Promising Findings – Scientists Successfully Revive Lost Brain Function Following Stroke
Researchers have successfully revived brain function in mice affected by stroke through the use of small molecules, which could potentially be developed into a stroke recovery therapy. “Communication between nerve cells in large parts of the brain changes after a stroke and we show that it can be
mGluR5 from primary sensory neurons promotes opioid-induced hyperalgesia and tolerance by interacting with and potentiating synaptic NMDA receptors
Aberrant activation of presynaptic NMDA receptors (NMDARs) in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms responsible for opioid-induced NMDAR hyperactivity remain poorly identified. Here, we show that repeated treatment with morphine or fentanyl reduced monomeric mGluR5 protein levels in the dorsal root ganglia (DRG) but increased levels of mGluR5 monomers and homodimers in the spinal cord in mice and rats of both sexes. Co-immunoprecipitation analysis revealed that monomeric and dimeric mGluR5 in the spinal cord, but not monomeric mGluR5 in the DRG, directly interacted with GluN1. By contrast, mGluR5 did not interact with μ-opioid receptors in the DRG or spinal cord. Repeated morphine treatment markedly increased the mGluR5-GluN1 interaction and protein levels of mGluR5 and GluN1 in spinal synaptosomes. The mGluR5 antagonist MPEP reversed morphine treatment–augmented mGluR5-GluN1 interactions, GluN1 synaptic expression, and dorsal root–evoked monosynaptic EPSCs of dorsal horn neurons. Furthermore, CRISPR-Cas9–induced conditional mGluR5 knockdown in DRG neurons normalized mGluR5 levels in spinal synaptosomes and NMDAR-mediated EPSCs of dorsal horn neurons increased by morphine treatment. Correspondingly, intrathecal injection of MPEP or conditional mGluR5 knockdown in DRG neurons not only potentiated the acute analgesic effect of morphine but also attenuated morphine treatment–induced hyperalgesia and tolerance. Together, our findings suggest that opioid treatment promotes mGluR5 trafficking from primary sensory neurons to the spinal dorsal horn. By directly interacting with NMDARs, presynaptic mGluR5 potentiates and/or stabilizes NMDAR synaptic expression and activity at primary afferent central terminals, thereby maintaining opioid-induced hyperalgesia and tolerance.
Significance Statement:
Opioids are essential analgesics for managing severe pain caused by cancer, surgery, and tissue injury. However, these drugs paradoxically induce pain hypersensitivity and tolerance, which can cause rapid dose escalation and even overdose mortality. This study demonstrates for the first time that opioids promote trafficking of mGluR5, a G protein-coupled glutamate receptor, from peripheral sensory neurons to the spinal cord; there, mGluR5 proteins dimerize and physically interact with N -methyl- D -aspartate receptors to augment their synaptic expression and activity. Through dynamic interactions, the two distinct glutamate receptors mutually amplify and sustain nociceptive input from peripheral sensory neurons to the spinal cord. Thus, inhibiting mGluR5 activity or disrupting mGluR5- N -methyl- D -aspartate receptor interactions could reduce opioid-induced hyperalgesia and tolerance and potentiate opioid analgesic efficacy.
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Des chercheurs ont découvert un biomarqueur prévenant le suicide
Des chercheurs de Yale ont découvert un marqueur présent dans le cerveau capable de prévenir du suicide.
Matt Willemsen
ℵ₀ 🏳️⚧️🏴☠️
Autism News International
Gregori Fabre