Dexmedetomidine attenuates persistent postsurgical pain by upregulating K⁺–Cl^− cotransporter-2 in the spinal dorsal horn in rats

Abstract

BackgroundDexmedetomidine (DEX) could have an analgesic effect on pain transmission through the modulation of brain-derived neurotrophic factor (BDNF). In addition, KCC2-induced shift in neuronal Cl− homeostasis is crucial for postsynaptic inhibition mediated by GABAA receptors. Accumulating evidence shows that nerve injury, peripheral inflammation and stress activate the spinal BDNF/TrkB signal, which results in the downregulation of KCC2 transport and expression, eventually leads to GAGAergic disinhibition and hyperalgesia. The aim of this experiment was to explore the interaction between DEX and KCC2 at a molecular level in rats in the persistent postsurgical pain (PPSP).MethodsPPSP in rats was evoked by the skin/muscle incision and retraction (SMIR). Mechanical hypersensitivity was assessed with the Dynamic Plantar Aesthesiometer. Western blot and immunofluorescence assay were used to assess the expressions of related proteins.ResultsIn the first part of our experiment, the results revealed that the BDNF/TrkB-KCC2 signal plays a critical role in the development of SMIR-evoked PPSP; the second part showed that intraperitoneal administrations of 40 µg/kg DEX at 15 min presurgery and 1 to 3 days post-surgery significantly attenuated SMIR-evoked PPSP. Simultaneously, SMIR-induced KCC2 downregulation was partly reversed, which coincided with the inhibition of the BDNF/TrkB signal in the spinal dorsal horn. Moreover, intrathecal administrations of KCC2 inhibitor VU0240551 significantly reduced the analgesic effect of DEX on SMIR-evoked PPSP.ConclusionThe results of our study indicated that DEX attenuated PPSP by restoring KCC2 function through reducing BDNF/TrkB signal in the spinal dorsal horn in rats, which provides a new insight into the treatment of chronic pain in clinical postsurgical pain management.

Breaking a Dogma: Acute Anti-Inflammatory Treatment Alters Both Post-Lesional Functional Recovery and Endogenous Adaptive Plasticity Mechanisms in a Rodent Model of Acute Peripheral Vestibulopathy.

“…KCC2 upregulation was also reported after SCI and administration of corticosteroids (Dai et al, 2018). The reactive microglia -BDNF -TrkB signaling was shown to be a main actor for KCC2 downregulation (Coull et al, 2005;Ferrini and De Koninck, 2013;Rivera, 2004;Rivera et al, 2002). In accordance with this, we have previously shown that the administration of a TrkB receptor antagonist after UVN increases KCC2 expression (Dutheil et al, 2016).…”

“…Their inhibition after acute anti-inflammatory treatment is associated with altered vestibular compensation, probably highlighting their contribution to functional recovery. Glial reactions are crucial for adaptative post-lesional plasticity mechanisms in the VNs, since they promote preservation of tissue integrity and wound repair (Cherry et al, 2014;Myer, 2006;Quintana, 2017) and modulate neuronal network excitability through various mechanisms such as K + clearance (Bellot-Saez et al, 2017) and Brain-Derived-Neurotrophic-Factor (BDNF) signaling (Coull et al, 2005;Ferrini and De Koninck, 2013).…”

“…Our previous studies have shown that UVN induces a significant reduction of KCC2 expression in the deafferented lateral VNs (Dutheil et al, 2016), possibly leading to an intracellular accumulation of [Cl-] ions, inducing a depolarizing outward current through GABAA receptors (Coull et al, 2005(Coull et al, , 2003. This mechanism likely plays a role in vestibular compensation through the transitory restoration of spontaneous activity in the deafferented VNs during the acute phase (Dutheil et al, 2016).…”

The Role of the Peripheral Nerve Surgeon in the Treatment of Pain

“…If operating for neuroma, we have the patient mark their point of maximum tenderness and any trigger points with a permanent marker. After undergoing the induction of general anesthesia, patients receive a pre-operative IV regional block (Bier) with lidocaine and dexmedetomidine [85][86][87][88]. If this is not possible because we are not operating on a limb amenable to tourniquet application, a pre-operative proximal nerve block or epidural is performed.…”

Placenta Therapy: Its Biological Role of Anti-Inflammation and Regeneration

“…However, in chronic pain conditions, there may be spontaneous pain, as well as intermittent pain, which is induced by persistent inflammation from structural damage or functional degeneration. Chronic pain is also associated with complex changes in peripheral and central signal processing [24].…”