"Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients," says senior author Doctor Yves De Koninck of Université Laval in Quebec City.
The research not only identifies a target pathway to suppress morphine-induced pain but teases apart the pain hypersensitivity caused by morphine from tolerance to morphine, two phenomena previously considered to be caused by the same mechanisms.
"When morphine does not 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," explains co-author Doctor Michael Salter.
"Pain experts have thought tolerance and hypersensitivity (or hyperalgesia) are simply different reflections of the same response," says De Koninck, "but we discovered that cellular and signalling processes for morphine tolerance are very different from those of morphine-induced pain."
Salter adds, "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."
The researchers also identified the molecule responsible for this side effect of morphine. "It is a protein called KCC2, which regulates the transport of chloride ions and the proper control of sensory signals to the brain," explains De Koninck. "Morphine inhibits the activity of this protein, causing abnormal pain perception. By restoring normal KCC2 activity we could potentially prevent pain hypersensitivity." 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, says De Koninck. "Thus, we have the foundation for new strategies to improve the treatment of post-operative as well as chronic pain."
Salter adds, "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."
MEDICA.de; Source: Université Laval