Disruption of the CRF/CRF1 Receptor Stress System Exacerbates the Somatic Signs of Opiate Withdrawal

Abstract

Escape from the extremely stressful opiate withdrawal syndrome may motivate opiate seeking and taking. The corticotropin-releasing factor receptor-1 (CRF1) pathway mediates behavioral and endocrine responses to stress. Here, we report that genetic inactivation (CRF1-/-) as well as pharmacological antagonism of the CRF/CRF1 receptor pathway increased and prolonged the somatic expression of opiate withdrawal. Opiate-withdrawn CRF1-/- mice also showed aberrant CRF and dynorphin expression in the paraventricular nucleus of the hypothalamus (PVN) and the striatum, indicating profound impairments in stress-responsive brain circuitry. Intake of nonstressful amounts of corticosterone effectively reduced the exaggerated somatic reactions of CRF1-/- mice to opiate withdrawal. Exogenous corticosterone also restored "wild-type-like" patterns of CRF and dynorphin gene expression in the PVN and the striatum of opiate-withdrawn CRF1-/- mice, respectively. The present findings unravel a key role for the hypothalamus-pituitary-adrenal (HPA) system and brain extra-hypothalamic CRF/CRF1 receptor circuitry in somatic, molecular, and endocrine alterations induced by opiate withdrawal.

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

“…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). Thus, our previous studies indicate a complex physiopathological role for the CRF 1 receptor pathway in opiate dependence.…”

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

“…Similarly, the latter brain stress systems are not affected by long-term (42 days) cocaine withdrawal (Morisot et al, 2014). In contrast, wildtype mice as those used herein show increased LC-TH, CeA-, and PVN-CRF expression 8 h after morphine administration (Ingallinesi et al, 2012;Papaleo et al, 2007). Thus, unlike early drug withdrawal, the behavioral effects of long-term drug withdrawal phases may be independent of LC-TH, CeA-, or PVN-CRF expression.…”

“…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.…”

“…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. Drug-withdrawn animals also show altered motivation for drugs or food, especially during initial drug withdrawal phases.…”

“…To further investigate the neural substrates underlying the CRF 2 receptor-mediated vulnerability, in situ hybridization studies are also carried out. In particular, expression of the key catecholamine and γ-aminobutyric acid (GABA) synthesis enzymes tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD 67 ) is assessed in stress-and drug dependence-relevant brain regions, such as the ventral tegmental area (VTA), the locus coeruleus (LC), the central (CeA), and the basolateral (BLA) nucleus of the amygdala (Esclapez et al, 1994;Ingallinesi et al, 2012;Koob, 2008;Papaleo et al, 2007;Phelps and LeDoux, 2005;Vrana et al, 1993).…”