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Since the heterologous tolerance that develops after chronic morphine administration has been proposed to be an adaptive process, it follows that the time course of the change in the cellular components should coincide with the time course of the altered responsiveness. This study correlated the time course over which heterologous tolerance develops with changes in the abundance of selected proteins in the guinea-pig longitudinal muscle/myenteric plexus (LM/MP) preparation. Tissues were obtained at various times following a single surgical implantation procedure and heterologous tolerance confirmed by a significant reduction in the sensitivity of the LM/MP to inhibition of neurogenic twitches by morphine, DAMGO, and 2-CADO. Tolerance developed with a delayed onset (significant 2-5-fold reduction in sensitivity by day 4 after pellet implantation) that reached a maximum by 7 days (4-8-fold reduction in responsiveness) that was maintained through 14 days with normal sensitivity spontaneously returning by 21 days post-implantation. Dot blot analysis was used to examine the abundance of the alpha1 and alpha3 subunit isoforms of the Na+/K+ ATPase and beta-actin over the same time course. The results showed significant decreases in abundance of the alpha3 subunit at 4, 7, and 10 days following pellet implantation but no change in beta-actin or the alpha1 subunit at any time period. These data support the idea that heterologous tolerance following chronic morphine exposure results from a cellular adaptive change that may involve a change in the abundance of the alpha3 subunit isoform of the Na+/K+ ATPase.