| Abstract |
Spinophilin (SPL), also termed Neurabin II, was initially discovered as a protein phosphatase 1 (PP1) binding protein and was first cloned in 1997 [Allen PB et al, 1997]. SPL, although ubiquitous, was found to be highly expressed in dendritic spines [Feng et al, 2000], suggesting that it has a specific involvement in the regulation of excitatory transmission. Since then SPL has been shown to bind to a growing number of proteins. Due to spinophilin enrichment at dendritic spines, and for its choice of partners, it has been hailed as having a major role in regulation of excitatory synaptic transmission, signal transduction, dendritic spine formation and plasticity. The role that SPL plays in the adaptive process underlying opiate addiction is not fully understood. The present study examined, by western blot analysis, the regulation of SPL levels in the nucleus accumbens (NAc) following acute and chronic morphine administration in mice. Following acute morphine administration, SPL levels appeared to be decreased compared to saline treated animals at both 10 minutes and 2 hours post injection. Following chronic morphine exposure the level of SPL protein appeared to be significantly increased. These results demonstrate that SPL is regulated in vivo after morphine administration and SPL plays a role in the adaptive molecular changes associated with opiate addiction. The development of dependence and tolerance to morphine is the major limiting factor to the treatment of chronic pain with the opiate. It has been previously reported that morphine, which binds solely to Mu family of opiate receptors (MOR), does not readily induce receptor endocytosis and this factor contributes to the development of tolerance. Confocal microscopic analysis in transiently transfected HEK293 cells revealed that in the presence of SPL, MOR was internalized after a 10min treatment with morphine but remained on the surface in the absence of SPL. These observations suggest that SPL plays and important role in GPCR endocytosis, the development of tolerance, and the addictive state. Interestingly, GFP-tagged SPL was also found to be translocated to the cytosol after MOR agonist treatment in PC12. The present data suggest an essential role of SPL in MOR functional responses, and in the adaptive changes associated with opiate addiction.
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The role of spinophilin in morphine addiction
