Abstract
We have previously shown an enhanced activity of the pituitary-adrenal response in rats dependent on morphine, which occurs concomitantly with an increase in the activity of catecholaminergic terminals in the hypothalamic paraventricular nucleus (PVN). The present study examined the possible role of noradrenergic system in the regulation of opioid withdrawal-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis activity. Rats were given morphine by s.c. implantation of morphine pellets for 7 days. On the seventh day, morphine withdrawal was induced by s.c. administration of naloxone (1 mg/kg), rats were sacrificed 30 min later, and changes in noradrenaline (NA) turnover (estimated by the 3-methoxy-4-hydroxyphenylethylen glycol/NA ratio) and in dopamine turnover (estimated by the 3,4-dihydroxyphenylacetic acid/dopamine ratio) in the PVN (HPLC with electrochemical detection) and in plasma corticosterone levels were determined. We found a parallelism between the behavioral signs of withdrawal, an increased activity of noradrenergic and dopaminergic terminals in the PVN, and the hypersecretion of the HPA axis. Pretreatment with α1- or α2-adrenoceptor antagonists prazosin or yohimbine, respectively, 15 min before naloxone administration significantly prevented the withdrawal-induced corticosterone hypersecretion and attenuated the behavioral signs of morphine withdrawal. In addition, biochemical analysis indicated that both prazosin and yohimbine completely abolished the withdrawal-induced increase in NA turnover in the PVN. In contrast, neither prazosin nor yohimbine modified the hyperactivity of dopaminergic terminals in the PVN during withdrawal. Collectively, these data suggest that the secretory activity in the HPA axis after morphine withdrawal results from an increase in noradrenergic activity that is dependent on α1- and α2-adrenoceptor activation. Activation of dopaminergic pathways might not contribute to the neuroendocrine response during withdrawal.
Footnotes
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Send reprint requests to: M. V. Milanés, Unit of Pharmacology, University School of Medicine, 30100 Murcia, Spain. E-mail: milanes{at}fcu.um.es
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↵1 This study was supported by Dirección General de Investigación Cientifica y Ténica Grant PM96-0095.
- Abbreviations:
- NA
- noradrenaline
- DA
- dopamine
- HPA
- hypothalamus-pituitary-adrenocortical
- ACTH
- adrenocorticotropic hormone
- CRF
- corticotropin-releasing factor
- PVN
- paraventricular nucleus
- MHPG
- 3-methoxy-4-hydroxyphenylethylen glycol
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- Received August 2, 1999.
- Accepted December 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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