Opioid dependence plays role in chronic pain

The bodies of mammals, including humans, respond to injury by releasing endogenous opioids—compounds that mitigate acute pain. A team of researchers led by those at the University of Kentucky has uncovered groundbreaking new information about how the body responds to traumatic injury with the development of a surprisingly long-lasting opioid mechanism of natural chronic pain control. Remarkably, the body develops both physical and physiological dependence on this opioid system, just as it does to opiate narcotic drugs. The research is featured on the cover of the current issue of the prestigious journal Science.

The paper, titled Constitutive Mu-Opioid Receptor Activity Leads to Long-term Endogenous Analgesia and Dependence, was authored by a team including lead author Bradley Taylor of the University of Kentucky College of Medicine Department of Physiology. Other authors include: Gregory Corder, Suzanne Doolen and Renee Donahue of the UK Department of Physiology; Brandon Jutras of the UK College of Medicine Department of Microbiology, Immunology and Molecular Genetics; Michelle Winter and Kenneth McCarson of the University of Kansas; Ying He, Zaijie Wang and Xiaoyu Hu of the University of Illinois; Jeffrey Wieskopf and Jeffrey Mogil of McGill University; and Daniel Storm of the University of Washington.

The scientists examined opioid function at sites of pain modulation in the spinal cord. When the opioids act at proteins, they "put the brakes" on the transmission of to the brain. For example, opioids are released when a patient undergoes surgery, a soldier is wounded in battle, or an athlete runs a marathon. Researchers have known for a while that blocking opioid receptors can increase the intensity of acute pain—the pain occurring immediately after injury. But up to this point, scientists had been unsure whether blocking opioids could increase chronic, long-term pain. They began their work with the idea that the opioid system is much more important than previously recognized, with an ability to indefinitely oppose chronic pain. If true, they reasoned, then blocking opioids should increase chronic pain.

This video is not supported by your browser at this time.
In a mouse with a history of injury that later received the opioid receptor antagonist naltrexone (NTX), physical dependence to mu-opioid receptor constitutive activity is manifested as endogenous withdrawal (jumping and paw tremor). Neither vehicle nor naltrexone methobromide (NMB), an opioid receptor blocker that does not cross the blood-brain-barrier, precipitated withdrawal. Credit: Greg Corder and Brad Taylor

To simulate human injury, the researchers produced inflammation, or skin incision, in a mouse model, then waited several weeks for signs of pain-like behaviors to subside. They then administered opioid receptor blockers, effectively halting the pain-relieving actions of the opioid system. When the opioid system (which the authors use the term MORCA, for mu opioid receptor constitutive activity) was blocked, the mice reverted to a set of behaviors associated with the experience of pain. Surprisingly, they also experienced symptoms similar to the known effects of opioid withdrawal in the drug addict: tremor, jumping and shakiness. These results were observed even up to six and a half months after pain had seemingly resolved. The long-lasting nature of the phenomenon suggests that endogenous opioid analgesia silently continues long after an injury has healed.

In other words, long after an acute injury has healed, MORCA continues to "put the brakes" on pain. When MORCAis blocked, the "accelerator" is allowed to run free, and chronic pain reappears.

Because the body appears to develop a reliance on MORCA that parallels the addiction of a synthetic opioid user, and because it is known that stress is a key factor in causing relapse in addicts, it follows that stress may also be a key factor in relapse in chronic pain patients. Thus, the authors speculate that stress could interfere with endogenous MORCA analgesia, leading to the emergence of widespread, rampant such as is observed in a range of conditions, including fibromyalgia.

This research provides some answers to how the body responds to pain, but also raises questions. To return to the "brake and accelerator" metaphor, future studies are needed to better understand the long-term consequences of simultaneously pressing the accelerator and the brake on . In other words, how can we either prevent the "brake pads" from wearing out, or replace them when they do?

More information: "Constitutive ?-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence," by G. Corder et al. Science, 2013.

Related Stories

FDA orders starker warnings on opioid painkillers

Sep 10, 2013

The Food and Drug Administration is requiring stronger warning labels on prescription painkillers like OxyContin, in the government's latest attempt to reduce overdose deaths caused by the long-acting medications.

Safe, long-term opioid therapy is possible

Mar 05, 2013

In a Clinical Crossroads article featured in the March 6, 2013 issue of the Journal of the American Medical Association (JAMA), Dr. Dan Alford from Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) ...

A new promising approach in the therapy of pain

Dec 04, 2012

The treatment of inflammatory pain can be improved by endogenous opioid peptides acting directly in injured tissue. Scientists at the Charité – Universitätsmedizin Berlin and the Université Paris Descartes showed that ...

Recommended for you

Protein in plasma may one day change transfusions

10 hours ago

In injured mice, the naturally occurring protein fibronectin is instrumental in stopping bleeding but interestingly also at preventing life-threatening blood clots – according to new research published ...

User comments