Mu-opioid receptor signalling switch to excitatory following chronic morphine persists upon treatment cessation
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1
Faculty of Medicine, University of Porto, Portugal
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2
i3S, Instituto de Investigação e Inovação em Saúde, Portugal
Opioids are used for the treatment of pain but they also cause a paradoxical effect known as Opioid-Induced Hyperalgesia (OIH). The exposure to opioids induces adaptations at µ-opioid receptor (MOR) and its intracellular pathways. It is not known whether these alterations remain after opioid cessation which could impact on future treatments. Here we aim to study MOR alterations during OIH and after reversal of OIH (Post-OIH) at a medullary pain facilitatory area, the dorsal reticular nucleus (DRt). We evaluated: i) the expression of MOR, the phosphorylated cAMP response element binding protein (pCREB) and the phosphorylated extracellular signal-regulated kinases (pERKs); ii) the effects of MOR activation on pain behaviours.
Male Wistar rats were implanted with osmotic mini-pumps for the continuous release of morphine or saline in control animals. In the OIH group, the animals were euthanized one week later. In the Post-OIH group, the mini-pumps were removed one week after implantation and the animals were euthanized two weeks later. A guide cannula was stereotaxically implanted at the DRt for the administration of the MOR agonist DAMGO. Pain behaviours were evaluated by the von-Frey and Hot plate tests assessing mechanical and thermal sensitivity, respectively. The expression of MOR, pCREB and pERKs was evaluated at the DRt by immunohistochemistry.
In the OIH group, morphine, compared to saline, increased pain hypersensitivity and increased MOR, pCREB and pERKs expression. In the Post-OIH group, pain behaviours as well as MOR expression returned to normal levels and were similar in morphine- and saline-treated animals but not pCREB and pERKs expression which remained increased. DAMGO injection induced antinociceptive effects in controls and increased pain behaviours in morphine-treated animals both at OIH and Post-OIH timings.
Morphine increased both pain sensitivity and intracellular markers of a switch of MOR signalling from inhibitory to excitatory which was confirmed by the pronociceptive effects of DAMGO. Despite pain behaviours and MOR expression returned to normal upon morphine cessation, the switch of MOR signalling was maintained. This enhances DRt facilitation which can impact negatively on future treatments with opioids. Strategies normalizing intracellular cascades may prove useful in the prevention of OIH and its consequences.
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,
pain modulation,
μ-opioid receptor,
Dorsal reticular nucleus,
Opioid Cessation
Conference:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.
Presentation Type:
Poster presentation
Topic:
Sensory Processing
Citation:
Sousa
M,
Costa
AR,
Tavares
I and
Martins
I
(2019). Mu-opioid receptor signalling switch to excitatory following chronic morphine persists upon treatment cessation.
Front. Cell. Neurosci.
Conference Abstract:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019).
doi: 10.3389/conf.fncel.2019.01.00042
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Received:
16 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
Dr. Marília Sousa, Faculty of Medicine, University of Porto, Porto, Portugal, mariliasousa0403@gmail.com