Chronic treatment with agonists of β2-adrenergic receptors in neuropathic pain

Expression of β2-adrenoceptors (β2-ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of β2-ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of β2-ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the β2-AR antagonist ICI 118,551 or a transgenic approach with mice deficient for β2-ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on β2-ARs. We also showed that chronic treatment with the β1-AR agonist xamoterol or with the β3-AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of β2-ARs, but not β1- or β3-ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of β2-AR agonists might implicate the endogenous opioid system; indeed chronic clenbuterol effect can be acutely blocked by the delta-opioid receptor antagonist naltrindole. Present results show that β2-ARs are not only essential for the antiallodynic action of antidepressant drugs on sustained neuropathic pain, but also that the stimulation of these receptors is sufficient to relieve neuropathic allodynia in a murine model. Our data suggest that β2-AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain.