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Attenuation of dynamin‐dependent internalization decreases antinociception during the expression of morphine tolerance
Author(s) -
Macey Tara A.,
Fyfe Leon W.,
Morgan Michael M.,
Ingram Susan L.
Publication year - 2010
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.24.1_supplement.585.4
Subject(s) - morphine , internalization , chemistry , microinjection , pharmacology , agonist , saline , dynamin , opioid , μ opioid receptor , inhibitory postsynaptic potential , endocrinology , receptor , medicine , endocytosis , biochemistry
Mu‐opioid receptor (MOP) internalization has been proposed as a cellular mechanism of morphine tolerance. In order to test this hypothesis in vivo , the fluorescent MOP agonist, DERM‐A594, was microinjected into the periaqueductal gray (vlPAG). Rats were pretreated with either saline (0.4 μl) or morphine (5 μg/0.4 μl) 2X/day for 2 days. On day 3, rats were given either a saline or morphine challenge 30 min prior to DERM‐A594 (300 ng/0.4 μl). Intracellular DERM‐A594 intensity was similar in all groups except for a significant decrease in DERM‐A594 label in morphine tolerant rats given a morphine challenge (F (3, 34) = 3.899, p<0.05). These results suggest that repeated morphine administration increases morphine‐induced internalization of MOPs. To further test this idea, a myr‐dynamin inhibitory peptide (Dyn + ) and a scrambled peptide (Dyn − ) were microinjected into the vlPAG prior to microinjection of DERM‐A594. Dyn + reduced DERM‐A594 antinociception compared to Dyn − (15 ± 3 s vs. 33 ± 5 s). Dyn + also reduced morphine antinociception in both saline (D50 = 8.1 μg vs. Dyn − = 3.8 μg) and morphine pretreated rats (D50 = 10.7 μg vs. Dyn − = 5.8 μg). A comparable shift in D50 values in saline and morphine pretreated rats suggests that Dyn + attenuates antinociception similarly in both groups. Thus, these studies demonstrate that internalization is important for MOP signaling in the vlPAG. Supported by DA023318(TM), DA015498(MM).