• Xiang Cui, Jing Liu, Ankit Uniyal, Qian Xu, Chi Zhang, Guangwu Zhu, Fei Yang, Eellan Sivanesan, Bengt Linderoth, Srinivasa N Raja, and Yun Guan.
• Department of Anaesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
• Br J Anaesth. 2024 Apr 1; 132 (4): 746757746-757.

BackgroundThe mechanisms for spinal cord stimulation (SCS) to alleviate chronic pain are only partially known. We aimed to elucidate the roles of adenosine A1 and A3 receptors (A1R, A3R) in the inhibition of spinal nociceptive transmission by SCS, and further explored whether 2'-deoxycoformycin (dCF), an inhibitor of adenosine deaminase, can potentiate SCS-induced analgesia.MethodsWe used RNAscope and immunoblotting to examine the distributions of adora1 and adora3 expression, and levels of A1R and A3R proteins in the spinal cord of rats after tibial-spared nerve injury (SNI-t). Electrophysiology recording was conducted to examine how adenosine receptor antagonists, virus-mediated adora3 knockdown, and dCF affect SCS-induced inhibition of C-fibre-evoked spinal local field potential (C-LFP).ResultsAdora1 was predominantly expressed in neurones, whereas adora3 is highly expressed in microglial cells in the rat spinal cord. Spinal application of antagonists (100 μl) of A1R (8-cyclopentyl-1,3-dipropylxanthine [DPCPX], 50 μM) and A3R (MRS1523, 200 nM) augmented C-LFP in SNI-t rats (DPCPX: 1.39 [0.18] vs vehicle: 0.98 [0.05], P=0.046; MRS1523: 1.21 [0.07] vs vehicle: 0.91 [0.03], P=0.002). Both drugs also blocked inhibition of C-LFP by SCS. Conversely, dCF (0.1 mM) enhanced SCS-induced C-LFP inhibition (dCF: 0.60 [0.04] vs vehicle: 0.85 [0.02], P<0.001). In the behaviour study, dCF (100 nmol 15 μl-1, intrathecal) also enhanced inhibition of mechanical hypersensitivity by SCS in SNI-t rats.ConclusionsSpinal A1R and A3R signalling can exert tonic suppression and also contribute to SCS-induced inhibition of spinal nociceptive transmission after nerve injury. Inhibition of adenosine deaminase may represent a novel adjuvant pharmacotherapy to enhance SCS-induced analgesia.Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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