Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla

Abstract

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.

Keywords: 5-HT3; dorsal horn; hyperalgesia; incision; raphe magnus; spinal cord.