Apadoline

Agonists at kappa-opioid receptors may preserve the analgesic properties of mu-opioidergic agonists while avoiding their major adverse effects. The present study was aimed to investigate the antinociceptive effects of the new kappa-opioid receptor agonist RP 60180. An experimental pain model was used based on specific pain stimuli and event-related potentials. Effects of RP 60180 were compared to placebo and to pentazocine that served as positive control. Twenty healthy male volunteers participated in a placebo-controlled, randomized, double-blind, five-way cross-over study. Single peroral doses of RP 60180 (0.1, 0.5, and 1.0 mg), pentazocine (50 mg), and placebo were administered. Pain was induced by means of short pulses of gaseous CO2 applied to the nasal mucosa. In response to these stimuli, chemo-somatosensory event-related potentials (CSSERP) and pain ratings were recorded. Maximum antinociceptive effects were observed 2 h after the administration of 1.0 mg of RP 60180 and 50 mg of pentazocine. This was shortly after RP 60180 had reached the maximum plasma concentration and when highest plasma concentrations of pentazocine were measured. Both RP 60180 and pentazocine reduced pain-related CSSERP amplitudes by approximately 40% at this time. Pentazocine tended to produce more side effects. These results indicate the potential therapeutic value of kappa-agonist analgesics.

1. The authors describe here the effects of intravenous administration of RP 60180, a novel kappa agonist, on conscious baboons of the species Papio papio, which spontaneously present photically induced epileptic responses. 2. Animals (n = 2) were chronically implanted with epidural recording electrodes and tested whilst seated in a primate chair. The electrocorticogram (ECoG) and electrocardiogram (ECG) were recorded during a control period of at least 30 minutes before the injection of RP 60180 (1 to 4.5 mg/kg i.v.) and immediately afterwards. 3. Qualitatively, up to the dose of 4.5 mg/kg i.v., RP 60180 did not modify ECoG background in term of paroxysmal activity in comparison with that observed during the control period. It did not cause any manifest focal or generalized seizure discharges, nor did it consistently enhance or reduce photically induced myoclonic responses. 4. From the dose of 1 mg/kg i.v., RP 60180 slowed ECG frequency. This effect, which lasted for about 30 minutes post-injection, was most often seen at the higher doses. 5. In another set of experiments, one baboon received the kappa agonist U-50488 (a benzacetamide derivative of spiradoline) at 1 and 3 mg/kg i.v. U-50488, at 3 and to a lesser degree at 1 mg/kg i.v., induced paroxysmal bursts of slow wave ECoG activity and a slowing of the ECG. These effects lasted about 1 hour post-drug administration. During this period, we observed spontaneous vocalization, as if the animal were complaining, as well as shaking.