The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal

Abstract

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF 1) and CRF2. eroin addiction is one of the most common and serious substance-related disorders (1). In addicted individuals, heroin ''highs'' are inexorably followed by a severe opiate withdrawal syndrome composed of somatic signs and negative affective states, such as dysphoria and depressed mood (2). The negative affective states of opiate withdrawal dramatically motivate compulsive heroin-seeking behavior and opiate abuse (3, 4). However, available treatments do not effectively relieve the negative affective symptoms of opiate withdrawal, thus leaving opiate addicts vulnerable to relapse to heroin.The corticotropin-releasing factor (CRF) system might mediate the motivational effects of drug dependence. Functional antagonism of CRF neurotransmission reduces stress-induced reinstatement of drug-seeking behavior and may attenuate anxiety-like and affective states associated with drug withdrawal (5). The latter findings point to the CRF system as a potential therapeutic target for treating the negative affective consequences of drug addiction. However, recent studies showing opposite functions for the two known CRF receptor pathways, CRF receptor-1 (CRF 1 ) and CRF 2 , in anxiety-like and depression-like behaviors indicate a complex role for the CRF system in affect regulation (6-11). Elements in the CRF circuitry might also differentially contribute to the negative affective states of drug withdrawal. However, the specific role for the different components of the CRF system in drug withdrawal-induced negative affect is still unknown.Mutant mice bearing targeted mutations of the CRF system are unique tools to elucidate the role of CRF in drug dependence and withdrawal. Here we used genetically engineered mice lacking functional CRF 1 receptor levels to study the role for CRF͞CRF 1 receptor pathways in the negative affective states of opiate withdrawal (6). Moreover, in keeping with the clinical setting where signs and symptoms of opiate withdrawal ''spontaneously'' and gradually rise along with the drug removal from the body, behavioral and molecular studies reported here were conducted in mice undergoing spontaneous opiate withdrawal. In contrast, previous studies that have examined the role of CRF in the somatic and aversive effects of opiate withdrawal have all used opioid receptor antagonist-precipitated opiate withdrawal procedures (12-16). However, high-affinity competitive opioid receptor antagonists ''precipitate'' behavioral, endocrine, and molecular patterns that greatly differ from those observed upon spontaneous opiate withdrawal (17-20), thus making questi...

Disruption of the CRF2 Receptor Pathway Decreases the Somatic Expression of Opiate Withdrawal

“…In net contrast, CRF 2 receptor-deficient mice show increased HPA axis and affective-like responses to stressors (Bale et al, 2000;Bale and Vale, 2003;Coste et al, 2000Coste et al, , 2006Kishimoto et al, 2000). In line with a major role for the CRF 1 receptor pathway in stress-responsive circuitry, we found that genetic disruption of the CRF 1 receptor pathway eliminated the negative affective-like states of opiate withdrawal (Contarino and Papaleo, 2005). However, in net contrast to affective-like indices, disruption of the CRF 1 receptor pathway exacerbated the somatic expression of opiate withdrawal (Papaleo et al, 2007).…”

“…In particular, either CRF 1 receptor deficiency or functional antagonism of the CRF 1 receptor pathway decreased anxiety-like and depressionlike behavior (Contarino et al, 1999;Griebel et al, 2002;Hodgson et al, 2007;Nielsen et al, 2004;Okuyama et al, 1999;Smith et al, 1998;Timpl et al, 1998;Zorrilla et al, 2002). Also, CRF 1 À/À mice displayed deficient HPA axis responses to stressful events (Contarino and Papaleo, 2005;Papaleo et al, 2007;Smith et al, 1998;Timpl et al, 1998). In net contrast, genetic disruption of the CRF 2 receptor pathway increased the expression of anxiety-like and depression-like behavior, and exacerbated HPA axis responses to an immobilization stress (Bale et al, 2000;Bale and Vale, 2003;Coste et al, 2000Coste et al, , 2006Kishimoto et al, 2000).…”

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

“…Furthermore, long-term opiate-withdrawn wild-type and CRF 2 − / − mice display similar locomotor activity and anxietylike behavior, indicating that CRF 2 receptor-mediated motivational states are independent of ambulatory or negative affective-like effects of drug withdrawal. Accordingly, studies indicate dissociation of motivational, ambulatory, somatic, and affective-like effects of opiate withdrawal (Contarino and Papaleo, 2005;Delfs et al, 2000;Papaleo et al, 2007;Rouibi and Contarino, 2012). Nevertheless, the FWS and the EPS used herein reliably increase nonrewarded nose-poking in longterm opiate-withdrawn wild-type, but not CRF 2 − / − , mice.…”

“…In mammals, CRF-like signaling is transmitted by two types of receptors, termed CRF 1 and CRF 2 (Hauger et al, 2003), that may differentially contribute to the multiple signs and symptoms of drug dependence and withdrawal. Indeed, CRF 1 or CRF 2 receptor deficiency completely eliminates the negative affective-like states of opiate withdrawal in mice (Contarino and Papaleo, 2005;Ingallinesi et al, 2012). However, CRF 1 receptor deficiency exacerbates whereas CRF 2 receptor deficiency reduces the somatic signs of opiate withdrawal (Papaleo et al, 2007(Papaleo et al, , 2008.…”

Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates κ-Opioid-Dependent Dysphoria

“…MAPK activation KOR activation also causes CPA (Spanagel et al, 1994;Sante et al, 2000;Contarino and Papaleo, 2005). We next asked whether KOR-induced CPA requires p38 MAPK activity.…”