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CRF2 receptor-deficiency eliminates opiate withdrawal distress without impairing stress coping

Abstract

The opiate withdrawal syndrome is a severe stressor that powerfully triggers addictive drug intake. However, no treatment yet exists that effectively relieves opiate withdrawal distress and spares stress-coping abilities. The corticotropin-releasing factor (CRF) system mediates the stress response, but its role in opiate withdrawal distress and bodily strategies aimed to cope with is unknown. CRF-like signaling is transmitted by two receptor pathways, termed CRF1 and CRF2. Here, we report that CRF2 receptor-deficient (CRF2−/−) mice lack the dysphoria-like and the anhedonia-like states of opiate withdrawal. Moreover, in CRF2−/− mice opiate withdrawal does not increase the activity of brain dynorphin, CRF and periaqueductal gray circuitry, which are major substrates of opiate withdrawal distress. Nevertheless, CRF2 receptor-deficiency does not impair brain, neuroendocrine and autonomic stress-coping responses to opiate withdrawal. The present findings point to the CRF2 receptor pathway as a unique target to relieve opiate withdrawal distress without impairing stress-coping abilities.

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Acknowledgements

We thank Dr Wylie Vale (The Salk Institute, La Jolla, CA, USA) and Dr Tracy Bale (University of Pennsylvania, Philadelphia, PA, USA) for generously donating the CRF2 receptor mutant mouse breeders. We also thank Dr Paul Higueret, Dr Serge Alfos, Dr Incarnation Aubert and Ms Marianna Tancredi for help with the in situ hybridization and the HPF studies. MI, KR, FP and AC were supported by the Université Victor Segalen Bordeaux 2. AC was also supported by the Prix Pfizer 2005 de la Société Française d’Endocrinologie. CLM was supported by the CNRS. AC dedicate this manuscript to Sara, une petite merveille.

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Correspondence to A Contarino.

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Ingallinesi, M., Rouibi, K., Le Moine, C. et al. CRF2 receptor-deficiency eliminates opiate withdrawal distress without impairing stress coping. Mol Psychiatry 17, 1283–1294 (2012). https://doi.org/10.1038/mp.2011.119

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