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 α2-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 β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-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 as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-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 β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.

Cellular and Molecular Mechanisms Underlying Pain Chronicity

“…Chronic pain can have different aetiologies. This Special Issue discusses, for example, chronic pain due to nerve injury [ 4 , 5 ], chronic pain associated with a genetic disease [ 6 ], or chronic pain associated with cancer [ 7 ]. Hirth et al characterized two mouse models (KPC and KPPC models) based on the most common genetic alteration found in human pancreatic cancer tissues (i.e., p53 and Kras) and suitable to study pain associated with pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer [ 8 , 9 ].…”

“…Modulation of inflammatory signaling was also found in a model of chronic pain induced by nerve injury [ 5 ]. Using a new conditional mouse line, which loses ß2-AR exclusively in microglial cells, Damo et al demonstrated that specific activation of the microglial ß2 adrenergic receptor can modulate nerve injury-associated neuropathic pain by inducing a structural and functional change in microglial cells compared with an activated state associated to the nerve injury model used in the study (spared nerve injury, SNI) [ 5 ]. Interestingly, this alteration of microglia was associated, at least in vitro, with changes in cytokine release [ 5 ].…”

“…Using a new conditional mouse line, which loses ß2-AR exclusively in microglial cells, Damo et al demonstrated that specific activation of the microglial ß2 adrenergic receptor can modulate nerve injury-associated neuropathic pain by inducing a structural and functional change in microglial cells compared with an activated state associated to the nerve injury model used in the study (spared nerve injury, SNI) [ 5 ]. Interestingly, this alteration of microglia was associated, at least in vitro, with changes in cytokine release [ 5 ]. Application of a ß2 agonist to a culture of activated primary microglia induced a reduction in pro-inflammatory cytokines and an increase in the release of anti-inflammatory cytokines [ 5 ].…”

“…Interestingly, this alteration of microglia was associated, at least in vitro, with changes in cytokine release [ 5 ]. Application of a ß2 agonist to a culture of activated primary microglia induced a reduction in pro-inflammatory cytokines and an increase in the release of anti-inflammatory cytokines [ 5 ].…”

“…In addition to the original article by Damo et al [ 5 ], the special role of glial cells in pain is also highlighted in the review of Damo and Simonetti, which discusses the current knowledge on the involvement of developmental molecules, such as Wnt, ephrins, and semaphorins, in the pathogenesis and progression of chronic pain, both from the neuronal, as well as glial, point of view [ 21 ]. Indeed, receptors and ligands of these pathways are expressed in a wide variety of neuronal and glial cells.…”