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Supraspinal Gβγ‐dependent stimulation of PLCβ 3 originating from G inhibitory protein‐μ opioid receptor‐coupling is necessary for morphine induced acute hyperalgesia
Author(s) -
Bianchi Enrica,
Norcini Monica,
Smrcka Alan,
Ghelardini Carla
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06308.x
Subject(s) - hyperalgesia , morphine , excitatory postsynaptic potential , pharmacology , inhibitory postsynaptic potential , chemistry , opioid , antagonist , periaqueductal gray , stimulation , opioid receptor , receptor , medicine , nociception , central nervous system , biochemistry , midbrain
Although alterations in μ‐opioid receptor (μOR) 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 μOR coupling, is presently unknown. A pronounced coupling of μOR to the α 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 μOR 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 μOR activated G inhibitory protein at supraspinal level. When Gβγ 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 Gβγ dimer‐dependent signaling, a complete prevention of low dose morphine induced acute thermal hyperalgesia was obtained. Phospholipase C β3, an enzyme necessary to morphine hyperalgesia, was revealed to be associated with Gβγ in PAG. Although opioid administration induces a shift in μOR‐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.