Spinal Cord Stimulation Reduces Emotional Aspect of Chronic Pain
Experiments to block receptors deep within spinal neurons, metabotropic glutamate 5 receptors (mGluR5), may open the door to more effective treatments for neuropathic pain.
Understanding how the body processes pain is essential to understanding how to better treat it. Aiding in that understanding has been intense research on one of the key players that transmit nociceptive information through the body. G-protein-couple receptors (GPCRs) play a critical role in various bodily functions, including as a mediator of neuroplasticity underlying chronic pain. One specific receptor, metabotropic glutamate 5 receptor (mGluR5), is heavily abundant in the dorsal horn (DH),1,2 prime real estate for the relay of pain information throughout the central nervous system (CNS).3
While researchers already know that mGluR5 influences hypersensitivity following a nerve injury, they haven’t understood whether these effects are due to signaling of the receptor on the surface of spinal cells or inside of them. In a new study published online in Nature Communications,4 it appears that not only does mGluR5 proliferate in the DH following a nerve injury, the receptor is far more influential inside the cell, specifically on the membranes of the nucleus.
“To our knowledge, these are the first experiments demonstrating a role for an intracellular GPCR in an in vivo behavioral model,” wrote the researchers. While many GPCR’s can be found on the nuclear membrane, deducing their significance has been tricky. Now, the researcher team from Washington University School of Medicine in St. Louis, Missouri, and McGill University in Montreal, Canada, believe nuclear mGluR5 could become a measurable treatment target for analgesia, something that would influence future therapies to come.
Block the Receptor, Curb the Pain
The investigators wanted to analyze how mGluR5 responded when rats received a spared-nerve injury (SNI), which is a typical neuropathic pain model that helps to simulate human neuropathic pain, like spontaneous pain, allodynia, and hyperalgesia. The researchers found nuclear mGluR5 inside DH neurons increased following the trauma. The mGluR5 binding sites also appeared to increase, suggesting a pathophysiological role. Effector molecules, known to impact neuropathic plasticity, increased as well. Based on this reaction, mGluR5 appeared to be a key component in a systemic chain signaling nociception, something that potentially may be suppressed using selective drugs, the authors noted.
For instance, when researchers blocked intracellular mGluR5 using a permeable antagonist called fenobam (IC50 80 nM), they found marked, dose-dependent reductions in the rats’ pain behaviors for about one hour after the injection. By contrast, inhibiting only the mGluR5 found on the cell surface using an impermeable antagonist had no effect, which supported the notion that mGluR5 found inside the cell is far more influential in pain transmission.
Interestingly, when rats without nerve injury were treated with fenobam, their pain sensitivities didn’t change at all. For the animals with nerve injury, not only were allodynia and spontaneous pain significantly reduced when treated with the intracellular mGluR5 antagonist, downstream signalers of the pain also decreased.
Continue reading about how pain signals are sent through the body.
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