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Role of increased GABAergic synaptic transmission in morphine tolerance
Author(s) -
Bobeck Erin N.,
Suchland Katherine L.,
Haseman Rachel,
Ingram Susan L.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.843.5
Subject(s) - morphine , chemistry , gabaergic , desensitization (medicine) , forskolin , potency , pharmacology , opioid , saline , disinhibition , neurotransmission , nociception , medicine , endocrinology , receptor , neuroscience , biology , biochemistry , in vitro
Repeated administration of morphine increases desensitization of mu‐opioid receptor (MOP) coupling to many cellular effectors and has long been thought to be a cellular correlate of antinociceptive tolerance. However, recent studies observed no evidence of MOP desensitization in presynaptic terminals, although a shift in potency to the right was observed in morphine pretreated rats. Since opioid disinhibition of PAG output neurons is thought to drive antinociception, these results suggest that a cellular mechanism other than receptor desensitization may account for decreased opioid potency following repeated administration of morphine. We determined that repeated morphine administration (5mg/kg twice a day for 2 days) increased GABA release (1.1 ± 0.2 Hz) compared to saline pretreatment (0.5 ± 0.1 Hz) without altering the amplitude cumulative distribution in the PAG. ME (1 μM) inhibited GABAergic mIPSCs by 49 ± 6% in slices from saline compared to 30 ± 8% in morphine pretreated slices. Superfusion of forskolin (20 μM) also increased mIPSC frequency in slices from both saline and morphine pretreated rats. Interestingly, forskolin superfusion in slices from saline pretreated rats was sufficient to significantly decrease ME‐induced inhibition of mIPSCs suggesting that increased release of GABA causes an “apparent” change in affinity of opioid agonists at MOPs. Supported by NIDA grant DA027625.