Conditional expression of HIV‐1 tat in the mouse alters the onset and progression of tonic, inflammatory and neuropathic hypersensitivity in a sex‐dependent manner
Deniz Bağdaş, Jason J. Paris, Moriah Carper, Rachel Wodarski, Andrew S.C. Rice, Pamela E. Knapp, Kurt F. Hauser, M. Imad Damaj
Abstract
BACKGROUND: At least one-third of HIV-1-afflicted individuals experience peripheral neuropathy. Although the underlying mechanisms are not known, they may involve neurotoxic HIV-1 proteins. METHODS: in fibrillary acidic protein-expressing glia in the central and peripheral nervous systems. RESULTS: Tat induction significantly attenuated the time spent paw-licking following formalin injection (2.5%, i.pl.) in both male and female mice. However, significant sex differences were observed in the onset and magnitude of inflammation and sensory sensitivity following complete Freund's adjuvant (CFA) injection (10%, i.pl.) after Tat activation. Unlike female mice, male mice showed a significant attenuation of paw swelling and an absence of mechanical/thermal hypersensitivity in response to CFA after Tat induction. Male Tat(+) mice also showed accelerated recovery from chronic constrictive nerve injury (CCI)-induced neuropathic mechanical and thermal hypersensitivity compared to female Tat(+) mice. Morphine (3.2 mg/kg) fully reversed CCI-induced mechanical hypersensitivity in female Tat(-) mice, but not in Tat(+) females. CONCLUSIONS: The ability of Tat to decrease oedema, paw swelling, and limit allodynia suggests a sequel of events in which Tat-induced functional deficits precede the onset of mechanical hypersensitivity. Moreover, HIV-1 Tat attenuated responses to inflammatory and neuropathic insults in a sex-dependent manner. HIV-1 Tat appears to directly contribute to HIV sensory neuropathy and reveals sex differences in HIV responsiveness and/or the underlying peripheral neuroinflammatory and nociceptive mechanisms.