Multiple actions of spinophilin regulate mu opioid receptor function.
Spinophilin, a dendritic spine-enriched scaffold protein, modulates synaptic transmission via multiple functions mediated by distinct domains of the protein. Here, we show that spinophilin is a key modulator of opiate action. Knockout of the spinophilin gene causes reduced sensitivity to the analgesic effects of morphine and early development of tolerance but a higher degree of physical dependence and increased sensitivity to the rewarding actions of the drug. At the cellular level, spinophilin associates with the mu opioid receptor (MOR) in striatum and modulates MOR signaling and endocytosis. Activation of MOR by opiate agonists such as fentanyl and morphine promotes these events, which feedback to suppress MOR responsiveness. Our findings support a potent physiological role of spinophilin in regulating MOR function and provide a potential new target for the treatment of opiate addiction.
Charlton
Joanna J
JJ
Department of Pharmacology, University of Crete, 71409 Heraklion, Crete, Greece.
Allen
Patrick B
PB
Psifogeorgou
Kassi
K
Chakravarty
Sumana
S
Gomes
Ivone
I
Neve
Rachael L
RL
Devi
Lakshmi A
LA
Greengard
Paul
P
Nestler
Eric J
EJ
Zachariou
Venetia
V
D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology; D000242:Cyclic AMP / Q000494:pharmacology; D004622:Embryo, Mammalian; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009020:Morphine / Q000009:adverse effects; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection / Q000379:methods; D000099273:Neurabins
D000701:Analgesics, Opioid; D000242:Cyclic AMP; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D008840:Microfilament Proteins; D009020:Morphine; D009419:Nerve Tissue Proteins; D017450:Receptors, Opioid, mu; D000099273:Neurabins