Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines.

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-1beta (IL-1) and tumor necrosis factor-alpha (TNF-alpha)], 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.

Systemic administration of CNI-1493, a p38 mitogen-activated protein kinase inhibitor, blocks intrathecal human immunodeficiency virus-1 gp120-induced enhanced pain states in rats.

Intrathecal administration of the human immunodeficiency virus-1 envelope glycoprotein, gp120, activates astrocytes and microglia to release products that induce thermal hyperalgesia and mechanical allodynia. Both pain states are disrupted by intrathecal CNI-1493, a p38 mitogen-activated protein (MAP) kinase inhibitor. Whether CNI-1493, or any other p38 MAP kinase inhibitor, can cross the blood-brain barrier to affect spinal cord function is unknown. Given that several such drugs are in clinical trials, it is of interest to determine whether they may be potentially useful in treating centrally mediated pain. The aim of the present studies was to determine whether systemic CNI-1493 could block intrathecal gp120-induced thermal hyperalgesia and/or mechanical allodynia. Because p38 MAP kinase inhibition would be expected to prevent proinflammatory cytokine release and/or signal transduction, we sought to determine from the same animals the likely mechanism by which CNI-1493 blocks gp120-induced pain states. These studies show that systemic CNI-1493 blocks intrathecal gp120-induced thermal hyperalgesia and mechanical allodynia. Because CNI-1493 did not block proinflammatory cytokine release, this may suggest disruption at the level of signal transduction. These studies provide the first evidence that systemic p38 MAP kinase inhibitors can prevent centrally mediated exaggerated pain states. Thus, CNI-1493 may provide a novel therapeutic approach for the treatment of pain.

Over five-year follow-up of Oka/Merck varicella vaccine recipients in 465 infants and adolescents.

A total of 465 healthy infants and adolescents ages 12 months to 17 years without a known history of varicella or recent exposure to varicella-zoster virus VZV were immunized with live attenuated Oka/Merck varicella vaccine from November, 1984, through April, 1989. The vaccine administered was from 1 of 7 production lots containing from 950 to 3265 plaque-forming units and was well-tolerated with few side effects. The seroconversion rate for seronegative subjects was 94.6% (403 of 426). This varied by lot from 85% (950 plaque-forming units) to 100% (3010 and 3265 plaque-forming units). Breakthrough disease after exposure to varicella in seroconverters during 5 to 10 years of follow-up was 18.6% (75 of 403). The breakthrough disease was characterized by a maculopapular rash with a median of 35 lesions, most of which were macules. Breakthrough disease lasted a median of 5 days and the median temperature was 99 degrees F; 65.3% (49 of 75) of subjects were afebrile and 2.7% (2 of 75) of subjects had temperatures of > 102.9 degrees F. Varicella vaccine provides excellent (94.6%) seroconversion, and most children who developed breakthrough disease (18.6%) experienced a modified, milder form of illness than has been observed with natural varicella in unvaccinated subjects.