Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain.

Rhian Alice Ceredig,Pierre Hener,Stéphane Doridot,Claire Gaveriaux-Ruff,Eric Salvat,Florian Pierre,Michel Barrot,Ipek Yalcin,Unai Alduntzin,Dominique Massotte

doi:10.3389/fnmol.2019.00324

Abstract

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.

Highlights

Neuropathic pain arises from traumatic nerve injury or from a disease that affects the somatosensory system and is characterized by spontaneous pain, mechanical allodynia and/or thermal hypersensitivity
Since DOP receptors are required for the anti-allodynic effect of a chronic treatment with the β2 agonist clenbuterol (Yalcin et al, 2010), we investigated whether the specific deletion of DOP receptors in primary afferents expressing Nav1.8 voltage-gated sodium channels (DOPcKO; Gaveriaux-Ruff et al, 2011) was abolishing the antiallodynic action of a β2-adrenergic agonist
We first showed that oral administration of the β2 adrenergic agonist formoterol was as effective as its intraperitoneal injection (Yalcin et al, 2010) to alleviate mechanical allodynia in the cuff model of neuropathy

Summary

Introduction

Neuropathic pain arises from traumatic nerve injury or from a disease that affects the somatosensory system and is characterized by spontaneous pain, mechanical allodynia and/or thermal hypersensitivity (von Hehn et al, 2012). Activation of the β2-adrenergic receptors has been shown to be mandatory for the antiallodynic action of antidepressants (Yalcin et al, 2009; Kremer et al, 2016a, 2018) and chronic administration of several β2-adrenergic agonists such as formoterol has been successfully used to alleviate mechanical allodynia (Choucair-Jaafar et al, 2009, 2014; Yalcin et al, 2010; Jourdain and Hatakeyama, 2019). Formoterol is already routinely used in clinics to treat chronic obstructive pulmonary disease (Vanfleteren et al, 2018).

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