Dexmedetomidine Attenuates Hyperalgesia Induced By Brachial Plexus Root Avulsion By Restoring The GLT-1 Function Via PKA Signaling

Abstract Background: Chronic neuropathic pain often occurs with unclear mechanisms after brachial plexus root avulsion (BPRA) injuries. Emerging evidence suggests that the maladaptation of spinal glial glutamate transporter GLT-1 causes extracellular glutamate accumulation, contributing to central sensitization of chronic pain. Dexmedetomidine (DMET), an α2-adrenergic receptor (α2AR) agonist, widely used in the clinic as a sedative and analgesic drug, has been shown to inhibit glial activation. This study assessed DMET effects on BPRA induced pain and the possible involvement of GLT-1 regulation. Methods: The right C8 and T1 roots were avulsed to establish a lower trunk BPRA injury rat model and LPS-induced activation of rat primary cultured astrocytes. Then we used the molecular and behavioral assay combined with pharmacological manipulation to test the hypothesis that DMET attenuates the pain and neuroinflammation through restoring the GLT-1 function via PKA signaling.Results: The mechanical allodynia and thermal hyperalgesia appeared and reached the peak at 1-day post-injury (dpi) and persisted for at least 28 dpi. Notably, BPRA enhanced phosphorylated PKA levels, reduced GLT-1 expression, and caused an imbalance between anti- and proinflammatory cytokines in the affected spinal segments. Acute systemic or local DMET administration, at the un-sedative doses, demonstrated an analgesic effect. Moreover, a 3-days intrathecal DMET treatment ameliorated hyperalgesia and allodynia of BPRA injured rats by attenuating PKA phosphorylation, IL-1β, and IL-6, while restoring the levels of GLT-1, IL-4, and IL-10 in the spinal cord. Significantly, intrathecal administration of the selective PKA inhibitor H89 mimicked, but the PKA activator 8-Br-cAMP blocked DMET’s effects. Conclusion: Overall, these results suggest that PKA inactivation mediates DMET's analgesic effect for the pain induced by BPRA injury through the recovery of GLT-1 function.