HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS) - PubMed (original) (raw)

Comparative Study

. 2004 Aug;110(3):517-530.

doi: 10.1016/j.pain.2004.02.018.

Kevin A O'Connor, Joseph Biedenkapp, Jay Campisi, Julie Wieseler-Frank, Erin D Milligan, Michael K Hansen, Leah Spataro, Elena Maksimova, Courtenay Bravmann, David Martin, Monika Fleshner, Steven F Maier, Linda R Watkins

Affiliations

Comparative Study

HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS)

Adelina Holguin et al. Pain. 2004 Aug.

Abstract

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.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Albright AV, Shieh JT, Itoh T, Lee B, Pleasure D, O'Connor MJ, Doms R, Gonzalez-Scarano F. Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J Virol. 1999;73:205-213.
    1. Andrew PJ, Harant H, Lindley I. Up-regulation of interleukin-1beta-stimulated interleukin-8 in human keratinocytes by nitric oxide. Biochem Pharmacol. 1999;57:1423-1429.
    1. Asensio VC, Maier J, Milner R, Boztug K, Kincaid C, Moulard M, Phillipson C, Lindsley K, Krucker T, Fox HS, Campbell IL. Interferon-independent, human immunodeficiency virus type 1 gp120- mediated induction of CXCL10/IP-10 gene expression by astrocytes in vivo and in vitro. J Virol. 2001;75:7067-7077.
    1. Babbedge RC, Bland-Ward PA, Hart SL, Moore PK. Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br J Pharmacol. 1993;110:225-228.
    1. Bagetta G, Corasaniti MT, Costa N, Berliocchi L, Finazzi-Agro A, Nistico G. The human immunodeficiency virus type 1 (HIV-1) glycoprotein gp120 reduces the expression of neuronal nitric oxide synthase in the hippocampus but not in the cerebral cortex and medial septal nucleus of rat. Neurosci Lett. 1997;224:75-78.

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources