In findings published in Proceedings of the National Academy of Sciences (PNAS), scientists report progress on this front with definitive new understandings about how neuropathic pain occurs at the cellular and molecular level and how it can be turned off in a laboratory setting. This work lays a foundation for the development of new non-opioid pain-killing therapies.
Chronic neuropathic pain can result from a wide range of injuries and illnesses, including spinal cord injury, diabetes, multiple sclerosis and cancer. Experts believe the condition affects anywhere from 15 to 30 million people in the U.S. and that treatment carries an economic burden of more than $600 billion.
"Neuropathic pain can be severe and does not always respond to treatment," the senior author said. "Opioid pain killers are widely used but can cause strong side effects and carry risks of addiction and abuse. "There is an urgent need for better options for patients suffering from chronic pain."
Building on previous research, researchers found that a particular cellular receptor appears to be the culprit in the development of traumatic nerve injury pain in an animal model.
In response to a nerve injury, the body generates a molecule called sphingosine-1-phosphate (S1P) in the dorsal horn of the spinal cord. S1P, in turn, can activate the receptor protein sphingosine 1-phosphate receptor subtype 1 (S1PR1) on the surface of specialized nervous system support cells called astrocytes, resulting in neuroinflammation.
In fact, pain pathways appear to depend on the activation of S1PR1; conversely, blocking this signal limits or stops pain.
"For the first time, this study clearly establishes that S1P activation of S1PR1 signaling in astrocytes is required for the development and maintenance of traumatic nerve injury-induced neuropathic pain," the senior author said. "Several important findings have emerged from our studies. We unequivocally established that activation and not inhibition of S1PR1 drives and maintains neuropathic pain. Consequently, turning S1PR1 off - not on -- is required to inhibit the development of neuropathic pain and to reverse it once established."
Mice with astrocyte-specific knockout of S1PR1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine.
These findings lay the groundwork to develop a new class of medications that offer pain-killing benefits without the risks and side-effects of opioids.
"It is noteworthy that drugs that inhibited S1PR1 did not lose their beneficial effects during prolonged use nor did they engage the molecular pathways opioids use, suggesting that targeting S1PR1 is unlikely to cause opioid-like abuse," the senior author said. "Collectively, our results establish S1PR1 as a good target for developing new therapies, creating a new class of non-narcotic pain-killers."
An astrocyte receptor linked to neuropathic pain!
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