Abstract
The adrenergic system, because of its reported implication in pain mechanisms, may be a potential target for chronic pain treatment. We previously demonstrated that β2-adrenoceptors (β2-ARs) are essential for neuropathic pain treatment by antidepressant drugs, and we showed that agonists of β2-ARs, that is, β2-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) β2-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 β2-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 β2-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 β2-mimetics in a context of neuropathic pain requires the endogenous opioid system, and more specifically peripheral δ-opioid receptors.