Role of corticotropin-releasing factor receptor-1 in opiate withdrawal

Previous studies indicate that corticotropin-releasing factor (CRF) contrib utes to the anxiety-like and aversive states associated with drug-induced w ithdrawal. The present study extends this work by analyzing the CRF recepto r subtype involved in withdrawal responses. First, the influence of a selec tive CRF receptor-1 (CRF-R1) antagonist, CP-154,526, on opiate withdrawal b ehavior was examined. Pretreatment with the CRF-R1 antagonist significantly attenuated several behavioral signs of naltrexone-induced morphine withdra wal, including writhing, chewing, weight loss, lacrimation, salivation, and irritability, measured during the first hour of withdrawal. Next the expre ssion of CRF-R1 was determined as a second measure of the involvement of th is receptor in opiate withdrawal. Naltrexone-induced morphine withdrawal re sulted in down-regulation of CRF-R1 mRNA in several brain regions, includin g the frontal cortex, parietal cortex, striatum, nucleus accumbens, and amy gdala, but not in the hypothalamus or periaqueductal gray. Expression of CR F-R2, the other major CRF receptor subtype, was not down-regulated signific antly by withdrawal in any of the regions examined, although morphine alone significantly increased levels of this receptor subtype. Taken together, t he behavioral and receptor regulation findings indicate that CRF-R1 is the primary mediator of the actions of the CRF system on opiate withdrawal, alt hough it is possible that CRF-R2 contributes to the response.