For individuals with agonizing pain, it is a cruel
blow when the gold-standard medication actually
causes more pain. Adults and children whose pain
gets worse when treated with morphine may be closer
to a solution, based on research published in the
January 6 on-line edition of Nature Neuroscience.
Papaver somniferum, Opium poppy at Chatsworth House, UK
“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 Dr. Yves De
Koninck, Professor at Université Laval in Quebec
City. The team included researchers from The
Hospital for Sick Children (SickKids) in Toronto,
the Institut universitaire en santé mentale de
Québec, the US and Italy.
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 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,” explains
co-author Dr. Michael Salter. Dr. Salter is Senior
Scientist and Head of Neurosciences & Mental Health
at SickKids, Professor of Physiology at University
of Toronto, and Canada Research Chair in
Neuroplasticity and Pain.
“Pain experts have thought tolerance and
hypersensitivity (or hyperalgesia) are simply
different reflections of the same response,” says
Dr. De Koninck, “but we discovered that cellular and
signalling processes for morphine tolerance are very
different from those of morphine-induced pain.”
Dr. 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’s
a protein called KCC2, which regulates the transport
of chloride ions and the proper control of sensory
signals to the brain,” explains Dr. De Koninck.
“Morphine inhibits the activity of this protein,
causing abnormal pain perception. By restoring
normal KCC2 activity we could potentially prevent
pain hypersensitivity.” Dr. 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
Dr. De Koninck. “Thus, we have the foundation for
new strategies to improve the treatment of
post-operative as well as chronic pain.”
Dr. 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.”
Pain has been labelled the silent health crisis,
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. The
Canadian Pain Society estimates that chronic pain
affects at least one in five Canadians and costs
Canada $55-60 billion per year, including health
care expenses and lost productivity.
“People with incapacitating pain may be left with no
alternatives when our most powerful medications
intensify their suffering,” says Dr. De Koninck, who
is also Director of Cellular and Molecular
Neuroscience at Institut universitaire en santé
mentale de Québec.
Dr. Salter adds, “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.
Canadian funding for this international research
included Canadian Institutes for Health Research,
Krembil Foundation, Ontario Research Fund Research
Excellence Program, Fonds de la recherche en santé
du Québec, Canada Research Chair funding, The Anne
and Max Tanenbaum Chair Program, SickKids Foundation,
and Université Laval.
For more information
Nature Neuroscience
Université Laval
(MDN)
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