From the Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children, and Harvard Medical School, Boston, Massachusetts.
Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Anesth Analg. 2021 Jan;132(1):240-252. doi: 10.1213/ANE.0000000000005274.
Burn injury (BI) pain consists of inflammatory and neuropathic components and activates microglia. Nicotinic alpha 7 acetylcholine receptors (α7AChRs) expressed in microglia exhibit immunomodulatory activity during agonist stimulation. Efficacy of selective α7AChR agonist GTS-21 to mitigate BI pain and spinal pain-mediators was tested.
Anesthetized rats after hind-paw BI received intraperitoneal GTS-21 or saline daily. Allodynia and hyperalgesia were tested on BI and contralateral paw for 21 days. Another group after BI receiving GTS-21 or saline had lumbar spinal cord segments harvested (day 7 or 14) to quantify spinal inflammatory-pain transducers or microglia activation using fluorescent marker, ionized calcium-binding adaptor protein (Iba1).
BI significantly decreased allodynia withdrawal threshold from baseline of ~9-10 to ~0.5-1 g, and hyperalgesia latency from ~16-17 to ~5-6 seconds by day 1. Both doses of GTS-21 (4 or 8 mg/kg) mitigated burn-induced allodynia from ~0.5-1 to ~2-3 g threshold (P = .089 and P = .010), and hyperalgesia from ~5-6 to 8-9 seconds (P < .001 and P < .001) by day 1. The GTS-21 group recovered to baseline pain threshold by day 15-17 compared to saline-treated, where the exaggerated nociception persisted beyond 15-17 days. BI significantly (P < .01) increased spinal cord microgliosis (identified by fluorescent Iba1 staining), microglia activation (evidenced by the increased inflammatory cytokine), and pain-transducer (protein and/or messenger RNA [mRNA]) expression (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], nuclear factor-kappa B [NF-κB], interleukin-6 [IL-6], Janus-associated kinase signal transducer and activator of transcription 3 [JAK-STAT3], and/or N-methyl-D-aspartate receptor [NMDAR]). GTS-21 mitigated pain-transducer changes. The α7AChR antagonist methyllycaconitine nullified the beneficial effects of GTS-21 on both increased nociception and pain-biomarker expression.
Nonopioid, α7AChR agonist GTS-21 elicits antinociceptive effects at least in part by decreased activation spinal-cord pain-inducers. The α7AChR agonist GTS-21 holds promise as potential therapeutic adjunct to decrease BI pain by attenuating both microglia changes and expression of exaggerated pain transducers.
烧伤（BI）疼痛由炎症和神经病理性成分组成，并激活小胶质细胞。在激动剂刺激下，小胶质细胞中表达的烟碱型乙酰胆碱受体α7（α7AChR）表现出免疫调节活性。测试了选择性α7AChR 激动剂 GTS-21 减轻 BI 疼痛和脊髓疼痛介质的功效。
麻醉后的大鼠在接受后肢 BI 后每天接受腹腔内 GTS-21 或生理盐水治疗。在 21 天内测试 BI 和对侧足部的痛觉过敏和痛觉过敏。接受 GTS-21 或生理盐水治疗的另一组大鼠在 BI 后第 7 或 14 天采集腰椎脊髓节段，使用荧光标记物离子钙结合衔接蛋白（Iba1）来量化脊髓炎症性疼痛转导物或小胶质细胞激活。
BI 显著降低了从基线的9-10 到0.5-1 g 的痛觉过敏退缩阈值，从16-17 到5-6 秒的痛觉过敏潜伏期，到第 1 天。两种剂量的 GTS-21（4 或 8 mg/kg）均将烧伤引起的痛觉过敏从0.5-1 降低至2-3 g 阈值（P =.089 和 P =.010），从~5-6 降低至 8-9 秒（P <.001 和 P <.001）第 1 天。与生理盐水处理相比，GTS-21 组在第 15-17 天恢复到基线疼痛阈值，而过度的痛觉过敏持续时间超过 15-17 天。BI 显著（P <.01）增加了脊髓小胶质细胞增生（通过荧光 Iba1 染色鉴定）、小胶质细胞激活（通过增加炎症细胞因子证明）和疼痛转导物（蛋白和/或信使 RNA [mRNA]）表达（肿瘤坏死因子-α[TNF-α]、白细胞介素-1β[IL-1β]、核因子-κB [NF-κB]、白细胞介素-6 [IL-6]、Janus 相关激酶信号转导和转录激活因子 3 [JAK-STAT3]和/或 N-甲基-D-天冬氨酸受体 [NMDAR]）。GTS-21 减轻了疼痛转导物的变化。α7AChR 拮抗剂甲基烟酰胺完全消除了 GTS-21 对增加的伤害感受和疼痛生物标志物表达的有益影响。
非阿片类 α7AChR 激动剂 GTS-21 至少部分通过降低脊髓疼痛诱导物的激活来产生镇痛作用。α7AChR 激动剂 GTS-21 有望作为一种潜在的治疗辅助手段，通过减轻小胶质细胞变化和过度表达的疼痛转导物来减轻 BI 疼痛。
