PT  - JOURNAL ARTICLE
AU  - David A. Taylor
AU  - William W. Fleming
TI  - Unifying Perspectives of the Mechanisms Underlying the Development of Tolerance and Physical Dependence to Opioids
DP  - 2001 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 11--18
VI  - 297
IP  - 1
4099  - http://jpet.aspetjournals.org/content/297/1/11.short
4100  - http://jpet.aspetjournals.org/content/297/1/11.full
SO  - J Pharmacol Exp Ther2001 Apr 01; 297
AB  - The cellular basis of tolerance to, and dependence upon, many types of drugs, including opioids, has long defied identification. Tolerance to opioids cannot be explained solely on the basis of modification of opioid receptors or altered metabolism or disposition of the opioid. The development of tolerance following chronic exposure to opioids presents at least three different types of change in cellular responsiveness, each of which has been suggested to represent some type of adaptive modification in cellular responsiveness. These different forms of tolerance are distinguishable on the basis of their time course and whether or not the tolerance is specific for opioid receptor agonists (homologous) or extends to agonists of other systems (heterologous). The adaptive modulation of responsiveness via regulation of cellular proteins has been proposed to be the basis for both longer-term forms of tolerance. The divergent signaling pathways activated by G-protein-coupled receptors like the μ-opioid receptor provide multiple downstream targets for both short- and long-term regulation of cell function that is associated with the development of tolerance and/or dependence. Since the magnitude of receptor activation is an important determinant of the degree to which various signaling pathways are activated, the expressed characteristics of tolerance and/or dependence may be functionally related to which of these diverse pathways are stimulated to the greatest degree. Thus, the possibility that different signaling events are activated either sequentially or concurrently offers the possibility to explain the interaction between these different forms of tolerance and/or dependence. The American Society for Pharmacology and Experimental Therapeutics