Deletion of guanine nucleotide binding protein alpha z subunit in mice induces a gene dose dependent tolerance to morphine.
The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout mouse develops significantly increased tolerance to morphine, which depends on Galpha(z) gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.
Leck
K J
KJ
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
Bartlett
S E
SE
Smith
M T
MT
Megirian
D
D
Holgate
J
J
Powell
K L
KL
Matthaei
K I
KI
Hendry
I A
IA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits; D019204:GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D017353:Gene Deletion; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects / Q000235:genetics
D044385:GTP-Binding Protein alpha Subunits; C490964:Gnaz protein, mouse; D021122:Protein Subunits; D009020:Morphine; D019204:GTP-Binding Proteins