Corticotropin-releasing factor (CRF) receptor-1 is involved in cardiac noradrenergic activity observed during naloxone-precipitated morphine withdrawal.
OBJECTIVE
The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [noradrenergic activity, induction of the hypothalamic-pituitary-adrenocortical (HPA) axis and activation of heat shock proteins (Hsps)]. Corticotropin-releasing factor (CRF) pathways are important mediators in the negative symptoms of opioid withdrawal. We performed a series of experiments to characterize the role of the CRF₁ receptor in the response of stress systems to morphine withdrawal and its effect in the heart using genetically engineered mice lacking functional CRF₁ receptors.


METHODS
Wild-type and CRF₁ receptor-knockout mice were treated with increasing doses of morphine. Precipitated withdrawal was induced by naloxone. Plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, the expression of myocardial Hsp27, Hsp27 phosphorylated at Ser⁸², membrane (MB)- COMT, soluble (S)-COMT protein and NA turnover were evaluated by RIA, immunoblotting and HPLC.


RESULTS
During morphine withdrawal we observed an enhancement of NA turnover in parallel with an increase in mean arterial blood pressure (MAP) and heart rate (HR) in wild-type mice. In addition, naloxone-precipitated morphine withdrawal induced an activation of HPA axis and Hsp27. The principal finding of the present study was that plasma ACTH and corticosterone levels, MB-COMT, S-COMT, NA turnover, and Hsp27 expression and activation observed during morphine withdrawal were significantly inhibited in the CRF₁ receptor-knockout mice.


CONCLUSIONS
Our results demonstrate that CRF/CRF₁ receptor activation may contribute to stress-induced cardiovascular dysfunction after naloxone-precipitated morphine withdrawal and suggest that CRF/CRF₁ receptor pathways could contribute to cardiovascular disease associated with opioid addiction.
Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain.
Elena
E
Martínez-Laorden
Juan-Antonio
JA
García-Carmona
Alberto
A
Baroja-Mazo
Paola
P
Romecín
Noemí M
NM
Atucha
María-Victoria
MV
Milanés
María-Luisa
ML
Laorden
D059331:Adrenergic Neurons / Q000378:metabolism*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000209:etiology; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009021:Morphine Dependence / Q000378:metabolism* / Q000503:physiopathology; D009270:Naloxone; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D011499:Protein Processing, Post-Translational; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013610:Tachycardia / Q000209:etiology; D000099052:CRF Receptor, Type 1
D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D009419:Nerve Tissue Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D009270:Naloxone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
CRF1 receptor knockout mice; Hsp 27; NA turnover; heart; naloxone-precipitated morphine withdrawal