Abstract
The cardiovascular and central nervous system effects of the kappa opioid receptor agonist U-62066E were investigated in ten normal male subjects who received U-62066E or placebo with low or high dose naloxone in a randomized, double blind study.
Blood pressure and heart rate in the supine and standing position, plasma adrenaline and noradrenaline, regional Doppler blood velocity indices and psychometric assessments were recoreded for 1.25 h before and 6 h following injection. U-62066E caused sedation and dysphoria but no euphoria.
Plasma noradrenaline was increased by U62066E when compared with basal levels. This action of U62066E was prevented by high but not low dose naloxone.
U-62066E had no significant effect on blood pressure, heart rate or regional blood flow indices in the vessels studied and no effect on plasma adrenaline levels.
Since U62066E at a dose known to have marked kappa effects was not found to influence cardiovascular indices our results do not support a major role for kappa opioids in the control of the circulation. However, U62066E may influence noradrenaline release or clearance and cause sedation and psychotomimetic effects.
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Medvedev OS, Martynova ER, Hoque AM (1988) Effects of Mu- and Delta- opiate receptor agonists on systemic and regional haemodynamics in conscious rats. In: Stumpe KO, Kraft K, Faden AI (eds) Opioid peptide and blood pressure control. Springer, Berlin Heidelberg New York, pp 159–167
Zelis R, Mansour EJ, Capone RJ, Mason DT (1974) The cardiovascular effects of norphine. J Clin Invest 54: 1247–1258
Lowenstein E, Hallowell P, Levine FH, Daggett WM, Austen WG, Laver MB (1969) Cardiovascular responses to large doses of intravenous morphine in man. N Engl J Med 281: 1389–1393
Drew JH, Dripps RD, Comroe JH (1946) Clinical studies on morphine II. The effect of morphine upon the circulation of man and upon the circulatory and respiratory responses to tilting. Anaesthesiol 7: 44–61
Rubin PC, McLean K, Reid JL (1983) Endogenous opioids and baroreflex control in man. Hypertension 5: 535–538
Pasanisi F, Sloan L, Rubin PC (1985) Cardiovascular properties of methkephamid a delta opioid agonist: U-62066E. J Pharmacol Exp Ther 240: 128–131
Frederichson RLA, Smithwick EK, Shuman R, Bemis KG (1981) Metkephanid, a systematically active analogue of methionine enkephalin with potent opioid receptor activity. Science 211: 603–605
Hardy GW, Sang PY, Simpkin DSA, Wilkinson S, Follenfant RL, Lowe LA, Smith TW (1988) Peripherally acting enkephalin analogue 1 polar pentapeptides. J Med Chem 31: 960–966
Cohen AF, Harkin N, Posner J (1990) Cardiovascular effects of a novel enkephalin analogue 443C81 in humans. J Cardiovasc Pharmacol 16: 455–460
Posner J, Moody SG, Peck AW, Rutter D, Telekes A (1990) Analgesic, central, cardiovascular and endocrine effects of the enkephalin analogue Tyr-D-Arg-Gly-Phe-(NO2)-Pro-NH2 (443C81) in healthy volunteers. Eur J Clin Pharmacol 38: 213–218
Rubin PC (1984) Opioid peptides in blood pressure regulation in man. Clin Sci 66: 625–630
Lahti RA, Michelson MM, McCall JM, Von Voigtlander PF (1985) [3H] U-69593: a highly selective ligand for the opioid K-receptor. Eur J Pharmacol 109: 281–284
Peters GR, Ward NJ, Antal EF, Lai DY, DeMaar EW (1987) Diuretic actions in man of a selective kappa opioid agonist: U-62066E. J Pharmacol Exp Ther 240: 128–131
Rimoy GH, Bhaskar NK, Wright DM, Rubin PC (1991) Mechanism of diuretic action of U-62066E — a kappa opioid receptor agonist in the human. Br J Clin Pharmacol 32: 611–615
MacDonald IA, Lake DM (1985) An improved technique for extracting catecholamines from body fluids. J Neuroscience Meth 13: 239–249
Preston KL, Bigelow GE (1993) Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers. J Pharmacol Exp Ther 264: 813–823
Babkoff H, Caspy T, Mikulincer M (1991) Subjective sleepiness ratings: the effects of sleep deprivation, circadian rhythmicity and cognitive performance. Sleep 14: 534–539
Hastie SJ, Howie CA, Whittle MJ, Rubin PC (1988) Daily variability of umbilical and lateral uterine wall artery blood velocity waveform measurements. Br J Obstet Gynaecol 95: 571–574
Rimoy GH, Bhaskar NK, Rubin PC (1991) Reproducibility of Doppler Blood flow waveform measurements: study on variability within and between day during haemodynamic intervention in normal subjects. Eur J Clin Pharmacol 41: 125–129
MacDonald NJ, Butters L, O'Shaughnessy DJ, Riddell AJ, Rubin PC (1989) A comparison of the effects of human alpha calcitonin gene-related peptide and glyceryl trinitrate on regional blood velocity in man. Br J Clin Pharmacol 28: 257–261
Gosling RG, King DH (1974) Continuous wave ultrasound as an alternative and complement to X-rays in vascular examinations. In: Reneman RS (ed) Cardiovascular applications of ultrasound. North-Holland, Amsterdam, pp 266–282
Burns PN (1987) The physical principles of Doppler and spectral analysis. J Clin Ultrasound 15: 567–590
Kindman LA, Kates RE, Ginsburg R (1991) Opioids potentiate contractile response of rabbit myocardium to the beta adrenergic agonist isoproterenol. J Cardiovasc Pharmacol 17: 61–67
Wright DM, Clarke G (1986) Inhibitory effect of U-50488H on suckling-evoked oxytocin release is blocked by propranolol. Br J Pharmacol 89: 646P
Clarke G, Wright DM (1986) Do mu- and kappa- selective opioids inhibit oxytocin release in the same way? Br J Pharmacol Proc Suppl 89: 758P
Ensinger H, Hedler L, Schnurr C, Starke K (1984) Ethylketocyclazocine decreases noradrenaline release and blood pressure in rabbit at a peripheral receptor. Naunyn Schmiedebergs Arch Pharmacol 328: 20–23
Ensinger H, Hedler L, Szabo B and Starke K (1986) Bremazocine causes sympatho-inhibition and hypotension in rabbits by activating peripheral K-receptors. J Cardiovasc Pharmacol 8: 470–475
Szabo B, Hedler L, Ensinger H, Starke K (1986) Opioid peptides decrease noradrenaline release and blood pressure in the rabbit at peripheral receptors. Naunyn Schmiedebergs Arch Pharmacol 329: 206–209
Starke K, Schoffel E, Illes P (1985) The sympathetic axons innervating the sinus node of the rabbit possess presynaptic opioid K- but not mu or delta-receptors. Naunyn Schmiedebergs Arch Pharmacol 329: 206–209
Roizen MF, Weisse V, Moss J, Kopin IJ (1975) Plasma catecholamines: arterial-venous differences and the influence of body temperature. Life Sci 16: 1133–1144
Esler MD, Hosking CJ, Willet IR, Leonard PW, Jennings GL (1985) Noradrenaline release and sympathetic nervous system activity. J Hypertens 3: 117–129
Goldstein DS, McCarty R, Polinsky RJ, Kopin IJ (1983) Relationship between plasma noradrenaline and sympathetic neuronal activity. Hypertension 5: 552–559
Kunihara M, Ohyama M, Nakano M (1992) Central monoaminergic mechanisms in mice and analgesic activity of spiradoline mesylate, a selective kappa opioid receptor agonist. Eur J Pharmacol 214: 111–118
Best JD, Halter JB (1982) Release and clearance rates of epinephrine in man: importance of arterial measurements. J Clin Endocrinol Metab 55: 263–268
Blackburn TP, Borkowski KR, Friend J, Rance MJ (1986) On the mechanisms of K-opioid induced diuresis. Br J Pharmacol 89: 593–598
Borkowski KR (1989) Studies on the adrenomedullary dependence of K-opioid agonist-induced diuresis in conscious rats. Br J Pharmacol 98: 1151–1156
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Rimoy, G.H., Wright, D.M., Bhaskar, N.K. et al. The cardiovascular and central nervous system effects in the human of U-62066E. Eur J Clin Pharmacol 46, 203–207 (1994). https://doi.org/10.1007/BF00192549
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DOI: https://doi.org/10.1007/BF00192549