Antinociceptive effect of centrally administered cyclo(N-methyl-L-Tyr-L-Arg) in the rat

The tail-flick test was used to test cyclo(N-methyl-L-Tyr-L-Arg) (C.NMTA), kyotorphin (L-Tyr-L-Arg) and morphine for antinociceptive effects following injection into the cerebroventricles (lateral ventricle (VL), third ventricle (V3) and fourth ventricle (V4)) and into the spinal subarachnoid space in the rat. When injected into the VL, V3 and V4, but not into the spinal subarachnoid space, C.NMTA produced a dose-dependent inhibition of the tail-flick response to thermal stimulation. The ED50 values for each site were 61.0 (48.0-77.5), 40.0 (27.4-58.4) and 163.0 (86.7-306.4) nmol/rat, respectively. Behavioral sedation was seen when C.NMTA was injected into the VL, V3 and V4, but not into the spinal subarachnoid space. Kyotorphin was without antinociceptive effect when given by all routes. However, weak sedation was seen after injection into the cerebroventricles. Naloxone (2, 4 and 20 mg/kg), an opiate antagonist, injected intraperitoneally (i.p.) 20 min before C.NMTA injection, did not significantly alter the C.NMTA-induced antinociceptive effect. Additionally, naloxone (2, 4 and 20 mg/kg i.p.) did not abolish the sedative effect of this peptide. It is suggested that C.NMTA produced a naloxone-resistant antinociceptive effect mainly on the upper brain stem.