Neural substrates of opioid tolerance and dependence

Opiate dependence is not represented by a single neuronal substrate but probably reflects actions at multiple functional sites in the central nervous system. Classical measures of opiate dependence such as escape reactions and wet dog shakes may be elicited by neural substrates in the medial thalamus and periaqueductal gray. Our work and others suggests that the region in the nucleus accumbens and its afferent and efferent connections may be an important substrate to reinforcing properties of opiates. The nucleus accumbens is also an important substrate for the reinforcing properties of stimulant drugs. These data suggest that opiate dependence may represent functional changes not only in neural substrates responsible for physical dependence, but also in brain sites responsible for the reinforcing actions of opiates. It should be noted that there was inability in the early days when the endorphins first came to the forefront, to show correlations between changes in opiate binding and endorphin levels associated with dependence. This may be due to a failure to identify functionally significant substrates that may be implicated from what one would call the top-down approach. Perhaps the "neurohumor" that Dr. Cochin was thinking about is an opioid peptide located in brain regions high in opiate receptors and functionally sensitive to opiate antagonists. New work isolating particular loci for opiate actions may point to potential sites and neurochemical substrates for opiate dependence.