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The Journal of Neuroscience, April 15, 2001, 21(8):2808-2819
Intrathecal HIV-1 Envelope Glycoprotein gp120 Induces Enhanced
Pain States Mediated by Spinal Cord Proinflammatory Cytokines
Erin D.
Milligan1,
Kevin A.
O'Connor1,
Kien
T.
Nguyen1,
Charles B.
Armstrong1,
Carin
Twining1,
Ron P. A.
Gaykema1,
Adelina
Holguin1,
David
Martin2,
Steven F.
Maier1, and
Linda R.
Watkins1
1 Department of Psychology and The Center for
Neuroscience, University of Colorado, Boulder, Colorado 80309-0345, and
2 Department of Pharmacology, Amgen, Thousand Oaks,
California 91320
Perispinal (intrathecal) injection of the human
immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120 creates
exaggerated pain states. Decreases in response thresholds to both heat
stimuli (thermal hyperalgesia) and light tactile stimuli (mechanical
allodynia) are rapidly induced after gp120 administration. gp120 is the
portion of HIV-1 that binds to and activates microglia and astrocytes. These glial cells have been proposed to be key mediators of
gp120-induced hyperalgesia and allodynia because these pain changes are
blocked by drugs thought to affect glial function preferentially. The aim of the present series of studies was to determine whether gp120-induced pain changes involve proinflammatory cytokines
[interleukin-1 (IL-1) and tumor necrosis factor-
(TNF-)], substances released from activated glia. IL-1 and TNF
antagonists each prevented gp120-induced pain changes. Intrathecal
gp120 produced time-dependent, site-specific increases in TNF and IL-1
protein release into lumbosacral CSF; parallel cytokine
increases in lumbar dorsal spinal cord were also observed. Intrathecal
administration of fluorocitrate (a glial metabolic inhibitor), TNF
antagonist, and IL-1 antagonist each blocked gp120-induced increases in
spinal IL-1 protein. These results support the concept that activated
glia in dorsal spinal cord can create exaggerated pain states via the
release of proinflammatory cytokines.
Key words:
Hargreaves test; von Frey test; microglia; astrocytes; interleukin-1; tumor necrosis factor; rats; thermal hyperalgesia; mechanical allodynia
Copyright © 2001 Society for Neuroscience 0270-6474/01/2182808-12$05.00/0
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