Supraspinal Gbetagamma-dependent stimulation of PLCbeta originating from G inhibitory protein-mu opioid receptor-coupling is necessary for morphine induced acute hyperalgesia.
Although alterations in micro-opioid receptor (microOR) signaling mediate excitatory effects of opiates in opioid tolerance, the molecular mechanism for the excitatory effect of acute low dose morphine, as it relates to microOR coupling, is presently unknown. A pronounced coupling of microOR to the alpha subunit of G inhibitory protein emerged in periaqueductal gray (PAG) from mice systemically administered with morphine at a dose producing acute thermal hyperalgesia. This coupling was abolished in presence of the selective microOR antagonist d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH(2) administered at the PAG site, showing that the low dose morphine effect is triggered by microOR activated G inhibitory protein at supraspinal level. When Gbetagamma downstream signalling was blocked by intra-PAG co-administration of 2-(3,4,5-trihydroxy-6-oxoxanthen-9-yl)cyclohexane-1-carboxylic acid, a compound that inhibits Gbetagamma dimer-dependent signaling, a complete prevention of low dose morphine induced acute thermal hyperalgesia was obtained. Phospholipase C beta3, an enzyme necessary to morphine hyperalgesia, was revealed to be associated with Gbetagamma in PAG. Although opioid administration induces a shift in microOR-G protein coupling from Gi to Gs after chronic administration, our data support that this condition is not realized in acute treatment providing evidence that a separate molecular mechanism underlies morphine induced acute excitatory effect.
Bianchi
Enrica
E
Department of Neuroscience, University of Siena, Siena, Italy. bianchi16@unisi.it
Norcini
Monica
M
Smrcka
Alan
A
Ghelardini
Carla
C
D000818:Animals; D003510:Cyclohexanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D054799:Phospholipase C beta / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
D003510:Cyclohexanes; D044387:GTP-Binding Protein beta Subunits; C509953:M119 compound; D017450:Receptors, Opioid, mu; D014966:Xanthenes; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D013004:Somatostatin; D009020:Morphine; D054799:Phospholipase C beta