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1.
Pain ; 156(7): 1311-1319, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25840108

ABSTRACT

Pathological pain is one of the most common neurological complications in patients with HIV-1/AIDS. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is upregulated in the spinal cord dorsal horn (SDH) of the patients with HIV who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly upregulates Wnt5a in the mouse SDH. Using a mouse model, we show here that a specific Wnt5a antagonist, Box-5, attenuated gp120-induced mechanical allodynia. Conversely, a Wnt5a agonist, Foxy5, facilitated the allodynia. To elucidate the molecular mechanism by which Wnt5a regulates gp120-induced allodynia, we tested the role of the JNK/TNF-α pathway. We observed that the JNK-specific inhibitor SP600125 blocked either gp120- or Foxy5-induced allodynia. Similarly, the TNF-α-specific antagonist Enbrel also reversed either gp120- or Foxy5-induced allodynia. These data suggest that JNK and TNF-α mediate the biological effects of Wnt5a in regulating gp120-induced allodynia. To investigate the cellular mechanism, we performed extracellular single-unit recording from SDH neurons in anesthetized mice. Both Box-5 and SP600125 negated gp120-induced potentiation of SDH neuron spiking evoked by mechanical stimulation of the hind paw. Furthermore, while Foxy5 potentiated spike frequency of SDH neurons, either SP600125 or Enbrel blocked the potentiation. The data indicate that Wnt5a potentiates the activity of SDH neurons through the JNK-TNF-α pathway. Collectively, our findings suggest that Wnt5a regulates the pathogenesis of gp120-induced pain, likely by sensitizing pain-processing SDH neurons through JNK/TNF-α signaling.


Subject(s)
HIV Envelope Protein gp120/toxicity , Pain/chemically induced , Pain/metabolism , Signal Transduction/physiology , Wnt Proteins/metabolism , Animals , HIV Envelope Protein gp120/administration & dosage , Injections, Spinal , Mice , Mice, Inbred C57BL , Pain Measurement/drug effects , Pain Measurement/methods , Signal Transduction/drug effects , Wnt Proteins/agonists , Wnt Proteins/antagonists & inhibitors , Wnt-5a Protein
2.
Ann Neurol ; 75(6): 837-50, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24633867

ABSTRACT

OBJECTIVE: Chronic pain is a common neurological comorbidity of human immunodeficiency virus (HIV)-1 infection, but the etiological cause remains elusive. The objective of this study was to identify the HIV-1 causal factor that critically contributes to the pathogenesis of HIV-associated pain. METHODS: We first compared the levels of HIV-1 proteins in postmortem tissues of the spinal cord dorsal horn (SDH) from HIV-1/acquired immunodeficiency syndrome patients who developed chronic pain (pain-positive HIV-1 patients) and HIV-1 patients who did not develop chronic pain (pain-negative HIV-1 patients). Then we used the HIV-1 protein that was specifically increased in the pain-positive patients to generate mouse models. Finally, we performed comparative analyses on the pathological changes in the models and the HIV-1 patients. RESULTS: We found that HIV-1 gp120 was significantly higher in pain-positive HIV-1 patients (vs pain-negative HIV-1 patients). This finding suggested that gp120 was a potential causal factor of the HIV-associated pain. To test this hypothesis, we used a mouse model generated by intrathecal injection of gp120 and compared the pathologies of the model and the pain-positive human HIV-1 patients. The results showed that the mouse model and pain-positive human HIV-1 patients developed extensive similarities in their pathological phenotypes, including pain behaviors, peripheral neuropathy, glial reactivation, synapse degeneration, and aberrant activation of pain-related signaling pathways in the SDH. INTERPRETATION: Our findings suggest that gp120 may critically contribute to the pathogenesis of HIV-associated pain.


Subject(s)
HIV Envelope Protein gp120/metabolism , HIV Infections/complications , Pain/etiology , Pain/metabolism , Adult , Animals , Case-Control Studies , Disease Models, Animal , Female , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , HIV Envelope Protein gp120/genetics , Humans , Hyperalgesia/virology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pain/virology , Pain Threshold , Peripheral Nervous System Diseases/etiology , Peripheral Nervous System Diseases/virology , Rats , Rats, Sprague-Dawley , Signal Transduction/physiology , Spinal Cord/pathology , Viral Load
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