HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS).
It has become clear that spinal cord glia (microglia and astrocytes) importantly contribute to the creation of exaggerated pain responses. One model used to study this is peri-spinal (intrathecal, i.t.) administration of gp120, an envelope protein of HIV-1 known to activate glia. Previous studies demonstrated that i.t. gp120 produces pain facilitation via the release of glial proinflammatory cytokines. The present series of studies tested whether spinal nitric oxide (NO) contributes to i.t. gp120-induced mechanical allodynia and, if so, what effect NO has on spinal proinflammatory cytokines. gp120 stimulation of acutely isolated lumbar dorsal spinal cords released NO as well as proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta (IL1), interleukin-6 (IL6)), thus identifying NO as a candidate mediator of gp120-induced behavioral effects. Behaviorally, identical effects were observed when gp120-induced mechanical allodynia was challenged by i.t. pre-treatment with either a broad-spectrum nitric oxide synthase (NOS) inhibitor (L-NAME) or 7-NINA, a selective inhibitor of NOS type-I (nNOS). Both abolished gp120-induced mechanical allodynia. While the literature pre-dominantly documents that proinflammatory cytokines stimulate the production of NO rather than the reverse, here we show that gp120-induced NO increases proinflammatory cytokine mRNA levels (RT-PCR) and both protein expression and protein release (serial ELISA). Furthermore, gp120 increases mRNA for IL1 converting enzyme and matrix metalloproteinase-9, enzymes responsible for activation and release of proinflammatory cytokines.
Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA Department of Kinesiology and Applied Physiology, and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA Department of Pharmacology, Amgen, Thousand Oaks, CA 91320, USA.
Adelina
A
Holguin
Kevin A
KA
O'Connor
Joseph
J
Biedenkapp
Jay
J
Campisi
Julie
J
Wieseler-Frank
Erin D
ED
Milligan
Michael K
MK
Hansen
Leah
L
Spataro
Elena
E
Maksimova
Courtenay
C
Bravmann
David
D
Martin
Monika
M
Fleshner
Steven F
SF
Maier
Linda R
LR
Watkins
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D010146:Pain / Q000201:enzymology* / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D015699:HIV Envelope Protein gp120; D018836:Inflammation Mediators; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat