• Ana Rita Costa, Marília Sousa, Steven P Wilson, Carlos Reguenga, Armando Teixeira-Pinto, Isaura Tavares, and Isabel Martins.
• From the Department of Biomedicine-Unit of Experimental Biology, Faculty of Medicine (A.R.C., M.S., C.R., I.T., I.M.) I3S-Institute for Research and Innovation in Health (A.R.C., M.S., C.R., I.T., I.M.) IBMC-Institute for Molecular and Cell Biology (A.R.C., M.S., C.R., I.T., I.M.), University of Porto, Porto, Portugal Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina (S.P.W.) Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (A.T.-P.).
• Anesthesiology. 2020 Sep 1; 133 (3): 628-644.

BackgroundIncreased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling.MethodsThe authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling. The authors used pharmacologic and gene-mediated approaches. Nociceptive behaviors were evaluated by the von Frey and hot-plates tests.ResultsLidocaine fully reversed mechanical and thermal hypersensitivity induced by chronic morphine. Morphine-infusion increased µ-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. µ-opioid receptor knockdown in morphine-infused animals attenuated the decrease of mechanical thresholds and heat-evoked withdrawal latencies compared with the control vector (von Frey [mean ± SD]: -17 ± 8% vs. -40 ± 9.0%; P < 0.001; hot-plate: -10 ± 5% vs. -32 ± 10%; P = 0.001). µ-opioid receptor knockdown in control animals induced the opposite (von Frey: -31 ± 8% vs. -17 ± 8%; P = 0.053; hotplate: -24 ± 6% vs. -3 ± 10%; P = 0.001). The µ-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heat-evoked withdrawal latencies in morphine-infused animals. In control animals, DAMGO increased both mechanical thresholds and heat-evoked withdrawal latencies. Ultra-low-dose naloxone, which prevents the excitatory signaling of the µ-opioid receptor, administered alone, attenuated mechanical and thermal hypersensitivities, and coadministered with DAMGO, restored DAMGO analgesic effects and decreased phosphorylated cAMP response element-binding levels.ConclusionsChronic morphine shifted µ-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat.

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