Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 345, Issue 4, pp 466–472 | Cite as

Attenuation of the morphine withdrawal syndrome by inhibition of catabolism of endogenous enkephalins in the periaqueductal gray matter

  • R. Maldonado
  • M. C. Fournie-Zaluski
  • B. P. Roques
Original Articles


We have investigated the effects of the local administration into the periaqueductal gray matter of thiorphan, a selective inhibitor of endopeptidase 24.11 “enkephalinase”, kelatorphan, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-alanine, and RB 38 A, (R)-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine, two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats.

Local administration of these inhibitors decreased the severity of the withdrawal syndrome. Jumping, chewing, diarrhea, piloerection, salivation and hypothermia were decreased by all drugs. Lacrimation and weight loss were reduced by kelatorphah and RB 38 A whereas teeth chattering, tremor, eye twitch and rhinorrhea were decreased only by RB 38 A. The rise in plasma corticosterone levels was only slightly reduced by the three inhibitors. Wet dog shakes and ptosis remained unchanged.

These results indicate that during the morphine withdrawal syndrome in rats there is a tonic or/and naloxone evoked release of opioid peptides, presumably enkephalins, into the periaqueductal gray matter and that inhibition of their degradation strongly decreases the severity of the withdrawal syndrome.

Key words

Morphine withdrawal Periaqueductal gray matter Enkephalin catabolism inhibitors Kelatorphan Thiorphan 


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Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • R. Maldonado
    • 1
  • M. C. Fournie-Zaluski
    • 1
  • B. P. Roques
    • 1
  1. 1.Département de Chimie Organique, U 266 INSERM, UA 498 CNRSFaculté des Sciences Pharmaceutiques et BiologiquesParisFrance

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