Changes in right atrial catecholamine content in naïve rats and after naloxone-induced withdrawal.

In this study, we determined if changes in heart catecholamine content during naloxone-induced withdrawal correlated with modifications in heart rate. In addition, we determined plasma concentrations of corticosterone as an index of the hypothalamo-pituitary-adrenal (HPA) axis. The effects of naloxone on norepinephrine, epinephrine or dopamine content and turnover, plasma concentrations of corticosterone and the mechanical response of the right atria of the rat were studied. Male rats were implanted with placebo or morphine pellets for 7 days. On the day of sacrifice, animals were injected with saline or naloxone 1 mg kg-1 s.c. to precipitate a withdrawal syndrome. Administration of naloxone to morphine-treated (tolerant) animals induced a decrease in atrial content of norepinephrine, epinephrine and dopamine (290.2 (11.9) ng g-1, 15.6 (2.1) ng g-1 and 9.52 (0.5) ng g-1, respectively) and an increase (1.38 (0.2) ng g-1 in the dihydroxy phenyl acetic acid/dopamine (DOPAC/DA) ratio. Administration of naloxone to morphine-treated animals enhanced plasma concentrations of corticosterone (435.8 (27.6) ng ml-1). In the isolated right atria, L-naloxone induced an increase in atrial rate in preparations from morphine-treated rats whereas in placebo-pelleted (naïve) rats, L-naloxone induced a decrease. In contrast, administration of D-naloxone (inactive isomer) produced a decrease in atrial rate in preparations from placebo or morphine-treated rats. We conclude that this study has provided evidence that naloxone-induced withdrawal was characterized by activation of catecholaminergic neurones in the heart that was accompanied by an increase in atrial rate.

Effects of U-50,488H on isolated atria from rats chronically treated with the kappa-opioid agonist, U-50,488H.

The present investigation was aimed at determining if chronic activation of kappa- or mu-opioid receptors induce development of tolerance and dependence to kappa-opioid agonists on the isolated left atria of the rat. Tolerance to a kappa-agonist (specific tolerance) was induced by chronic administration of U-50,488H, a selective kappa-agonist (15 mg kg(-1) i.p. twice a day for 4 days). The animals were rendered tolerant to morphine by subcutaneous implantation of morphine pellets (75 mg per pellet) for 7 days. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve, it was accompanied by a decrease in the maximum response and in the slope. Preparations from morphine-treated rats were not tolerant to the selective kappa-agonist, that is, there was no cross-tolerance between mu- and kappa-agonists. Dependence to the kappa-agonist was tested by administration in the organ bath of Mr-2266 (preferential kappa-antagonist) or nor-binaltorphimine (nor-BNI; selective kappa-antagonist). The administration in the organ bath of the kappa-antagonists Mr-2266 or nor-BNI to preparations from U-50,488H-treated rats induced an increase in atrial force of contraction. In contrast, the administration of the kappa-antagonists to preparations from control rats induced a decrease in atrial force of contraction. These findings demonstrate that left atria from chronically U-50488H-treated rats exhibit tolerance to the negative inotropic effects of U-50,488H as well as opioid withdrawal after nor-BNI.

Effects of chronic U-50,488H treatment on the isolated right atrium of the rat.

The aim of the present investigation was to determine if chronic activation of kappa-opioid receptor induces development of tolerance and dependence to kappa-opioid agonists on the isolated right atrium of the rat. Tolerance to the kappa-agonist was induced by chronic administration of U-50,488H, a selective kappa-agonist (15 mg/kg i.p. twice a day for 4 days). The rats were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve; it was accompanied by a decrease in the maximum response and in the slope. Withdrawal to the kappa-agonist was induced by administration of Mr-2266 (preferentially kappa-antagonist) or nor-binaltorphimine (nor-bni; selective kappa-antagonist) to the organ bath. The administration of the kappa-antagonists Mr-2266 or nor-bni to preparations from tolerant rats in the organ bath induced an increase in auricular contraction frequency. In contrast, the administration of the kappa-antagonists to preparations from vehicle-treated rats induced a decrease in auricular contraction frequency. These findings demonstrate that the hearts of rats that had received chronic U-50,488H treatment develop tolerance to the cardiac effects of U-50,488H and exhibit excitatory reactions to kappa-antagonist's precipitated withdrawal.

Effects of acute administration of morphine on right atrial catecholamine content and heart rate in chronically morphine-treated rats.

The purpose of this study was to determine if chronic administration of the preferential mu agonist, morphine, induced changes in cardiac catecholamine content. In rats treated with morphine for 7 days, a challenge dose of morphine 30 mg kg-1 i.p. increased atrial noradrenaline (mean 1123.8 (SEM 62.2) ng g-1), adrenaline (79.48 (8.5) ng g-1) and dopamine (46.0 (1.0) ng g-1) content whereas dopamine turnover was decreased; this was accompanied by a decrease in the frequency of contraction of the isolated right atria. There were no changes in noradrenaline, adrenaline, dihydroxy phenylacetic acid (DOPAC) or DOPAC:dopamine ratio in placebo-treated rats. These results demonstrated that acute administration of morphine in morphine-treated rats produced inhibition of neuronal catecholamine activity in the heart which could be responsible for the decrease in atrial contraction frequency.

Effects of chronic morphine treatment on catecholamines content and mechanical response in the rat hearts.

Our investigation was aimed at elucidating if the chronic administration and withdrawal of a preferential mu-agonist, morphine, induce changes on the heart catecholaminergic neuronal activity. With this purpose the effects of morphine or naloxone (preferentially mu-antagonist) on noradrenaline, adrenaline or dopamine (DA) content and the mechanical response of the left atria were studied in chronically placebo- or morphine-treated rats (implanted s.c. with pellets for 7 days). In morphine-treated rats, a challenge dose of morphine (30 mg/kg i.p.) increased the auricular noradrenaline, adrenaline and DA content and decreased dihydroxy phenyl acetic acid/DA ratio; these changes were accompanied by a decrease in the force of contraction in the isolated left atria. No changes were observed in placebo-treated rats. The administration of naloxone (1 mg/kg s.c.) to morphine-treated animals induced a decrease on the auricular content of noradrenaline, adrenaline and DA and an increase in dihydroxy phenyl acetic acid/DA ratio. The study of the mechanical response to naloxone in the isolated left atria showed an enhancement in the force of contraction in preparations from morphine-treated rats, whereas in the placebo-pelleted rats naloxone induced a decrease in this parameter. These findings demonstrate that the heart of rats that had received chronic morphine-treatment exhibit excitatory reactions to naloxone-precipitated withdrawal and suggest that the changes observed in the heart by the chronic administration of morphine and after naloxone precipitated withdrawal are mostly mediated by the catecholaminergic system.