Newly Published
Pain Medicine  |   June 2020
Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats
Author Notes
  • 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.), and 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.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication October 7, 2019. Accepted for publication May 15, 2020.
    Submitted for publication October 7, 2019. Accepted for publication May 15, 2020.×
  • Correspondence: Address correspondence to Dr. Martins: Departamento de Biomedicina, Unidade de Biologia Experimental, Centro de Investigação Médica, Faculdade de Medicina do Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal. isabmart@med.up.pt. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology / Opioid
Pain Medicine   |   June 2020
Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats
Anesthesiology Newly Published on June 17, 2020. doi:https://doi.org/10.1097/ALN.0000000000003412
Anesthesiology Newly Published on June 17, 2020. doi:https://doi.org/10.1097/ALN.0000000000003412
Abstract

Background: Increased 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.

Methods: The 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.

Results: Lidocaine 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.

Conclusions: Chronic 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.

Editor’s Perspective:

What We Already Know about This Topic:

  • The phenomenon of opioid-induced hyperalgesia is supported by descending pain facilitation from brainstem nuclei

  • The dorsal reticular nucleus is modulated by opioids and mediates descending pain facilitation in some settings

What This Article Tells Us That Is New:

  • Using a rat model of opioid-induced hyperalgesia, it was shown that reducing dorsal reticular activity with lidocaine blocked nociceptive sensitization from opioid infusion

  • Knockdown of µ-opioid receptors or prevention of excitatory signaling using naloxone in the dorsal reticular nucleus prevented and reversed opioid-induced hyperalgesia