Abstract
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.
Footnotes
-
Send reprint requests to: Dr. David A. Taylor, Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, P.O. Box 9223, West Virginia University School of Medicine, Morgantown, WV 26506-9223. E-mail:dtaylor{at}hsc.wvu.edu
-
Funding for work from the authors' laboratory upon which this perspective is based has been provided by the National Institute on Drug Abuse through National Institutes of Health Grants RO1 DA03773 and DA03773S1 and through funds from the Mylan Chair of Pharmacology, West Virginia University.
- Abbreviations:
- AC
- adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing)
- EC 4.6.1.1]
- CREB, cyclic AMP response element-binding protein
- GPCR
- G-protein coupled receptor
- GRK
- G-protein coupled receptor kinase
- GIRK
- inwardly rectifying K+ channel(s)
- LM/MP
- longitudinal muscle/myenteric plexus
- LC
- locus ceruleus
- nTS
- nucleus tractus solitarius
- RGS
- regulators of G-protein signaling
- PKA
- protein kinase A
- PKC
- protein kinase C
- Ek
- potassium equilibrium potential
- MAP kinase
- mitogen-activated protein kinase
- GABA
- γ-aminobutyric acid
- Received September 13, 2000.
- Accepted November 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|