title: Studies on the effect of SCH-34826 and thiorphan on [Met5]enkephalin levels and release in rat spinal cord.
abstract: SCH-34826 and thiorphan are inhibitors of the neutral endopeptidase (NEP; E.C. 3.4.24.11;) that cleaves the opiate peptides [Met5]- and [Leu5]enkephalin at the glycinylphenylalanine bond. These compounds were evaluated for their ability to affect the levels of [Met5]enkephalin-like immunoreactivity (MELI) in the brain and the spinal cord and the release into the extracellular space under resting and K+-evoked conditions. The results showed that oral administration of SCH-34826 (30-100 mg/kg p.o.) or thiorphan (10-30 mg/kg p.o.) had no effect on tissue levels of MELI. In contrast, both agents caused a dose-dependent increase in both the resting and the K+-evoked levels in spinal perfusates, which reached up to 10 times the control values. These data indicate that tissue (presumably intracellular) stores of [Met5]enkephalin are not affected by NEP inhibition and that it is the extracellular effects of the peptide that are potentiated by enzyme blockade. This agrees with the prior results demonstrating that NEP inhibitors require a nociceptive stimulus sufficient to release endogenous stores of [Met5]enkephalins for their actions to be observed.
authors: Anesthesiology Research Laboratory, University of California San Diego, La Jolla 92093.
authors: T L
authors: TL
authors: Yaksh
authors: R E
authors: RE
authors: Chipkin
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D004148:Dioxolanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D004744:Enkephalin, Methionine / Q000378:metabolism*; D008297:Male; D011188:Potassium / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D015244:Thiorphan / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D004148:Dioxolanes; D004149:Dioxoles; D004151:Dipeptides; C056319:Sch 34826; D004744:Enkephalin, Methionine; D015244:Thiorphan; D011188:Potassium