• Yang Ren, Yinhui Zhou, Zerong You, Hao Deng, William R Kem, Jianren Mao, Wei Zhang, and MartynJ A JeevendraJAJDepartment of Anaesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Shriners Hospital for Children - Boston, Boston, MA, USA; Harvard Medical School, Boston, MA, USA..
• Department of Anaesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Shriners Hospital for Children - Boston, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Anaesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: jmartyn@mgh.harvard.edu.
• Br J Anaesth. 2022 Dec 1; 129 (6): 959969959-969.

BackgroundRepetitive opioid use does not always alleviate basal pain, procedural pain, or both after burn injury. Mitigation of burn injury-site pain can be achieved by GTS-21 stimulation of α7-acetylcholine nicotinic receptors (α7AChRs) and reduced microglia activation in rat. We tested the hypothesis that morphine exaggerates burn injury-site pain and GTS-21 alleviates both morphine-induced aggravated burn injury pain and microglia activation.MethodsYoung rats with dorsal paw burn injury or sham-burn received intraperitoneal saline, morphine, GTS-21, or a combination twice daily for 14 days. Ipsilateral plantar pain thresholds were tested every other day before morning drugs from days 0-20. Spinal microglia activation, evidenced as pain-transducer (tumour necrosis factor-α [TNF-α], interleukin [IL]-6, IL-1β, nuclear factor kappa B [NF-κB], Toll-like receptor 4 [TLR4]) expression, was examined using immunohistochemistry and immunoblot. In cultured microglia, morphine-induced cytokine expression was measured (quantitative polymerase chain reaction/enzyme-linked immunosorbent assay [qPCR/ELISA]).ResultsMorphine aggravated allodynia at day 5 in sham-burn (P=0.039, n=8-11) but significantly aggravated burn injury site allodynia by day 3 (P=0.010, n=8-11). Microgliosis paralleled nociceptive behaviour changes where burn injury with morphine had highest microgliosis compared with burn injury, morphine alone, or controls (number of cells per field [SD]: 33.8 [2.4], 18.0 [4.1], 8.2 [1.9], and 4.8 [2.0], respectively; P<0.001, n=4-5]. GTS-21 reversed the morphine-induced pain component in sham-burn and burn injury rats together with reduced microgliosis and spinal pain-transducer expression (TNF-α, IL-6, IL-1β, NF-κB, and TLR4). Morphine-exposed microglial cells showed increased cytokine expression, which was mitigated by GTS-21.ConclusionsMorphine or burn injury alone increases pain together with microgliosis and pain-transducer expression. Morphine administration augments burn injury-site nociception sooner and aggravated spinal microgliosis and inflammatory pain-transducer expression. GTS-21 has the potential to treat morphine-induced pain in burn injury.Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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