µ-opioid receptor activation at the dorsal reticular nucleus shifts diffuse noxious inhibitory controls to hyperalgesia in chronic joint pain in male rats.

BACKGROUND: The 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.

METHODS: Monoarthritis 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.

RESULTS: At 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.

CONCLUSIONS: The 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.