The Role of Pain and Anxiety in the Transition to Opioid Addiction

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 dependenc