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) a fter chronic administration of morphine. Male rats (200-220 g) were randoml y divided into four groups. Two groups were injected (s.c.) with morphine ( 10 mg/kg) twice daily, whereas the other two received saline under identica l conditions. After 8 days, when animals were completely tolerant to morphi ne, one of the morphine-treated groups and one group of saline-injected rat s were given naloxone, (s.c. 2 mg/kg). Withdrawal signs were observed and r ecorded. The enzyme activity was measured in extracts of the various CNS ti ssues by following the conversion of synthetic substance P (SP) to its N-te rminal fragment SP1-7 using a radioimmunoassay detecting this product. In d iscrete CNS areas including periaqueductal grey, spinal cord, substantia ni gra and ventral tegmental area (VTA) a significant increase in enzyme activ ity was observed in the withdrawal group, while tolerant rats exhibited dec reased SPE-like activity in the striatum (see Table 1). The enhanced enzyme activity during withdrawal is in agreement with our previous observation t hat the levels of SP1-7 in rat brain are affected following naloxone precip itated withdrawal. In some tissues, including VTA, a correlation between th e 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 SP1-7 in rats during morphine withdrawal, affirming a m odulatory or regulative role of this enzyme in this state of opioid depende nce. (C) 2001 Elsevier Science Ltd. All rights reserved.