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The Journal of Neuroscience, November 15, 2002, 22(22):9980-9989
The Role of Spinal Neuroimmune Activation in Morphine
Tolerance/Hyperalgesia in Neuropathic and Sham-Operated Rats
Vasudeva
Raghavendra1,
Maria D.
Rutkowski1, and
Joyce A.
DeLeo1, 2
Departments of 1 Anesthesiology and
2 Pharmacology, Dartmouth Hitchcock Medical Center,
Lebanon, New Hampshire 03756
Hypersensitivity resulting from nerve injury or morphine
tolerance/hyperalgesia is predicted to involve similar cellular and molecular mechanisms. One expected but incompletely explored mechanism is the activation of central neuroimmune responses associated with
these conditions. To begin to address this, we undertook three separate
studies: First, we determined the acute antinociceptive action of
morphine, the rate of development of opioid tolerance, and
withdrawal-induced hyperalgesia/allodynia in nerve-injured and
sham-operated rats using noxious (thermal and mechanical) and
non-noxious (mechanical allodynia) behavioral paradigms. Second, we
investigated the impact of chronic morphine treatment on spinal glial
activation and cytokine expression after L5 spinal nerve transection or
sham surgery. Third, we examined the consequences of spinal
administration of cytokine inhibitors on the development of morphine
tolerance and morphine withdrawal-induced hyperalgesia and allodynia.
Results demonstrated that after nerve injury, the antinociceptive
effect of acute morphine was significantly decreased, and the rate of
development of tolerance and opioid withdrawal-induced hyperalgesia/allodynia was significantly enhanced compared with that
after sham surgery. Chronic administration of morphine to sham-operated
rats activated spinal glia and upregulated proinflammatory cytokines
[interleukin (IL)-1 , IL-6, and tumor necrosis factor- ]. This
neuroimmune activation was further enhanced in nerve-injured rats after
chronic morphine treatment. Spinal inhibition of proinflammatory cytokines restored acute morphine antinociception in nerve-injured rats
and also significantly reversed the development of morphine tolerance
and withdrawal-induced hyperalgesia and allodynia in nerve-injured or
sham-operated rats. Targeting central cytokine production and glial
activation may improve the effectiveness of morphine and reduce the
incidence of morphine withdrawal-induced hyperalgesia and allodynia in
neuropathic pain conditions.
Key words:
neuropathy; morphine tolerance; hyperalgesia; glia; interleukin-1; interleukin-6; tumor necrosis factor-
Copyright © 2002 Society for Neuroscience 0270-6474/02/22229980-10$05.00/0
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