title: Prevention of degradation of endogenous enkephalins produces inhibition of nociceptive neurones in rat spinal cord.
abstract: The enkephalins, found in high levels in the superficial dorsal horn where they are associated with the terminals of afferent nociceptive fibres, are rapidly degraded by at least 3 peptidases. The use of inhibitors of these peptidases allows effects mediated by endogenous enkephalins to be observed. We report here the inhibitory effects on spinal nociceptive transmission of bestatin, a non-specific aminopeptidase inhibitor, thiorphan, an inhibitor of enkephalinase and kelatorphan, a mixed inhibitor of aminopeptidases, particularly aminopeptidase M, enkephalinase and dipeptidylaminopeptidase. The agents were applied intrathecally, directly onto the spinal cord, in halothane-anaesthetized intact rats. Bestatin (n = 23 neurones) produced weak inhibitions of C-fibre-evoked activity (maximum 17% inhibition) whereas thiorphan (n = 20) produced maximal 25% inhibitions. Kelatorphan (n = 32) produced maximal 46% inhibitions which were naloxone reversible. All 3 agents caused dose-dependent effects which were relatively selective for C-fibre evoked responses, sparing A beta-fibre inputs. The results are discussed in relation to roles of the enkephalins in sensory modulation and the potential of these compounds as novel therapeutic agents.
authors.forename: A H
authors.initials: AH
authors.lastname: Dickenson
authors.forename: A F
authors.initials: AF
authors.lastname: Sullivan
authors.forename: M C
authors.initials: MC
authors.lastname: Fournie-Zaluski
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism* / Q000502:physiology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects*; D009433:Neural Inhibition / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects; D010146:Pain / Q000503:physiopathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D004745:Enkephalins; D011480:Protease Inhibitors; D009270:Naloxone; C042591:kelatorphan; D015244:Thiorphan; D008625:Tiopronin; D007930:Leucine; C012211:ubenimex