n-methylnaloxone and naloxonazine

The cardiovascular and renal effects of a mu opioid agonist, [Dmt]DALDA, were studied in conscious Sprague-Dawley rats. During the first hour postinjection, [Dmt]DALDA (0.025-250 microg/rat, IV) evoked a dose-dependent diuresis. The dose of 2.5 microg increased urine volume from 1.0 +/- 0.2 to 3.4 +/- 0.3 mL/h (P < 0.001, n = 30), urinary excretion of sodium, potassium, and cGMP, and induced a mild antihypertensive effect. This dose increased cumulative 4-hour urine volume but significantly inhibited sodium and potassium excretions. The renal and cardiovascular effects were abolished by naloxone (4 mg/kg), but not by naloxonazine (35 mg/kg SC), a selective mu-1 receptor antagonist. Pretreatment with 8 mg/kg naloxone methiodide, an opioid antagonist with limited access to the brain, partially inhibited the renal effects of [Dmt]DALDA. Inhibition of nitric oxide synthases with L-NAME (1 mg/kg) had no effect on the renal and cardiovascular actions of [Dmt]DALDA. Plasma ANP and AVP, measured at 20 and 120 minutes after injection, were not altered by 2.5 and 25 microg [Dmt]DALDA. Therefore, [Dmt]DALDA evokes renal and cardiovascular effects that may primarily be mediated by central naloxonazine-insensitive mu opioid receptors (non-mu-1). These findings indicate that the central mu opioid system is involved in the regulatory mechanism of renal handling of sodium and water.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Enzyme Inhibitors; Female; Gene Expression; Heart Rate; Hemodynamics; Homeostasis; Kidney; Myocardium; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oligopeptides; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Vasopressins

1. Changes in respiratory variables, arterial blood pressure and heart rate were studied in awake rats after injection of the opioid peptide [Lys7]dermorphin and its main metabolites, [1-5]dermorphin and [1-4]dermorphin. 2. Fifteen minutes after injection, doses of [Lys7]dermorphin producing antinociception (i.c.v., 36-120 nmol; s.c., 0.12-4.7 micromol kg(-1)) significantly increased respiratory frequency and minute volume of rats breathing air or hypoxic inspirates. This respiratory stimulation was reversed to depression by the 5-HT receptor antagonist ritanserin (2 mg kg(-1), s.c.), was blocked by naloxone (0.1 mg kg(-1), s.c.), significantly reduced by the mu1 opioid receptor antagonist naloxonazine (10 mg kg(-1), s.c., 24 h before) but unaffected by peripherally acting opioid antagonist naloxone methyl bromide (3 mg kg(-1), s.c.). Forty five minutes after injection, doses of the peptide producing catalepsy (s.c., 8.3-14.2 micromol kg(-1), i.c.v., 360 nmol) significantly reduced respiratory frequency and volume of rats breathing air and blocked the hypercapnic ventilator response of rats breathing from 4% to 10% CO2. I.c.v. administration of [1-5]dermorphin and [1-4]dermorphin (from 36 to 360 nmol) never stimulated respiration but significantly reduced basal and CO2-stimulated ventilation. Opioid respiratory depression was only antagonized by naloxone. 3. In awake rats, [Lys7]dermorphin (0.1-1 mg kg(-1), s.c.) decreased blood pressure. This hypotensive response was abolished by naloxone, reduced by naloxone methyl bromide and unaffected by naloxonazine. 4. In conclusion, the present study indicates that analgesic doses of [Lys7]dermorphin stimulate respiration by activating central mu1 opioid receptors and this respiratory stimulation involves a forebrain 5-hydroxytryptaminergic excitatory pathway.

Topics: Analgesia; Animals; Blood Pressure; Hypercapnia; Injections, Intravenous; Injections, Intraventricular; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Oligopeptides; Prosencephalon; Pulmonary Ventilation; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid, mu; Ritanserin; Serotonin Antagonists; Tidal Volume

The acute effect of opioid antagonists on volitional ethanol intake was studied in unselected Sprague-Dawley rats using a two-bottle, free-choice model. The total daily intake of ethanol during saline treatment was 1.79 +/- 0.4 g/kg/day (n = 136). The rats were deprived of fluids for the last 4 hr of the light period. Saline or drug was given intraperitoneally 20 to 30 min before the onset of dark, and the ethanol and water intakes were measured during the following hour. The ethanol intake during this hour was 0.75 +/- 0.06 g/kg (n = 136). Naltrexone significantly reduced ethanol intake. There was also a significant reduction in ethanol intake following administration of ICI-174,864. Naloxonazine and naloxone methiodide lacked effect. None of the treatments had any effect on the water or food intake. The results suggest that central delta-opioid receptors modulate volitional ethanol intake in the rat.

Topics: Alcohol Drinking; Animals; Enkephalin, Leucine; Male; Naloxone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta