Background

The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of μ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition.

Methods

Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund’s adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of μ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using 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 (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC − DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC − DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; 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 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC − saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before 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.

Editor’s Perspective
What We Already Know about This Topic
  • Diffuse noxious inhibitory control is an endogenous pain modulatory pathway in which the response to an existing painful stimulus is inhibited by an additional, spatially distant noxious stimulus
  • Diffuse noxious inhibitory control analgesia relies on engagement of descending monoaminergic pathways and is opioid-dependent in various regions of the descending pain circuit, including that linking the medullary dorsal reticular nucleus to the spinal cord
  • Prolonged chronic joint inflammatory pain is associated with a loss of diffuse noxious inhibitory control analgesia
What This Article Tells Us That Is New
  • The hypothesis that altered signaling of μ-opioid receptors at the dorsal reticular nucleus contributes to the loss of diffuse noxious inhibitory control at prolonged stages of chronic inflammatory pain was tested in a Freund’s complete adjuvant male rat model of monoarthritis
  • Activation of μ-opioid receptors at the dorsal reticular nucleus enhanced diffuse noxious inhibitory control analgesia in normal rats but produced hyperalgesia in rats with a late stage of chronic inflammatory joint pain
  • In these latter rats, diffuse noxious inhibitory control analgesia was restored by administration of an ultra-low dose of naloxone at the dorsal reticular nucleus
  • Naloxone administered before an opioid prevented the hyperalgesic effect of the opioid in these animals