Prevention of degradation of endogenous enkephalins produces inhibition of nociceptive neurones in rat spinal cord.
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.
Dickenson
A H
AH
Sullivan
A F
AF
Fournie-Zaluski
M C
MC
Roques
B P
BP
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
D004151:Dipeptides; D004745:Enkephalins; D011480:Protease Inhibitors; D009270:Naloxone; C042591:kelatorphan; D015244:Thiorphan; D008625:Tiopronin; D007930:Leucine; C012211:ubenimex