The antinociceptive effects of SCH-32615, a neutral endopeptidase (enkephalinase) inhibitor, microinjected into the periaqueductal, ventral medulla and amygdala.

The local effects of SCH-32615, an inhibitor of enkephalinase (EC 3.4.24.11) on the hot-plate (HP) and tail-flick (TF) responses were examined following unilateral intracerebral microinjection into the periaqueductal brain (PAG), the medial ventral medulla (VM) and bilateral microinjection into the amygdala (AM) of the rat. In the PAG and VM, SCH-32615 resulted in a dose-dependent increase in HP and TF response latencies over a dose range of 1-30 micrograms with the ED50 values (micrograms) being PAG-TF = 17; PAG-HP = 11; VM-TF = 7; VM-HP = 6. In the AM, dose-dependent increases were only observed on the HP. (ED50 (micrograms) HP = 17). Peak effects were observed within 10 min and response latencies remained elevated for 45-60 min. Injections of SCH-32615 at sites outside of the PAG or VM were considerably less effective. All antinociceptive effects were antagonized by naloxone (1 mg/kg, i.p.). Twenty-four hours following the microinjection of beta-funaltrexamine (an irreversible opioid antagonist) into the PAG or the VM, the effects of SCH-32615 in the PAG were virtually abolished while in the VM, its effects were only moderately reduced. These data suggest that in the presence of a strong thermal stimulus, the behavioral response is subject to a tonically active or stimulus-evoked modulation by the local release in the PAG, VM and AM of an agent, presumably an enkephalin peptide, the degradation of which is altered by enkephalinase inhibition.