Scientists find why morphine increases pain in some people

Scientists have discovered a molecular pathway by which morphine, a common painkiller, actually increases pain in some individuals. "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 Universite Laval in Quebec City.

The team included researchers from The Hospital for Sick Children (SickKids) in Toronto, the Institut universitaire en sante mentale de Quebec, the US and Italy. The research not only identifies a target pathway to suppress morphine-induced pain but tears apart the pain hypersensitivity caused by morphine from tolerance to morphine, two phenomena previously considered to be caused by the same mechanisms.

"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, make the pain worse," explained co-author Dr Michael Salter.

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

"We identified specialised 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," Salter added.

The researchers 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," explained Koninck. "Morphine inhibits the activity of this protein, causing abnormal pain perception. By restoring normal KCC2 activity we could potentially prevent pain hypersensitivity," Koninck said in a statement.

The KCC2 pathway appears to apply to short-term as well as to long-term morphine administration, said Koninck. "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," Salter said. The study was published in the journal Nature Neuroscience.