Effects of Corticotropin-Releasing Factor Receptor-1 Antagonists on the Brain Stress System Responses to Morphine Withdrawal

Abstract

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 (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone-precipitated 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-154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A 2 cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases 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 was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawalactivation of brain stress neurocircuitry.

Restricted role of CRF1 receptor for the activity of brainstem catecholaminergic neurons in the negative state of morphine withdrawal

“…Data are expressed as the mean±SEM (n=4-6), ***p<0.001 versus morphine (mor)+saline (sal); +++ p<0.001 versus sal+naloxone (nx); && p<0.01, &&& p<0.001 versus wild-type mice mice showed less diarrhea and motor activity. These findings are consistent with a previous report from our laboratory (Navarro-Zaragoza et al 2010) showing that CP-15426 or antalarmin (CRF1R antagonists) decreased the weight loss and the irritability observed in morphine withdrawn rats.…”

Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors

“…However, the failure of CRH antagonists in our study to alter the nicotine-stimulated secretion of corticosterone was not due to the choice of the dose of these antagonists because both antagonists clearly blocked the effect of CRH and these doses have been used previously (Deak et al . 1999, Navarro-Zaragoza et al . 2010, Gulyas et al .…”

Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish

“…CRF signaling is mediated through the activities of two distinct G-protein coupled receptor subtypes, known as CRF-R1 and CRF-R2 [24], [25]. Indeed, studies have demonstrated the ability of CRF receptor antagonists in reducing negative motivational effects during withdrawal phase [26], [27]. The attenuation of aversive effects of opiate withdrawal in CRF-R1 and CRF-R2 deficient mice further validates the role of the CRF pathway in addiction and withdrawal [28], [29].…”