Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain
Front. Mol. Neurosci.. 2020-02-14; 12:
DOI: 10.3389/fnmol.2019.00324
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1. Front Mol Neurosci. 2020 Feb 14;12:324. doi: 10.3389/fnmol.2019.00324.
eCollection 2019.
Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a
Mouse Model of Neuropathic Pain.
Ceredig RA(1), Pierre F(1), Doridot S(2), Alduntzin U(1), Hener P(1), Salvat
E(1)(3), Yalcin I(1), Gaveriaux-Ruff C(4), Barrot M(1), Massotte D(1).
Author information:
(1)Institut des Neurosciences Cellulaires et Intégratives, Centre National de la
Recherche Scientifique, Université de Strasbourg, Strasbourg, France.
(2)Chronobiotron, Centre National de la Recherche Scientifique, Strasbourg,
France.
(3)Centre d’Evaluation et de Traitement de la Douleur, Hôpitaux Universitaires de
Strasbourg, Strasbourg, France.
(4)Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre
National de la Recherche Scientifique, Université de Strasbourg, INSERM,
Illkirch, France.
Neuropathic pain is a challenging condition for which current therapies often
remain unsatisfactory. Chronic administration of β2 adrenergic agonists,
including formoterol currently used to treat asthma and chronic obstructive
pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff
model of neuropathic pain. The limited clinical data currently available also
suggest that formoterol would be a suitable candidate for drug repurposing. The
antiallodynic action of β2 adrenergic agonists is known to require activation of
the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms
involved is necessary. Using a mouse line in which DOP receptors were selectively
ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that
these DOP peripheral receptors were necessary for the antiallodynic action of the
β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line
expressing a fluorescent version of the DOP receptor fused with the enhanced
green fluorescent protein (DOPeGFP), we established in a previous study, that
mechanical allodynia is associated with a smaller percentage of DOPeGFP positive
small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced
density of DOPeGFP positive free nerve endings in the skin and with increased
DOPeGFP expression at the cell surface. Here, we showed that the density of
DOPeGFP positive free nerve endings in the skin is partially restored and no
increase in DOPeGFP translocation to the plasma membrane is observed in mice in
which mechanical pain is alleviated upon chronic oral administration of
formoterol. This study, therefore, extends our previous results by confirming
that changes in the mechanical threshold are associated with changes in
peripheral DOP profile. It also highlights the common impact on DOP receptors
between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2
mimetic formoterol.
Copyright © 2020 Ceredig, Pierre, Doridot, Alduntzin, Hener, Salvat, Yalcin,
Gaveriaux-Ruff, Barrot and Massotte.
DOI: 10.3389/fnmol.2019.00324
PMCID: PMC7033630
PMID: 32116538