Fig 1.
Various virus-induced neuropathic pain model.
(Blue part) The HNP model can be established by intrathecal injection of gp120. Mice are administered gp120 intrathecally (5 μl, 20 ng/μl) on days 0, 3, and 7 [38]. One to 2 h postinjection, the mechanical withdrawal threshold and thermal withdrawal latency are significantly reduced, and the symptoms can persist for 21 days. This mouse model shares many similarities in pathological manifestations with pain in HIV-1–positive patients, such as pain behaviors, peripheral nerve lesions, activation of glial cells, synaptic degeneration, and abnormal activation of spinal dorsal horn pain-related signaling pathways. And the peripheral injury model can also be established by loosely wrapping oxidized regenerated cellulose around the sciatic nerve and soaking it in physiological saline containing 200 ng of gp120 [9]. Mechanical and thermal hyperalgesia can persist for more than 2 weeks. Conditional HIV-1 Tat transgenic mice, given doxycycline at 100 mg/kg per day intraperitoneally for 14 days, can conditionally induce Tat protein expression in the central nervous system to establish a model [8]. The HIV-1 Tg model can mimic defects observed in patients, such as changes in the nervous and immune systems, while also observing sensitization of pain-related behaviors [39]. Some antiretroviral drugs, especially those with higher mitochondrial toxicity, may affect the normal function of nerve cells. Continuous intraperitoneal injections of dideoxycytidine (ddc) (25 mg/kg) in mice for 5 days can induce mechanical stimulus sensitization, with no difference observed in sensitivity to heat or cold stimuli [40]. In HNP model, gp120 was intrathecally injected into mice on days 0, 3, 5, 11, and 16. Morphine was repeatedly injected into gp120 mice at a dose equivalent to the high end of clinical application (intraperitoneal, 20 mg/kg) on the same day [41]. (Yellow part) Since VZV cannot directly infect rodents, researchers have established models by inoculating African green monkey kidney fibroblast solutions infected with VZV or clinical patients’ herpes content into the toes or subcutaneous tissue of rats, leading to the onset of mechanical and thermal hypersensitivity after a certain period of infection [42]. Similarly, symptoms of trigeminal zoster can be simulated by injecting VZV-infected cells into the whisker pads [43]. Percutaneous inoculation of HSV-1 can induces herpes zoster-like skin lesions in mice [44]. When HSV-1 is locally inoculated into the hind limbs (tibia or femur), a small number of vesicles appear on the dorsal surface of the animals on the fifth day postinoculation, followed by herpes zoster-like skin lesions on days 6–10 postinoculation, which almost disappear by day 20. (Yellow part) Researchers inoculated 2–3-month-old hamsters with 100 μl of PBS containing 1,000 plaque-forming units (PFUs) of SARS-CoV-2 and 100,000 PFUs of IAV via intranasal route [34]. Within the first 24 h of nasal viral infection, SARS-CoV-2 transcripts were detected in the cervical, thoracic spinal cord, and DRGs. (Green part) Additionally, SARS-CoV-2–infected hamsters exhibited mechanical allodynia for approximately 1 month. Moreover, transcriptional characteristics closely resembled those of models of persistent inflammation and nerve damage [45]. Figure was produced using BioRender (IB26ZAQP1X).
Fig 2.
Potential molecular mechanisms in HNP models.
Under the stimulation of gp120/NRTIs, the expression of various molecules/receptors changes, leading to neuroinflammation, glial cell proliferation, and neuronal damage, ultimately resulting in neuropathic pain. (A) In spinal cord. The expression levels of Wnt3a and β-catenin increased in microglia, thereby regulating the expression of BDNF and impacting hypersensitivity. HIV-1 gp120 induces synaptic degeneration in the spinal pain neural circuit by activating microglia via Wnt3a/β-catenin–regulated FKN expression in neurons. Gp120 also regulates astrogliosis, which promotes the expression of hyperalgesia and neuropathic pain through a Wnt5a-ROR2-MMP2 axis. Administration of ddC up-regulates NF-M and pNF-H proteins, while HuD competitively inhibits the increase in pNF-H levels by binding to BDNF mRNA. (B) In DRG. Gp120 increased P2X7 expression, IL-1β and TNF-α levels, ERK1/2 phosphorylation levels, and also enhanced IL-10 expression in the SGCs and neuron. Schwann cell-derived CXCL1, secreted in response to gp120 exposure, is responsible for macrophage infiltration. In the DRG and spinal dorsal horn, administration of gp120 induces up-regulation of TNF-α, CXCR4, and SDF1α. TNF can regulate CXCR4 expression through SDF1. HIV gp120 induces glial cell activation, leading to the release of TNF-α. TNF binds to its receptor TNFR on neurons, causing an increase in mitochondrial ROS, which can activate various other cellular signaling pathways. Mitochondria also participate in the regulation of cellular Ca2+ homeostasis. BNDF, brain-derived neurotrophic factor; MMP2, matrix metalloproteinase 2; ROR2, receptor tyrosine kinase-like orphan receptor 2; NRTIs, nucleoside reverse transcriptase inhibitors; CX3CR1, CX3C chemokine receptor 1; TNFR, tumor necrosis factor receptor; CXCR4, C-X-C chemokine receptor type 4; NMDA, N-Methyl-D-Aspartate; BRD4, bromodomain-containing protein 4; SDF1, stromal-derived factor 1; Ca2+, calcium ions; ROS, reactive oxygen species; JNK, c-Jun N-terminal kinase; PKC, protein kinase C; HuD, human antigen D; NF-H, neurofilament heavy chain. Figure was produced using BioRender (IB26ZAQP1X).
Fig 3.
Potential molecular mechanisms in PHN models.
Upon stimulation by HSV-1/VZV infected cells, alterations occur in the expression of various molecules/receptors, culminating in neuroinflammation, glial cell proliferation, and neuronal damage, ultimately giving rise to neuropathic pain. (A) In spinal cord. HSV-1 is rapidly recognized by astrocytic cGAS, leading to self-activation of cGAS, thereby inducing the synthesis of cGAMP. Subsequently, cGAMP binds to STING, resulting in the phosphorylation of TBK1, which in turn stimulates the phosphorylation and nuclear translocation of IRF3, thereby promoting the transcription and production of IFN-I. Prmt6 mediates STING inactivation through methylation, reducing the phosphorylation of TBK1 and IRF3, resulting in the inhibition of IFN-I production and antiviral innate immunity. KCNA2-AS participates in PHN partly by enhancing the translocation of pSTAT3 from the cytoplasm to the nucleus and promoting the activation of spinal astrocytes. The P2X7 receptor antagonist BBG mitigates PHN by triggering ER stress activation and diminishing pyroptosis. NOS2 and NOS1 are responsible for herpetic and postherpetic allodynia. (B) In DRG. The production of TNF, mediated by TNF/TNFR1 signaling in SGCs, down-regulates the expression of potassium channels, indirectly enhancing the excitability of primary sensory neurons and ultimately leading to the development of herpetic neuralgia. Similarly, in PHN models, alterations in the expression of receptors such as TRPV1, sodium ion channels, calcium ion channels, and TLR4 can induce changes in the excitability of DRG neurons, leading to persistent pain. cGAS, cyclic GMP-AMP synthase; cGAMP, cyclic GMP-AMP; STING, stimulator of interferon genes; Prmt6, protein arginine methyltransferase 6; TBK1, TANK-binding kinase 1; IRF3, interferon regulatory factor 3; STAT3, signal transducer and activator of transcription 3; KCNA2, potassium voltage-gated channel subfamily A member 2; P2X7, P2X purinoceptor 7; CCR5, C-C chemokine receptor type 5; CCL5, C-C motif chemokine ligand 5; NMDA: N-Methyl-D-Aspartate; NOS1/2, nitric oxide synthase 1/2; SGCs, satellite glial cells; TNFR, tumor necrosis factor receptor; PAQR, progestin and AdipoQ receptor; TrKA, tropomyosin receptor kinase A; TRPV1, transient receptor potential vanilloid 1; Na+, sodium ion; Ca2+, calcium ion; TLR4, toll-like receptor 4; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B. Figure was produced using BioRender (PK26ZAQEIO).