Pain researchers know that, in the immediate aftermath of a severe injury, pain sensitization pathways become active, causing the body to produce opioids—naturally occurring chemicals that inhibit pain by activating receptors. But a mouse study published today in Science reveals that a specific type of opioid receptor found on the surface of nerve cells remains hyperactive months after an injury has healed—a period much longer than previously thought. Moreover, blocking this receptor from binding opioids can produce opioid withdrawal, much like that experienced by people addicted to heroin or codeine. This finding suggests that opioids only serve to mask underlying pain, shedding light on why some chronic nature of pain disorders.
To study the long-term role of ‘endogenous’ opioids produced naturally by the body, scientists created an inflammatory response in the paws of mice by injecting a dose of toxic bacteria fragments. The researchers then allowed the injury to heal for a period of three weeks or more, all the while monitoring how sensitive the area was by using molecular biomarkers and recording how often the rodents made facial grimaces or withdrew their paws when the injured area was touched.
Six months on, once the injury had healed, the researchers administered naltrexone methobromide, a drug that blocks the receptors that can normally bind to opioids. Surprisingly, blocking the receptor’s activity caused the pain to return, even though considerable time had passed. Moreover, the mice also exhibited the telltale signs of opioid withdrawal, such as jumping, shaking and teeth chattering. “We think it’s possible that the body becomes dependent on the endogenous opioid system after an injury,” says neurobiologist and co-author Bradley Taylor, of the University of Kentucky in Lexington, “but this is speculative.” If these results are further validated, this could be the first recorded expression of what the researchers call ‘endogenous opioid withdrawal’.
Following this initial discovery, the researchers were able to determine the specific receptor involved, mu-opioid receptor (MOR), using in vitro tests on cells taken from the mice. They found that the paw injury transformed the MOR into a state of constant activity, called “constitutive activity,” where the receptor remains active even in the absence of opioid signals. According to Taylor, the underlying pain from the injury might remain, “but we can’t see it because the pain is masked by the receptor’s constant activity.”
Taylor and his team of researchers think that with prolonged MOR activity, there might be an opposing adaptation that can perhaps occur, which can cause pain pathways to become over-sensitized, leading to chronic pain. “We speculate that stress could be involved,” Taylor says, “because stress is known to inhibit opioid systems and stress is a major factor in the development of chronic pain.” Humans also possess this opioid receptor, which has been implicated in morphine, nicotine and cannabinoid addiction.
“The data are quite convincing,” says Lindsay Hough, a neuropharmacologist at the Albany Medical Center in upstate New York who was unaffiliated with the study. Howard Fields, a neurologist of the University of California–San Francisco who did not participate in the study, agrees. “This study’s importance opens a new field of study. For example, why does MOR continue to signal? Is it independent of endogenous opioids? If not, what opioids are involved?”
These questions are important, but beyond those raised by Fields, Taylor hopes that further research on the MOR receptor and its role in long-term pain inhibition will uncover ways to prevent the transition from acute pain to chronic pain. “It is probably too early to know the biomedical significance of the findings,” Hough says, “but as with any really excellent advance, the reader thinks ‘yes that is exactly how it should have worked… Why didn’t we figure this out before?’”
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