Good news! Are we getting closer to strong painkillers without or with less negative side effects like addiction, tolerance etc.?
"Opioids are among the most effective painkillers on the market, and for many people, they’re indispensable. But their effectiveness tends to decrease over time, meaning people have to take higher doses to feel relief. Even worse, people can end up more sensitive to pain than they were before, setting the stage for dependence or addiction. Now, researchers have uncovered a key mechanism behind these effects—and with it, a potential target for preventing them.
Opioids work by activating μ-opioid receptors in sensory neurons, especially those that connect to the central nervous system. There, opioids essentially shut off pain sensations by tamping down on pain signaling.
But the drugs can also activate pathways that do the opposite—particularly via a protein called Gαq. When researchers inhibited this protein or reduced the amount of it in the spinal cords of mice, the animals didn’t develop a tolerance to morphine nor increase their sensitivity to pain. And, as a bonus, the effectiveness of the drug increased. ..."
From the editor's summary and abstract:
"Editor’s summary
Although opioids block nociceptive signaling, their prolonged use increases pain sensitivity and promotes analgesic tolerance. These adverse effects involve the activation of NMDA-type glutamate receptors (NMDARs) and the metabotropic glutamate receptor mGluR5 in sensory neuron terminals in the spinal cord. Jin et al. found that morphine treatment increased the coupling of mGluR5 to Gαq in the spinal cords of rodents and that Gαq was required for morphine-induced increases in NMDAR phosphorylation and synaptic trafficking. Inhibition or knockdown of Gαq reduced morphine-induced hyperalgesia and analgesic tolerance. Thus, Gαq might be targeted to improve the analgesic effects of these drugs while reducing the need for dose escalation. ...
Abstract
Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord.
Here, we identified a critical role for the G protein Gαq in this paradox. Pharmacological inhibition of Gαq in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gαq coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord.
Furthermore, targeted knockdown of Gαq in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation.
In addition, either pharmacological or genetic disruption of Gαq signaling enhanced morphine’s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gαq signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management."
Gαq signaling in primary sensory neurons shifts opioid analgesia to NMDA receptor–driven tolerance and hyperalgesia (open access)
Fig. 4. Inhibiting Gαq activity at the spinal cord level reduces morphine treatment–induced hyperalgesia and tolerance.
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