexiglas outer chambers separated by a smaller inner chamber as previously described (McLaughlin et al 2003). The two outer chambers were made visually distinct with 2.5-cm-wide alternating black and white stripes orientated either vertically or horizontally, while the smaller inner chamber was completely white.…”

“…Forced swim stress was conducted in opaque plastic 5-l beakers (40 cm H × 25 cm diameter) filled with 3.5l of 30°C (±1°C) water, as previously described (McLaughlin et al 2003). The conditioning, extinction, and reinstatement protocols are summarized (Fig.…”

“…Previously, we found that the dynorphin/kappa opioid system was one of the key mediators of the stress response affecting the reinforcing properties of cocaine (McLaughlin et al 2003). Repeated swim stress exposure or repeated social defeat stress, before cocaine conditioning, significantly enhanced subsequent place preference (CPP) to the cocaine-paired compartment in wild-type C57Bl/6 mice, but stress did not affect cocaine CPP in mice pretreated with the kappa receptor antagonist norbinaltorphimine (norBNI) or lacking prodynorphin-derived opioid peptides (McLaughlin et al 2003(McLaughlin et al , 2006b.…”

“…Repeated swim stress exposure or repeated social defeat stress, before cocaine conditioning, significantly enhanced subsequent place preference (CPP) to the cocaine-paired compartment in wild-type C57Bl/6 mice, but stress did not affect cocaine CPP in mice pretreated with the kappa receptor antagonist norbinaltorphimine (norBNI) or lacking prodynorphin-derived opioid peptides (McLaughlin et al 2003(McLaughlin et al , 2006b. Although co-administration of kappa agonists with cocaine inhibited CPP (Shippenberg et al 1996), pharmacological activation of the kappa opioid receptor by U50,488 60-min before cocaine conditioning mimicked stress exposure and potentiated cocaine CPP (McLaughlin et al 2006a).…”