Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal.
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 Opiate-withdrawn CRF1-/- mice also showed aberrant CRF and dynorphin expression in the paraventricular nucleus of the hypothalamus (PVN) and the striatum, indicating profound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also restored "wild-type-like" patterns of CRF and dynorphin gene expression in the PVN and the striatum of opiate-withdrawn CRF1-/- mice, respectively.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.
Papaleo
Francesco
F
Laboratoire Homéostasie-Allostasie-Pathologie, EA 3666, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
Kitchener
Pierre
P
Contarino
Angelo
A
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003345:Corticosterone / Q000097:blood / Q000627:therapeutic use; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications*; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D013997:Time Factors; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D004399:Dynorphins; D009020:Morphine; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone