Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

Abstract

Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50 years of age. Unfortunately, patients are required to stay on long-term HAART, which may be causally related to the development of neurological problems such as chronic pain. Little is known about the contribution of HAART or its therapeutic agents to the pathogenesis of pain during aging. In this study, we determined the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on the development of mechanical allodynia and the potential underlying mechanism in aging mice (15.5 months). We found that systemic administration of individual NRTIs, including ddC (2'-3'-dideoxycytidine), ddI (didanosine), AZT (3'-azido-3'-deoxythymidine) and d4T (2', 3'-didehydro-2', 3'-dideoxythymidine), induced allodynia in similar magnitudes and temporal profiles. We used ddC as a representative to investigate cellular and molecular processes induced by NRTIs in the spinal cord that probably underlie the development of allodynia. The results showed that ddC caused evident neuroinflammation in the spinal cord, suggested by the up-regulation of proinflammatory cytokines TNF-α and IL-1β and the reactions of microglia and astrocytes. In addition, we found that Wnt5a, a critical regulator of neuroinflammation, was also up-regulated. Pharmacological inhibition of Wnt5a blocked ddC-induced up-regulation of TNF-α and astrocyte reaction, while activation of Wnt5a signaling potentiated these processes. Furthermore, our data showed that inhibition of Wnt5a significantly reversed ddC-induced mechanical allodynia in aging mice. The results collectively suggest that NRTIs may contribute to the development of chronic pain in aging patients by inducing Wnt5a-regulated neuroinflammation.

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain

“…Treatment with ddC induced mechanical allodynia in mice similar to what has been reported previously in mice treated with different regimens of ddC [17,50,51]. These findings concur with what was observed in studies on patients with HIV-associated neuropathic pain where some patients had mechanical allodynia [52,53].…”

“…This suggests that astrocytes and microglia are not the source of cytokines in the brains of female mice with ddC-induced allodynia. However, in male rodents, ddC was found to induce astrocyte and microglia activation in the spinal cord [17,54,55]. The differences in our findings and these previous studies are possibly due to that we used female rodents, while they used male rodents, and we studied the brain, while they studied the spinal cord.…”

“…Treatment of rats with ddC resulted in increased levels of both transcripts and proteins of TNF-α in the spinal cord and dorsal root ganglion (DRG) neurons at a time point when the rats had developed mechanical allodynia [55]. Aging mice treated with ddC had increased TNF-α and IL-1β proteins in the spinal cord [17]. These studies and our current findings suggest that proinflammatory cytokines both in the periphery and the CNS play a role in the pathophysiology of antiretroviral drug-induced neuropathic pain.…”

Drosophilamodel of Anti-retroviral therapy Induced Peripheral Neuropathy and Nociceptive Hypersensitivity

“…Since anti-retroviral therapy can also lead to the development of mechanical allodynia 31,57 , we asked whether the larvae exposed to NRTI also showed nociceptive hypersensitivity to mechanical stimuli. To perform these assays, we designed and calibrated Von Frey filaments, in house.…”

Influence of Phosphatidylinositol-3-Kinase/Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway on the Neuropathic Pain Complicated by Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection

“…The use of nucleoside reverse transcriptase inhibitors (NRTIs) for high active antiretroviral therapy (HAART) has greatly prolonged the survival time and survival rate of human immunodeficiency virus (HIV)-infected patients. [ 1 ] However, NRTI drug therapy has been shown to lead to peripheral neuropathic pain, which is different from the slow progressive neuropathic pain caused by the HIV infection itself. [ 2 3 ] This neuropathic pain is mainly manifested as a sudden biting and burning pain after approximately 10 weeks of drug treatment and can extend to the upper limbs.…”