enkephalin-leu--ala(2)-arg(6)- and Pain

Peptides normally do not cross the blood-brain barrier (BBB). Previously, it has been shown that the hexapeptide enkephalin analogue dalargin with polysorbate-80-coated nanoparticles (DAL/NP) can be transported across the BBB and is able to exhibit an antinociceptive effect in mice. In the present study, the circadian time and dose dependencies of the antinociceptive effect of different dalargin preparations were investigated. The active preparation (DAL/NP, 5 mg/kg, 10 mg/kg), as well as a dalargin solution in phosphate buffered saline (DAL/SOL, 10 mg/kg) were injected intravenously to groups of 10-12 inbred DBA/2 mice at 12 different circadian times; mice were synchronized to a light-dark (LD) 12:12 regimen. The antinociceptive effect was determined 15 minutes postinjection by the hot-plate test. Experiments with DAL/NP were repeated using the tail-flick test system at two selected times (08:00 and 20:00) to test for dose dependency (2.5, 5, 7.5, 10 mg/kg). Hot-plate latencies were rhythmic under baseline and after DAL/SOL, with acrophases in the dark phase; DAL/SOL did not influence latency time. In contrast, DAL/NP significantly increased reaction time dose dependently; the maximal possible effect was rhythmic with the 10 mg/kg preparation, with a peak effect in the early light phase. Results were confirmed by the tail-flick test. The experiments demonstrate that an enkephalin analogue coated with nanoparticles can easily cross the BBB and is able to display a dose- and time-dependent antinociceptive effect.

Topics: Analgesics; Animals; Blood-Brain Barrier; Circadian Rhythm; Dose-Response Relationship, Drug; Enkephalin, Leucine-2-Alanine; Hot Temperature; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Microspheres; Pain; Polysorbates; Reaction Time

The antinociceptive effect of dalargin was studied by its influence on the amplitude of somatosensory induced potentials (IP) and by changes in the threshold pain sensitivity to heat stimulation. It was shown that it was necessary to taken into account the patients' individual sensitivity to the drug. The influence of dalargin on IP in the pre-operative period was compared with the quality of its analgetic defence in surgical interventions. The defence quality was determined according to the reduction in the consumption of the narcotic analgesic phentanyl during anesthesia. The studied parameters were found to be directly related to the correlation coefficient 0.75 (p less than 0.05). The findings allow for a reliable prediction of the antinociceptive effect of dalargin in its application in anaesthesiological practice.

Topics: Adult; Analgesics; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Evoked Potentials, Somatosensory; Humans; Middle Aged; Pain; Preanesthetic Medication; Sensory Thresholds