Activation of β2-adrenergic receptors in microglia alleviates neuropathic hypersensitivity in mice

Abstract

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on 2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of {beta}2-adrenergic receptors ({beta}2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of {beta}2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex-vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia and the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of {beta}2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to {beta}2-AR signaling in microglia. Our results underline the value of developing microglial {beta}2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/520924v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@166c767org.highwire.dtl.DTLVardef@ad3be9org.highwire.dtl.DTLVardef@1383f5eorg.highwire.dtl.DTLVardef@1c852b1_HPS_FORMAT_FIGEXP M_FIG C_FIG