Substance P endopeptidase-like activity is altered in various regions of the rat central nervous system during morphine tolerance and withdrawal.
In this study the level of a substance P endopeptidase (SPE)-like activity was measured in different regions of the rat central nervous system (CNS) after chronic administration of morphine. Male rats (200-220 g) were randomly divided into four groups. Two groups were injected (s.c.) with morphine (10 mg/kg) twice daily, whereas the other two received saline under identical conditions. After 8 days, when animals were completely tolerant to morphine, one of the morphine-treated groups and one group of saline-injected rats were given naloxone (s.c. 2 mg/kg). Withdrawal signs were observed and recorded. The enzyme activity was measured in extracts of the various CNS tissues by following the conversion of synthetic substance P (SP) to its N-terminal fragment SP(1-7) using a radioimmunoassay detecting this product. In discrete CNS areas including periaqueductal grey, spinal cord, substantia nigra and ventral tegmental area (VTA) a significant increase in enzyme activity was observed in the withdrawal group, while tolerant rats exhibited decreased SPE-like activity in the striatum (see Table 1). The enhanced enzyme activity during withdrawal is in agreement with our previous observation that the levels of SP(1-7) in rat brain are affected following naloxone precipitated withdrawal. In some tissues, including VTA, a correlation between the SPE-like activity and the intensity of the opioid abstinence was observed. Our result suggests that the elevated SPE-like activity is responsible for enhanced release of SP(1-7) in rats during morphine withdrawal, affirming a modulatory or regulative role of this enzyme in this state of opioid dependence.
Zhou
Q
Q
Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, Uppsala University, P.O. Box 591, S-751 24, Uppsala, Sweden.
Karlsson
K
K
Liu
Z
Z
Johansson
P
P
Le Grevés
M
M
Kiuru
A
A
Nyberg
F
F
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D009020:Morphine / Q000009:adverse effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000201:enzymology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000201:enzymology*
D009292:Narcotic Antagonists; D009294:Narcotics; D010446:Peptide Fragments; D013373:Substance P; D009270:Naloxone; C036877:substance P (1-7); D009020:Morphine; D008666:Metalloendopeptidases; C029610:substance P degrading enzyme