• Raquel Pereira-Silva, Armando Teixeira-Pinto, Fani L Neto, and Isabel Martins.
• Instituto de Investigação e Inovação em Saúde da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200 393 Porto, Portugal.
• Anesthesiology. 2024 Feb 21.

BackgroundThe dorsal reticular nucleus is a pain facilitatory area involved in the diffuse noxious inhibitory controls (DNIC), through opioidergic mechanisms that are poorly understood. We hypothesized that signaling of µ-opioid receptors is altered in this area at prolonged chronic inflammatory pain and that this accounts for the loss of DNIC occurring in this condition.MethodsMonoarthritis was induced in male Wistar rats (n=5-9/group) by tibiotarsal injection of complete Freund's adjuvant. We quantified the immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element-binding protein. Pharmacological manipulation of µ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC, through the Randall-Selitto test.ResultsAt 42 days of monoarthritis, µ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element-binding protein increased. D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals ([Mean ± SD]: pre-DNIC: 126.9 ± 7.0g; DNIC - DAMGO: 147.5 ± 8.0g vs. DNIC + DAMGO: 198.1 ± 19.3g, p < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5g; DNIC - DAMGO: 70.6 ± 7.7g vs. DNIC + DAMGO: 32.2 ± 2.6g, p < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the µ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - Naloxone: 60.0 ± 6.1g vs. DNIC + Naloxone: 98.0 ± 13.5g, p < 0.001), compared to saline (DNIC - Saline: 62.5 ± 5.2g vs. DNIC + Saline: 64.2 ± 3.8g). When injected prior to DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element-binding protein in monoarthritis.ConclusionsThe dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of µ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.

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