Altered gating of opiate receptor-modulated K+ channels on amygdala neurons of morphine-dependent rats

The molecular mechanism of tolerance to opiate drugs is poorly understood. We have used single-channel patch-clamp recordings to study opiate receptor effects on dissociated neurons from rat amygdala. a limbic region implicat ed in addiction processes. A 130-pS inwardly rectifying K+-preferring catio n channel was activated by mu opioid receptors in a membrane-delimited mann er. After chronic treatment of the rats with morphine, channel gating chang ed markedly, with an approximately 100-fold decrease in open probability at a given morphine concentration. The change in channel gating correlated bo th in time course and in dose of morphine treatment with the development of functional opiate dependence and appeared to arise at a step after G-prote in activation and before channel permeation by K+. This decreased receptor- channel coupling appears to be large enough to account quantitatively for o piate tolerance and may represent one of the mechanisms through which toler ance occurs.