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Chronic morphine enhances descending pain facilitation from the brain through a switch of µ-opioid receptor signaling

Ana R. Costa1, 2, 3*, Marília M. Sousa1, 2, 3, Steven P. Wilson4, Isaura Tavares1, 2, 3 and Isabel Martins1, 2, 3
  • 1 Faculty of Medicine, University of Porto, Portugal
  • 2 i3S, Instituto de Investigação e Inovação em Saúde, Portugal
  • 3 Instituto de Biologia Molecular e Celular (IBMC), Portugal
  • 4 Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, United States

Opioid-induced hyperalgesia (OIH) is a state of nociceptive sensitization caused by sustained opioid administration. The underlying mechanisms remain understudied namely the role of µ-opioid receptors (MOR) in supraspinal areas involved in descending pain modulation. Here we aimed to study the opioidergic modulation of the dorsal reticular nucleus (DRt), a medullary area involved in descending pain facilitation, in a rat model of OIH. First, we established the involvement of the DRt in descending pain facilitation in OIH. Then we used genetic and pharmacological approaches to study the MOR signaling at DRt during OIH. Male Wistar rats were implanted with osmotic mini-pumps for the delivery of morphine or saline for 7 days. Simultaneously, the DRt was injected with lentiviral vectors for MOR knock-down, or implanted with a guide cannula for the injection of lidocaine, or the MOR agonist DAMGO or an ultra-low dose naloxone, which prevents the coupling of MOR to a Gs-protein. The effects of the drugs and vectors were tested by the von-Frey and hot-plate tests which evaluate mechanical and thermal sensitivity, respectively. The expression of MOR and pCREB and pERKs, markers of MOR signaling cascades, were evaluated by immunohistochemistry. Morphine infusion induced mechanical and thermal hypersensitivity and increased the expression of pCREB and pERKs at the DRt. Lidocaine reversed morphine-induced hypersensitivity. MOR knock-down prevented the development of OIH in morphine-treated animals while in saline-treated animals it induced mechanical and thermal hypersensitivity. DAMGO induced antinociceptive effects in saline-treated animals and increased mechanical hypersensitivity in morphine-treated animals. Naloxone restored the antinociceptive effect of DAMGO in morphine-treated animals. Our results show that OIH involves descending facilitation from the DRt. MOR activation inhibits DRt descending facilitation and produces the opposite upon chronic opioid treatment. The increased expression of pCREB and pERKs together with the results of our pharmacological experiments indicate that morphine induces a switch of MOR signaling from inhibitory to excitatory through increased coupling of MOR to a Gs-protein. Preventing this switch in pain facilitatory areas may be a potential therapeutic strategy to prevent OIH.

Acknowledgements

IASP Early Career Research Grant, NORTE 2020- Programa Operacional Regional do Norte e Fundo Social Europeu (Norte-08-5369-FSE-000026)

Keywords: opioid-induced hyperalgesia (OIH), Dorsal reticular nucleus, pain descending facilitation, Opioids, mu-opiod receptor

Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.

Presentation Type: Pitch communication + Poster presentation

Topic: Sensory Processing

Citation: Costa AR, Sousa MM, Wilson SP, Tavares I and Martins I (2019). Chronic morphine enhances descending pain facilitation from the brain through a switch of µ-opioid receptor signaling. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00032

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Received: 16 Apr 2019; Published Online: 27 Sep 2019.

* Correspondence: Dr. Ana R Costa, Faculty of Medicine, University of Porto, Porto, Portugal, rritacostaa@gmail.com