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expressing CRF1R were seen at the level of the nucleus tractus solitarius-A2 cell group in both control and morphine-withdrawn rats.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 withdrawal-activation of brain stress neurocircuitry.
Footnotes
This work was supported by the Ministerio de Ciencia e Innovación of Spain [Grants SAF/FEDER 2006-00331, 2007-62758, 2009-07178] and Red de Trastornos Adictivos [Grant RD06/0001/1006]. J.N.-Z. was supported by a fellowship from the Ministerio de Ciencia e Innovación.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.062463.
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ABBREVIATIONS:
- CRF
- corticotropin-releasing factor
- CRFR
- CRF receptor
- CRF1R
- CRF receptor-1 subtype
- HPA
- hypothalamus-pituitary-adrenocortical
- NA
- noradrenaline
- PVN
- paraventricular nucleus
- TH
- tyrosine hydroxylase
- NTS
- nucleus tractus solitarius
- CeA
- central amygdala
- AP
- area postrema
- DAB
- diaminobenzidine
- MHPG
- 3-methoxy-4-hydroxyphenylethylen glycol
- HPLC
- high-performance liquid chromatography
- ANOVA
- analysis of variance
- CP-154526
- N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine
- AVP
- arginine-vasopressin
- CRA1000
- [2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine)]
- R121919
- 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine.
- Received November 16, 2009.
- Accepted February 16, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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