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The short-acting beta-2 adrenoceptor agonists (β(2)-agonists), such as salbutamol, are effective bronchodilators used to treat asthma. They lack significant anti-inflammatory effect in vivo as well as on isolated alveolar macrophages even though they exhibit this effect on freshly isolated monocytes. The purpose of this study was to determine if this observation is related to a change in the expression and/or function of surface β(2)-receptors during the differentiation of these cells to macrophages. Purified monocytes, cultured for 1-48 h were pre-treated with the β(2)-agonists (salbutamol or procaterol) or PGE(2) before being stimulated with bacterial lipopolysaccharide (LPS). Subsequently, the amount of TNF-α (a typical inflammatory mediator) released over 24 h, as well as agonist-stimulated cAMP, were determined by enzyme immunoassays. Western blotting techniques were used to study the expression of the membrane β(2)-receptor protein. Results showed that in freshly isolated human monocytes, both the β(2)-agonists and PGE(2) significantly inhibited LPS-induced TNF-α release as well as increased intracellular cAMP. After culturing adherent monocytes for 24-48 h, the ability of the β(2)-agonists to produce both effects was completely lost, whereas that of PGE(2) was essentially intact. Western blotting data showed a near complete loss of surface expression of β(2)-receptors in cells cultured for ≥24 h. These results show that as human monocytes adhere to surfaces to begin differentiation into macrophages, they selectively lose their surface β(2)-receptors and hence become insensitive to the anti-inflammatory effect of β(2)-agonists. This may explain why β(2)-agonists lack significant anti-inflammatory effect on alveolar macrophages or in clinical asthma., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Expression of beta(2)-adrenoceptors (beta(2)-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 beta(2)-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 beta(2)-ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the beta(2)-AR antagonist ICI 118,551 or a transgenic approach with mice deficient for beta(2)-ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on beta(2)-ARs. We also showed that chronic treatment with the beta(1)-AR agonist xamoterol or with the beta(3)-AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of beta(2)-ARs, but not beta(1)- or beta(3)-ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of beta(2)-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 beta(2)-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 beta(2)-AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain.