The antinociceptive effects of intrathecally administered SCH32615, an enkephalinase inhibitor in the rat.

The presence of opioid receptors and enkephalin-releasing neurons in the spinal dorsal horn prompted us to examine whether an enkephalinase inhibitor, SCH32615, given intrathecally would alter the response of the rat on several nociceptive endpoints: 49 degrees C hot plate (HP), 52 degrees C HP; tail flick (TF) and the paw pressure (PP) test. SCH (16-320 nmol, i.t.) resulted in a submaximal dose-dependent increase in the 49 degrees C HP, 52 degrees C HP, TF, and PP measures with the respective ED50 values being 40, 74, 68 and 83 nmol, respectively. AT 320 nmol, no additional increment in effect was observed. Concurrent examination of the effects of 0.1-10 nmol morphine on the 49 degrees C HP, 52 degrees C HP, TF and PP measures revealed i.t. ED50 values of 0.2, 0.8, 0.9 and 0.6 nmol, respectively, with the maximum dose leading to a complete block on all measures. The effects of SCH were totally reversed by naloxone (1 mg/kg, i.p.), a dose which had no detectable effect upon baseline nociceptive response measures. The effects of SCH, even at the highest dose were not accompanied by motor dysfunction or catalepsy. These results are consistent with the hypothesis that high-threshold thermal and mechanical stimuli will evoke the release of an opioid in the spinal space, the metabolism of which is significantly influenced by enkephalinase inhibition.