Opioid use for pain management has dramatically
increased, with little assessment of potential
pathophysiological consequences for the primary pain
condition. Here, a short course of morphine,
starting 10 d after injury in male rats,
paradoxically and remarkably doubled the duration of
chronic constriction injury (CCI)-allodynia, months
after morphine ceased.
Pain can help protect the body after an injury or
infection. It serves as a warning system to rest or
avoid certain activities. But pain may become
chronic when nerve cells that detect something
harmful alter the electrical or molecular signals
they send to the spinal cord. This can trigger the
production of chemicals in spinal cord neurons that
make pain persist beyond the healing period.
Opioids, such as morphine, are often used to treat
pain from a nervous system injury. These drugs
activate opioid receptors and mimic the effects of
natural chemicals produced by the body that both
inhibit pain signals and produce a euphoric feeling.
To investigate the long-term effects of using
opioids for pain relief, a team led by Drs. Peter
Grace and Linda Watkins at the University of
Colorado, Boulder, studied morphine treatment in
rats with nerve injuries. The research was funded in
part by NIH’s National Institute of Drug Abuse (NIDA)
and other NIH Institutes. Results were published on
June 14, 2016, in the Proceedings of the National
Academy of Sciences.
After a nerve injury, a non-painful stimulus, such
as a light touch, can cause pain or an unpleasant
sensation. The researchers tested rats for increased
sensitivity to non-painful stimulation following a
sciatic nerve injury or sham surgery. Rats were
treated with either morphine or saline twice a day
for 5 days beginning 10 days after surgery. Those
with a nerve injury were more sensitive to touch on
their hindpaws than the sham controls. Injured rats
treated with morphine were sensitive for longer and
to a higher degree; lighter touches caused them to
withdraw their paws from the stimulus more often
than saline-treated animals.
Experiments showed that the morphine-induced
sensitivity wasn’t mediated through opioid
receptors. Morphine is also known to activate
inflammation-inducing molecules, called cytokines.
Blocking cytokine IL-1ß or associated cytokines
prevented the prolonged sensitivity when given with
the morphine treatment. When delivered after
morphine treatment, cytokine inhibition dampened the
prolonged sensitivity.
Cytokine IL-1ß’s activity is regulated by a
molecular complex called the inflammasome, which
helps trigger the inflammatory process in immune
cells. Rats with the morphine-induced sensitivity
showed increased expression of inflammasomes within
specialized central nervous system immune cells
called microglia. Experiments revealed that the
morphine-induced pain sensitivity depended on the
activation of an inflammasome protein called NLRP3
in microglia. These results suggest that interfering
with the cytokine pathway could prevent opioid-induced
prolonged chronic pain without hindering the
painkilling properties.
“We are showing for the first time that even a brief
exposure to opioids can have long-term negative
effects on pain,” Grace says. “We found the
treatment was contributing to the problem.” Future
studies will be needed to confirm whether these
effects have clinical relevance.
See ALSO
Can antidepressant drugs worsen the long term course
of depression? (06/10/2011)
Link...
For more information
Morphine paradoxically prolongs neuropathic pain in
rats by amplifying spinal NLRP3 inflammasome
activation.
Grace PM, Strand KA, Galer EL, Urban DJ, Wang X,
Baratta MV, Fabisiak TJ, Anderson ND, Cheng K,
Greene LI, Berkelhammer D, Zhang Y, Ellis AL, Yin HH,
Campeau S, Rice KC, Roth BL, Maier SF, Watkins LR.
Proc Natl Acad Sci U S A. 2016 Jun
14;113(24):E3441-50.
doi: 10.1073/pnas.1602070113. Epub 2016 May 31. PMID:
27247388.
Link...
U.S. National Institutes of Health NIH
Link...
MDN |