Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain

Rhian Alice Ceredig, Florian Pierre, Stéphane Doridot, Unai Alduntzin, Eric Salvat, Ipek Yalcin, Claire Gaveriaux-Ruff, Michel Barrot, Dominique Massotte
Eur J Neurosci. 2018-08-20; 48(5): 2231-2246
DOI: 10.1111/ejn.14093

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Peripheral delta opioid (DOP) receptors are essential for the antiallodynic
effect of the tricyclic antidepressant nortriptyline. However, the population of
DOP-expressing cells affected in neuropathic conditions or underlying the
antiallodynic activity of antidepressants remains unknown. Using a mouse line in
which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium
channels (DOP cKO), we established that these DOP peripheral receptors were
mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain
model based on sciatic nerve cuffing. We then examined the impact of nerve
cuffing and duloxetine treatment on DOP-positive populations using a knock-in
mouse line expressing a fluorescent version of the DOP receptor fused with the
enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we
observed a reduced proportion of DOPeGFP-positive small peptidergic sensory
neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia
and a lower density of DOPeGFP-positive free nerve endings in the skin. These
changes were not present in nerve-injured mice chronically treated with oral
duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane
was observed in neuropathic conditions but not in duloxetine-treated neuropathic
mice, which may represent an additional level of control of the neuronal activity
by DOP receptors. Our results therefore established a parallel between changes in
the expression profile of peripheral DOP receptors and mechanical allodynia
induced by sciatic nerve cuffing.

© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


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