In real estate, location is key. It now seems the same concept holds true when it comes to stopping pain. New research published in Nature Communications indicates that the location of receptors that transmit pain signals is important in how big or small a pain signal will be; and therefore how effectively drugs can block those signals.
Blocking pain receptors in the nucleus of spinal nerve cells could more effectively control pain than interfering with the same type of receptors located on cell surfaces. The scientists also found that when spinal nerve cells encounter a painful stimulus, some of the receptors will migrate from the cell surface into the nucleus.
A team of researchers led by McGill University’s Director of Anesthesia Research Terence Coderre and Karen O’Malley at Washington University in St. Louis, found that rats treated with investigational drugs to block the activity of the receptors in the nucleus soon began behaving in ways that led them to believe the animals had gotten relief from neuropathic pain. According to Prof. Coderre, “drugs that penetrate the spinal nerve cells to block receptors at the nucleus were effective at relieving pain, while those that don’t penetrate the nerve cells were not. Rats with nerve injuries had less spontaneous pain and less pain hypersensitivity after blocking receptors at the nucleus, while the pain sensitivity of normal rats was not affected”.
Location is key
Scientists have been studying glutamate receptors in the pain pathway for decades. What’s new, Coderre explained, is that these most recent experiments, in cell cultures and rats, demonstrate that the location of the receptor in the cell has a major effect on the cell’s ability to transmit pain signals.
The researchers focused mainly on nerve cells in the spinal cord, an important area for transmitting pain signals coming from all parts of the body.
Location may be key to effectively controlling pain.
“We’ll now focus our research at determining what events cause the glutamate receptors to migrate to the nucleus, and how to produce drugs that more specifically block glutamate receptors only at the nucleus”, added Coderre.
Funding: Funding for this research comes from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH), grant number NS081454. Additional funding comes from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, a fellowship from the Canadian Institutes of Health Strategic Training Program in Pain: Molecules to Community, and the Louise and Alan Edwards Foundation, In addition, the drug used in the experiments, LY393053 was donated by Eli Lilly and Co.
Source: Cynthia Lee – McGill University
Image Credit: The image is adapted from the McGill press release
Video Source: The video is available at the McGill University YouTube page
Original Research: Full open access research for “Intracellular mGluR5 plays a critical role in neuropathic pain” by Kathleen Vincent, Virginia M. Cornea, Yuh-Jiin I. Jong, André Laferrière, Naresh Kumar, Aiste Mickeviciute, Jollee S. T. Fung, Pouya Bandegi, Alfredo Ribeiro-da-Silva, Karen L. O’Malley and Terence J. Coderre in Nature Communications. Published online February 3 2016 doi:10.1038/NCOMMS10604
Abstract
Intracellular mGluR5 plays a critical role in neuropathic pain
Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ~60% is located on nuclear membranes, where activation leads to sustained Ca2+ responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain.
“Intracellular mGluR5 plays a critical role in neuropathic pain” by Kathleen Vincent, Virginia M. Cornea, Yuh-Jiin I. Jong, André Laferrière, Naresh Kumar, Aiste Mickeviciute, Jollee S. T. Fung, Pouya Bandegi, Alfredo Ribeiro-da-Silva, Karen L. O’Malley and Terence J. Coderre in Nature Communications. Published online February 3 2016 doi:10.1038/NCOMMS10604
