Disruption of the CRF(2) receptor pathway decreases the somatic expression of opiate withdrawal.
Neuropsychopharmacol. 2008-02-20; 33(12): 2878-2887
DOI: 10.1038/npp.2008.8
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1. Neuropsychopharmacology. 2008 Nov;33(12):2878-87. doi: 10.1038/npp.2008.8. Epub
2008 Feb 20.
Disruption of the CRF(2) receptor pathway decreases the somatic expression of
opiate withdrawal.
Papaleo F(1), Ghozland S, Ingallinesi M, Roberts AJ, Koob GF, Contarino A.
Author information:
(1)Unité de Nutrition et Neurosciences, Universités Bordeaux 1 et Victor Segalen
Bordeaux 2, Talence, France.
Escape from the extremely aversive opiate withdrawal symptoms powerfully
motivates compulsive drug-seeking and drug-taking behaviors. The
corticotropin-releasing factor (CRF) system is hypothesized to mediate the
motivational properties of drug dependence. CRF signaling is transmitted by two
receptor pathways, termed CRF(1) and CRF(2). To investigate the role for the
CRF(2) receptor pathway in somatic opiate withdrawal, in the present study we
used genetically engineered mice deficient in the CRF(2) receptor (CRF(2)-/-). We
employed a novel, clinically relevant mouse model of ‘spontaneous’ opiate
withdrawal as well as a classical opioid receptor antagonist
(naloxone)-precipitated opiate withdrawal paradigm. To induce opiate dependence,
mice were treated with intermittent escalating morphine doses (20-100 mg/kg,
i.p.). We found that 8-128 h after the last opiate injection, CRF(2)-/- mice
showed decreased levels of major somatic signs of spontaneous opiate withdrawal,
such as paw tremor and wet dog shake, as compared to wild-type mice. Similarly,
challenge with naloxone 2 h after the last morphine injection induced lower
levels of paw tremor and wet dog shake in CRF(2)-/- mice as compared to wild-type
mice. Despite the differences in somatic signs, wild-type and CRF(2)-/- mice
displayed similar plasma corticosterone responses to opiate dosing and
withdrawal, indicating a marginal role for the hypothalamus-pituitary-adrenal
axis in the CRF(2) receptor mediation of opiate withdrawal. Our results unravel a
novel role for the CRF(2) receptor pathway in opiate withdrawal. The CRF(2)
receptor pathway might be a critical target of therapies aimed at alleviating
opiate withdrawal symptoms and reducing relapse to drug intake.
DOI: 10.1038/npp.2008.8
PMCID: PMC2760329
PMID: 18288089 [Indexed for MEDLINE]