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

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory m-opioid receptor constitutive activity (MORCA) 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-HT2AR antagonist MDL-11 939 had no effect. Second, to test for MORCA, we microinjected the MOR inverse agonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and/or neutral opioid receptor antagonist 6 beta-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws; 6 beta-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MORCA, rather than an opioid liganddependent 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 MORCA 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.

Automated summary

Following tissue injury, latent sensitization can be maintained in remission by the activity of μ-opioid receptors in the spinal cord. This sensitization is mediated by serotonergic neurons in the rostral ventral medulla that convey pronociceptive input to the spinal cord. The 5-HT3 receptor signaling in the dorsal horn and the activity of μ-opioid receptors in the rostral ventral medulla play opposing roles in maintaining this sensitization.