Delta opioid receptors are essential to the antiallodynic action of Β(2)-mimetics in a model of neuropathic pain

The adrenergic system, because of its reported implication in pain mechanisms, may be a potential target for chronic pain treatment. We previously demonstrated that β(2)-adrenoceptors (β(2)-ARs) are essential for neuropathic pain treatment by antidepressant drugs, and we showed that agonists of β(2)-ARs, that is, β(2)-mimetics, had an antiallodynic effect per se following chronic administration. To further explore the downstream mechanism of this action, we studied here the role of the opioid system. We used behavioral, genetic, and pharmacological approaches to test whether opioid receptors were necessary for the antiallodynic action of a short acting (terbutaline) and a long-acting (formoterol) β(2)-mimetic. Using the Cuff model of neuropathic pain in mice, we showed that chronic treatments with terbutaline (intraperitoneal) or formoterol (orally) alleviated mechanical hypersensitivity. We observed that these β(2)-mimetics remained fully effective in μ-opioid and in κ-opioid receptor deficient mice, but lost their antiallodynic action in δ-opioid receptor deficient mice, either female or male. Accordingly, we showed that the δ-opioid receptor antagonist naltrindole induced an acute relapse of allodynia in mice with neuropathic pain chronically treated with the β(2)-mimetics. Such relapse was also observed following administration of the peripheral opioid receptor antagonist naloxone methiodide. These data demonstrate that the antiallodynic effect of long-term β(2)-mimetics in a context of neuropathic pain requires the endogenous opioid system, and more specifically peripheral δ-opioid receptors.