Effects of corticotropin-releasing factor receptor-1 (CRF1R) antagonists on the brain stress system responses to morphine withdrawal

The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry (e.g. induction of hypothalamo-pituitary-adrenocortical –HPAaxis, noradrenergic and corticotrophin-releasing factor activity). The present study investigated the role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxoneprecipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal and c-Fos expression were measured in rats pretreated with vehicle, CP-154,526 or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase (TH)-positive neurons expressing CRF1R were seen at the level of nucleus tractus solitarius (NTS)-A2 cell group both in control and in morphine-withdrawn rats. CP-154,526 and antalarmin attenuated the increase in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels or c-Fos expression that were seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma ACTH levels. These results suggest that CRF1R subtype may be involved in the behavioral and somatic signs as well as in ACTH release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawal-activation of brain stress neurocircuitry. This article has not been copyedited and formatted. The final version may differ from this version. Molecular Pharmacology Fast Forward. Published on February 16, 2010 as DOI: 10.1124/mol.109.062463 at A PE T Jornals on N ovem er 4, 2016 m oharm .aspeurnals.org D ow nladed from