Aspects of Opioid Tolerance and Dependence in Peripheral Nerve Tissues

Abstract

Adaptation to chronic opioid exposure is expressed in cells carrying opioid receptors and this phenomenon has been termed “cellular opiate dependence” (Collier 1980). Evidence in support of this notion stems from experiments on neuroblastoma × glioma hybrid cells, using the activity of adenylate cyclase as an index of chronic opioid actions (Sharma et al. 1975). The findings reported for these cells were, at that time, best explained by a “unitary theory” which hypothesized that the biochemical adaptations producing tolerance were also responsible for dependence (Shuster 1961; Goldstein and Goldstein 1961). However, chronic opioid effects are not confined to the adenylate cyclase system. Subsequent studies with hybridomas chronically exposed to opioids also revealed changes at the opioid receptor level, namely, a down-regulation of binding sites (Chang et al. 1982; Law et al. 1983), the clustering of receptors (Hazum et al. 1979), and an uncoupling of the receptor from its effector (Wüster et al. 1985). Although these effects may underlie desensitization and/or tolerance, they do not explain the development of tolerance as well as dependence, and thus contrast with the “unitary theory”.