期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1982
卷号：79
期号：2
页码：690-694
DOI：10.1073/pnas.79.2.690
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Opioid agonists caused a rapid dose-related elevation of the cGMP content of N4TG1 murine neuroblastoma cells. An excellent correlation was found between the rank order of potency of agonists in stimulating cGMP accumulation and in displacing [3H]etorphine ([3H]ETP) bound to intact cells. The narcotic antagonists naloxone and diprenorphine failed to increase cGMP content; moreover, in the presence of 5 {micro}M naloxone, the EC50 of ETP increased from {approx}9 nM to > 1 {micro}M. N4TG1 cells that had been incubated for 20 min with 0.32 {micro}M ETP and thoroughly washed displayed a marked loss in sensitivity to subsequent ETP challenge. This desensitization was characterized by a 40-50% decrease in maximal response and an increase in the apparent Ka of ETP from 4 to 50 nM. Desensitization was complete after a 7-min incubation with 0.32 {micro}M ETP (t[1/2] {approx} 1 min) and was only slowly reversible (t[1/2] > 60 min). Naloxone (5 {micro}M) and diprenorphine (0.1 {micro}M) failed to elicit desensitization, but they blocked ETP-induced desensitization. Dextrophan and (+)-ethylketazocine were <1% as effective as levorphanol and (-)-ethylketazocine, respectively, in both stimulating cGMP accumulation and inducing desensitization. When the binding of [3H]ETP (0.2-20 nM) was examined under identical experimental conditions, cells that were completely desensitized by incubation with ETP (7 min with 0.32 {micro}M or 20 min with 15 nM) showed no loss of high-affinity recognition sites. After longer incubation with ETP (0.32 {micro}M for 20-60 min), the maximal binding of [3H]ETP was reduced 17-41%. The specific short-term desensitization of cGMP accumulation is not mediated or accompanied by a decrement in the number of agonist binding sites.
