Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MOR_CA) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3–4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished on chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HT₃R antagonist ondansetron; the 5-HT_2AR antagonist MDL-11 939 had no effect. Second, to test for MOR_CA, we microinjected the MOR inverse agonist d-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and/or neutral opioid receptor antagonist 6β-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws; 6β-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MOR_CA, rather than an opioid ligand-dependent mechanism, maintains LS in remission. We conclude that incision establishes LS in descending RVM 5-HT neurons that drives pronociceptive 5-HT₃R signaling in the dorsal horn, and this LS is tonically opposed by MOR_CA in the RVM. The 5-HT₃ receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.

SIGNIFICANCE STATEMENT Surgery leads to latent pain sensitization and a compensatory state of endogenous pain control that is maintained long after tissue healing. Here, we show that either chemogenetic inhibition of serotonergic neuron activity in the RVM or pharmacological inhibition of 5-HT₃ receptor signaling at the spinal cord blocks behavioral signs of postsurgical latent sensitization. We conclude that MOR_CA in the RVM opposes descending serotonergic facilitation of LS and that the 5-HT₃ receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.

组织损伤后，伤害性信号的潜在致敏作用 (LS) 可以无限期地持续，通过代偿性 μ-阿片受体组成性活性 (MOR _{CA ) 保持缓解}) 在脊髓的背角。为了证明 LS，我们在小鼠身上进行了足底切口，然后等待 3-4 周让超敏反应消退。此时（缓解），阿片受体拮抗剂/反向激动剂纳曲酮的全身给药恢复了机械和热超敏反应。我们首先测试了 LS 延伸到延髓头端腹侧 (RVM) 中的血清素能神经元的假设，这些神经元将伤害性输入传递到脊髓。我们报告说，在雄性和雌性小鼠中，超敏反应伴随着 RVM 血清素能神经元中 Fos 表达的增加，消除了 RVM 5-HT 神经元的化学遗传抑制，并通过鞘内注射 5-HT ₃ R 拮抗剂昂丹司琼阻断；5-HT _2AR 拮抗剂 MDL-11 939 没有效果。其次，为了测试 MOR _CA，我们显微注射了 MOR 反向激动剂d-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) 和/或中性阿片受体拮抗剂 6β-纳曲醇。RVM 内 CTAP 在两个后爪产生机械超敏反应；6β-纳曲醇本身没有作用，但可以阻断 CTAP 诱导的超敏反应。这表明 MOR _CA而非阿片样物质配体依赖性机制维持 LS 缓解。我们得出的结论是，切口在下行 RVM 5-HT 神经元中建立了 LS，驱动背角中的伤害感受器 5-HT ₃ R 信号，并且这种 LS与 RVM 中的 MOR _{CA强直相反。}5-HT ₃受体是用于开发药物以防止从急性术后疼痛转变为慢性术后疼痛的有前途的治疗靶标。

意义声明手术导致潜在的疼痛敏化和内源性疼痛控制的代偿状态，这种状态在组织愈合后很长时间内得以维持。在这里，我们表明 RVM 中 5-羟色胺能神经元活性的化学遗传抑制或脊髓5-HT _{3受体信号传导的药理学抑制可阻断术后潜在致敏的行为迹象。}我们得出结论，RVM 中的 MOR _CA反对 LS 的下行血清素能促进作用，并且 5-HT ₃受体是开发药物以防止从急性术后疼痛转变为慢性疼痛的有前途的治疗靶点。