Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain statesmediated by spinal cord proinflammatory cytokines

Perispinal (intrathecal) injection of the human immunodeficiency virus-1 (H IV-1) envelope glycoprotein gp120 creates exaggerated pain states. Decrease s in response thresholds to both heat stimuli (thermal hyperalgesia) and li ght tactile stimuli (mechanical allodynia) are rapidly induced after gp120 administration. gp120 is the portion of HIV-1 that binds to and activates m icroglia and astrocytes. These glial cells have been proposed to be key med iators of gp120-induced hyperalgesia and allodynia because these pain chang es are blocked by drugs thought to affect glial function preferentially The aim of the present series of studies was to determine whether gp120-induce d pain changes involve proinflammatory cytokines [interleukin-1 beta (IL-1) and tumor necrosis factor-alpha (TNF-alpha)], substances released from act ivated glia. IL-1 and TNF antagonists each prevented gp120-induced pain cha nges. Intrathecal gp120 produced time-dependent, site-specific increases in TNF and IL-1 protein release into lumbosacral CSF; parallel cytokine incre ases in lumbar dorsal spinal cord were also observed. Intrathecal administr ation of fluorocitrate (a glial metabolic inhibitor), TNF antagonist, and I L-1 antagonist each blocked gp120-induced increases in spinal IL-1 protein. These results support the concept that activated glia in dorsal spinal cor d can create exaggerated pain states via the release of proinflammatory cyt okines.