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Abstract

Chronic pain affects roughly one-fifth of the world’s population, and many patients do not respond to current therapies or conventional analgesics. Thus, studying the molecular mechanisms underlying neuropathic pain is crucial in identifying novel molecular targets that can be used to develop effective pain relief therapies. Previous studies have thus far focused on α2-adrenergic receptors (α2-ARs) and neuronal excitability, among others. However, recent research suggests that astrocytes and microglia, which express adrenergic receptors, contribute significantly to neuropathic pain. In particular, microglia have been found to express elevated levels of Gs-coupled β2-AR and they are responsive to norepinephrine application. Additionally, systemic administration of β2-AR agonists, such as Formoterol, has anti-inflammatory and anti-nociceptive properties in neuropathic pain, but the underlying processes are poorly understood. Therefore, this thesis work focuses on investigating glial noradrenergic signaling via β2-AR, specifically on microglia and its contribution to the modulation of neuropathic pain in mice. In the present study, activation of the β2-ARs through Formoterol induced a decrease of anti-inflammatory cytokine levels in primary isolated microglia and reversed nerve injury-induced morphological alterations in spinal dorsal horn microglia. Systemic administration of Formoterol inhibited evoked behaviors as well as aversive components related to neuropathic pain and reduced chronically-established neuropathic pain. The analgesic effects of Formoterol were mainly mediated by microglia, as demonstrated by employing the conditional knock-out mouse line lacking the β2-AR specifically in microglia. Remarkably, the effect of Formoterol on neuropathic pain-related behavior and microgliosis was lost in mice with the microglia-specific deletion of β2-ARs. In addition, microglia phenotype showed a sex-dependency in the late phase of neuropathic pain, which was not observed in response to β2-AR stimulation. Notably, Formoterol also reduced astrogliosis in the late stage of neuropathic pain independently of β2-AR signaling in microglia. Collectively, this work highlights the impact of microglial β2-AR stimulation in mediating the inhibition of pro-inflammatory signaling in the spinal cord during the initial phase of neuropathic pain. These results emphasize the importance of exploring microglial β2-AR agonists in alleviating neuropathic pain and elucidating the underlying mechanisms.