Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs, and the emergence of negative affective states during abstinence. These negative emotional states during withdrawal, such as anxiety and pain, are thought to contribute to compulsivity associated with dependence, ultimately leading to drug addiction. Increased anxiety and hypersensitivity to pain are symptoms of opioid withdrawal and are considered to be factors contributing to the continued use of drugs. In the transition to opioid dependence, neuroadaptive changes occur involving recruitment of brain stress systems, such as those mediated by corticotropin-releasing factor (CRF) and norepinephrine (NE). During withdrawal, CRF/NE signaling and release are increased in the extended amygdala, specifically the central nucleus of the amygdala and bed nucleus of stria terminalis. The anxiogenic effects of CRF are mediated by CRF₁ receptors, which have shown to play a critical role in the negative affective states of opiate withdrawal. A CRF-NE feed-forward stress system is thought to exist between the extended amygdala and brainstem where CRF and NE affect the activation and release of the other, contributing to the presentation of negative affective states during withdrawal and consequently, compulsive drug intake. The general hypothesis was that increased anxiety and pain contribute to opioid dependence and are mediated by activation of the brain stress system. Through this thesis, anxiety- and pain-like behaviors were characterized in rats during withdrawal from acute heroin dependence and heroin self-administration, and the role of CRF/NE was explored in these behaviors as well as in compulsive heroin intake. Increased anxiety- and pain-like behavior was present during withdrawal from acute heroin injections and self-administration of heroin. CRF₁ receptor antagonism reversed both anxiety- and pain-like behaviors during withdrawal while noradrenergic antagonism had differing effects. The main findings suggest that CRF possibly precedes NE in activating the brain stress system during opioid withdrawal and may be the driving force in the CRF-NE feed-forward brain stress system. In addition, CRF₁R antagonism blocks heroin escalation and NE blockade decreases heroin intake, implicating the role of CRF and NE in compulsive heroin intake and opioid dependence

The abuse of opioid drugs, both illicit and prescription, is a persistent problem in the United States, accounting for >1.2 million users who require treatment each year. Current treatments rely on suppressing immediate withdrawal symptoms and replacing illicit drug use with long-acting opiate drugs. However, the mechanisms that lead to preventing opiate dependence are still poorly understood. We hypothesized that κ opioid receptor (KOR) activation during chronic opioid intake contributes to negative affective states associated with withdrawal and the motivation to take increasing amounts of heroin. Using a 12 h long-access model of heroin self-administration, rats showed escalation of heroin intake over several weeks. This was prevented by a single high dose (30 mg/kg) of the long-acting KOR antagonist norbinaltorphimine (nor-BNI), paralleled by reduced motivation to respond for heroin on a progressive-ratio schedule of reinforcement, a measure of compulsive-like responding. Systemic nor-BNI also significantly decreased heroin withdrawal-associated anxiety-like behavior. Immunohistochemical analysis showed prodynorphin content increased in the nucleus accumbens core in all heroin-exposed rats, but selectively increased in the nucleus accumbens shell in long-access rats. Local infusion of nor-BNI (4 μg/side) into accumbens core altered the initial intake of heroin but not the rate of escalation, while local injection into accumbens shell selectively suppressed increases in heroin intake over time without altering initial intake. These data suggest that dynorphin activity in the nucleus accumbens mediates the increasing motivation for heroin taking and compulsive-like responding for heroin, suggesting that KOR antagonists may be promising targets for the treatment of opioid addiction.