The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal.
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.
Contarino
Angelo
A
Dipartimento di Farmacologia e Anestesiologia, Università degli Studi di Padova, Largo Meneghetti 2, 35131 Padua, Italy.
Papaleo
Francesco
F
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D004399:Dynorphins / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D017473:Receptors, Opioid, kappa; D000099052:CRF Receptor, Type 1; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins