The
adenylate cyclase (AC) of the
neuroblastoma-
glioma hybrid cells (NG108-15), is generally considered to be a model for the study of the biochemical correlates of
opiate tolerance and dependence. However, the
naloxone-induced rebound response of
adenylate cyclase, described in some recent reports, is much smaller than that originally described by Sharma, Klee and Nirenberg (1975). Possible explanations for these discrepancies are: (1) a marked down-regulation of
opioid receptors and tolerance produced by the use of delta agonists or (2) the use of
etorphine, a relatively hydrophobic
drug which has slower dissociation rates than
morphine. To test these possibilities,
neuroblastoma-
glioma hybrid cells were treated cells with
morphine,
etorphine, [D-Ala2,D-Leu5]
enkephalin (
DADLE), [D-Ala2]
Leu-enkephalinamide (
DALAMID) or vehicle. In addition, some of the cells treated with
etorphine were washed with
DADLE to replace the
etorphine without producing the rebound response of
adenylate cyclase prior to the addition of
naloxone. The cells treated with
morphine,
DADLE and
DALAMID, and incubated with
prostaglandin E1 (
PGE1) and
naloxone showed a significant rebound of
adenylate cyclase when compared with control groups and
opiate-treated cells, incubated only with
PGE1. In contrast,
naloxone did not induce any significant rebound response in cells treated with
etorphine unless they were previously washed with
DADLE. These results demonstrate that the lack of a rebound response in cells treated with
etorphine was due to the slow dissociation rates of the
opiate and not to tolerance or to down-regulation of
opioid receptors produced by agonists of high intrinsic activity.