The cardiovascular and central nervous system effects in the human of U-62066E

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 recorded 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.

Controlling signaling with a specifically designed G i -coupled receptor

“…Dynorphin is an opioid peptide hormone, bremazocine a nonselective opioid agonist (13), spiradoline a highly selective agonist (15,28), and ICI204,448 a agonist that does not cross the blood-brain barrier (29). The most dramatic differences between the receptors were seen in their binding affinities for dynorphin.…”

“…The receptor has been the focus of intense research by the pharmaceutical industry because agonists have the potential to induce analgesia without causing the respiratory depression or addiction associated with opioid receptor agonists like morphine (13,14). As a result, there are many nonaddictive synthetic small molecule agonists, some of which are orally available and well tolerated in humans (15,16). Opioid receptors have also been subjected to extensive mutagenesis, allowing us to choose mutations of the receptor that favor the construction of prototype RASSLs.…”

The Role of Delta Opioid Receptors in Ethanol Consumption and Seeking: Implications for New Treatments for Alcohol Use Disorders

“…However, as KOP-R agonists produce aversion, this may lead to reductions in ethanol consumption but this remains to be studied. The KOP-R agonist, U69593, produces conditioned place aversion (CPA) in animals (Shippenberg & Herz, 1986) and KOP-R agonists induce dysphoria in humans (Kumor et al, 1986;Pfeiffer et al, 1986;Rimoy et al, 1994). In contrast, the KOP-R agonist, enadoline (or CI-977), when delivered via mini-osmotic subcutaneous pumps increased 10 and 20% ethanol consumption (Holter et al, 2000).…”

“…MOP-R agonists increase and MOP-R antagonists decrease, respectively, ethanol-induced CPP in rats (Matsuzawa et al, 1998;Matsuzawa et al, 1999a;Matsuzawa et al, 1999b). In comparison, activation of the KOP-R is associated with general aversive activity in rats (Shippenberg & Herz, 1986) and induces dysphoria in humans (Kumor et al, 1986;Pfeiffer et al, 1986;Rimoy et al, 1994). The KOP-R agonist, U50488, attenuates ethanol-induced CPP in rats (Matsuzawa et al, 1999a).…”

Generalization of NMDA-Receptor Antagonists to the Discriminative Stimulus Effects of κ-Opioid Receptor Agonists U-50,488H, but Not TRK-820 in Rats

“…The ability of opioids to produce the discriminative stimulus effects is believed to be homologous to the subjective effects that opioids produce in humans. It has been reported that κ-opioid receptor agonists produce dysphoria and psychotomimetic effects in humans (10,11) and aversive effects in rodents (12 -14). These results may support our hypothesis that the cue of the discriminative stimulus effects of U-50,488H may be associated with aversive effects in rats, and the cue of the discriminative stimulus effects of U-50,488H and some NMDA-receptor antagonists may be, at least in part, accompanied by their aversive effects.…”