The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal.
Proceedings of the National Academy of Sciences. 2005-12-08; 102(51): 18649-18654
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1. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18649-54. Epub 2005 Dec 8.
The corticotropin-releasing factor receptor-1 pathway mediates the negative
affective states of opiate withdrawal.
Contarino A(1), Papaleo F.
(1)Dipartimento di Farmacologia e Anestesiologia, Università degli Studi di
Padova, Largo Meneghetti 2, 35131 Padua, Italy.
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 (CRF1) and
CRF2. Here we report that genetic disruption of CRF1 receptor pathways in mice
eliminates the negative affective states of opiate withdrawal. In particular,
neither CRF1 receptor heterozygous (CRF1+/-) nor homozygous (CRF1-/-) null mutant
mice avoided environmental cues repeatedly paired with the early phase of opiate
withdrawal. These results were not due to altered associative learning processes
because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions
to environmental cues paired with the kappa-opioid receptor agonist U-50,488H. We
also examined the impact of CRF1 receptor-deficiency upon opiate
withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular
mechanism thought to underlie the negative affective states of drug withdrawal.
Consistent with the behavioral indices, we found that, during the early phase of
opiate withdrawal, neither CRF1+/- nor CRF1-/- showed increased dynorphin mRNA
levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF1
receptor pathways in the negative affective states of opiate withdrawal and
suggests therapeutic strategies for the treatment of opiate addiction.
PMID: 16339307 [Indexed for MEDLINE]