Researchers Learn About Pain From Morphine FailuresMorphine is often the last resort to relieve intractable pain; however, for some unfortunate individuals the medication actually causes more pain.

A new study, found on the online edition of Nature Neuroscience, provides hope to adults and children whose pain gets worse when treated with morphine.

“Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients,” said senior author Dr. Yves De Koninck, professor at Université Laval in Quebec City in Canada.

Investigators say they have identified a target pathway to suppress morphine-induced pain; moreover, they also believe they now understand how pain hypersensitivity is caused by tolerance to morphine.

“When morphine doesn’t reduce pain adequately the tendency is to increase the dosage. If a higher dosage produces pain relief, this is the classic picture of morphine tolerance, which is very well known. But sometimes increasing the morphine can, paradoxically, makes the pain worse,” said co-author Dr. Michael Salter.

“Pain experts have thought tolerance and hypersensitivity (or hyperalgesia) are simply different reflections of the same response,” De Koninck said, “but we discovered that cellular and signaling processes for morphine tolerance are very different from those of morphine-induced pain.”

Salter added, “We identified specialized cells — known as microglia — in the spinal cord as the culprit behind morphine-induced pain hypersensitivity. When morphine acts on certain receptors in microglia, it triggers the cascade of events that ultimately increase, rather than decrease, activity of the pain-transmitting nerve cells.”

In the study, investigators also identified the molecule responsible for this side effect of morphine. “It’s a protein called KCC2, which regulates the transport of chloride ions and the proper control of sensory signals to the brain,” said De Koninck.

“Morphine inhibits the activity of this protein, causing abnormal pain perception. By restoring normal KCC2 activity we could potentially prevent pain hypersensitivity.”

As a consequence of this finding, De Koninck and researchers at Université Laval are testing new molecules capable of preserving KCC2 functions and thus preventing hyperalgesia.

The KCC2 pathway appears to apply to short-term as well as to long-term morphine administration, said De Koninck. “Thus, we have the foundation for new strategies to improve the treatment of post-operative as well as chronic pain.”

Said Salter, “Our discovery could have a major impact on individuals with various types of intractable pain, such as that associated with cancer or nerve damage, who have stopped morphine or other opiate medications because of pain hypersensitivity.”

Medical authorities call pain a silent epidemic, afflicting tens of millions of people worldwide. Pain has a profound negative effect on the quality of human life.

Pain affects nearly all aspects of human existence, with untreated or under-treated pain being the most common cause of disability.

“People with incapacitating pain may be left with no alternatives when our most powerful medications intensify their suffering,” says Dr. De Koninck.

Said Salter, “Pain interferes with many aspects of an individual’s life. Too often, patients with chronic pain feel abandoned and stigmatized. Among the many burdens on individuals and their families, chronic pain is linked to increased risk of suicide. The burden of chronic pain affects children and teens as well as adults.”

These risks affect individuals with many types of pain, ranging from migraine and carpel-tunnel syndrome to cancer, AIDS, diabetes, traumatic injuries, Parkinson’s disease and dozens of other conditions.

Source: Université Laval