Analysis of the Risk Factors for Mechanical Allodynia in Herpetic Neuralgia: A Retrospective Cross-Sectional Study.

Purpose: Mechanical allodynia is reportedly common during herpetic neuralgia. The purpose of this study was to establish a risk prediction model to predict the individual risk of allodynia in herpetic neuralgia. Methods: Three hundred and eighty-six patients with trunk herpetic neuralgia were divided into two regions, T2-5 and T6-11. The causality between allodynia and other factors was analyzed by a binary logistic regression model. Results: 42.2% of subjects had allodynia, 137 suffered from dynamic allodynia, and 110 with dynamic allodynia experienced local sweating. The following 5 items as predictors determined this model: local sweating (Odd Ratio = 27.57, P<0.001), lesion location (Odd Ratio=2.46, P =0.017), pain intensity (Odd Ratio=1.38, P =0.020), pain duration (Odd Ratio=0.94, P =0.006), and local scars (Odd Ratio=0.07, P<0.001). The presence and development of allodynia are associated with local sweating. The positive proportion of the Iodine-starch test between the T2-5 (50.0%) with the T6-11 (23.7%) had a statistically significant difference (χ2=5.36, P=0.021). 29.5% of patients at the T2-6 had obvious sweating, which was different from only sticky feelings at the T6-11 (70.5%, χ2=10.88, P=0.001). 19.2% of patients with residual scars and allodynia was significantly lower than 48.5% of patients without allodynia (χ2=15.28, P<0.001). Conclusion: This analysis suggests that local sweating is a concomitant symptom in dynamic allodynia, which imply the sympathetic nerves innervating the sweat glands of the skin were also involved during herpetic neuralgia. This may assist in the evaluation of dynamic allodynia and prove the role of sympathetic nerve intervention for herpetic neuralgia.

BDNF-TrkB signaling pathway-mediated microglial activation induces neuronal KCC2 downregulation contributing to dynamic allodynia following spared nerve injury.

Mechanical allodynia can be evoked by punctate pressure contact with the skin (punctate mechanical allodynia) and dynamic contact stimulation induced by gentle touching of the skin (dynamic mechanical allodynia). Dynamic allodynia is insensitive to morphine treatment and is transmitted through the spinal dorsal horn by a specific neuronal pathway, which is different from that for punctate allodynia, leading to difficulties in clinical treatment. K+-Cl- cotransporter-2 (KCC2) is one of the major determinants of inhibitory efficiency, and the inhibitory system in the spinal cord is important in the regulation of neuropathic pain. The aim of the current study was to determine whether neuronal KCC2 is involved in the induction of dynamic allodynia and to identify underlying spinal mechanisms involved in this process. Dynamic and punctate allodynia were assessed using either von Frey filaments or a paint brush in a spared nerve injury (SNI) mouse model. Our study discovered that the downregulated neuronal membrane KCC2 (mKCC2) in the spinal dorsal horn of SNI mice is closely associated with SNI-induced dynamic allodynia, as the prevention of KCC2 downregulation significantly suppressed the induction of dynamic allodynia. The over activation of microglia in the spinal dorsal horn after SNI was at least one of the triggers in SNI-induced mKCC2 reduction and dynamic allodynia, as these effects were blocked by the inhibition of microglial activation. Finally, the BDNF-TrkB pathway mediated by activated microglial affected SNI-induced dynamic allodynia through neuronal KCC2 downregulation. Overall, our findings revealed that activation of microglia through the BDNF-TrkB pathway affected neuronal KCC2 downregulation, contributing to dynamic allodynia induction in an SNI mouse model.

Microglial Depletion does not Affect the Laterality of Mechanical Allodynia in Mice.

Mechanical allodynia (MA), including punctate and dynamic forms, is a common and debilitating symptom suffered by millions of chronic pain patients. Some peripheral injuries result in the development of bilateral MA, while most injuries usually led to unilateral MA. To date, the control of such laterality remains poorly understood. Here, to study the role of microglia in the control of MA laterality, we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice. Surprisingly, the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA. Moreover, in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aß-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons. Consistent with behavioral results, microglial depletion did not prevent the opening of bilateral gates for Aß pathways in the superficial dorsal horn. This study challenges the role of microglia in the control of MA laterality in mice. Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.

Targeting Peripheral µ-opioid Receptors or µ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance.

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral µ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aß-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aß mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.

Microglial Depletion does not Affect the Laterality of Mechanical Allodynia in Mice / 神经科学通报·英文版

Mechanical allodynia (MA), including punctate and dynamic forms, is a common and debilitating symptom suffered by millions of chronic pain patients. Some peripheral injuries result in the development of bilateral MA, while most injuries usually led to unilateral MA. To date, the control of such laterality remains poorly understood. Here, to study the role of microglia in the control of MA laterality, we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice. Surprisingly, the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA. Moreover, in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons. Consistent with behavioral results, microglial depletion did not prevent the opening of bilateral gates for Aβ pathways in the superficial dorsal horn. This study challenges the role of microglia in the control of MA laterality in mice. Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.

Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance / 神经科学通报·英文版

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.

Low-Dose Interleukin-2 and Regulatory T Cell Treatments Attenuate Punctate and Dynamic Mechanical Allodynia in a Mouse Model of Sciatic Nerve Injury.

PURPOSE: Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known. In the present study, we addressed this knowledge gap by treating mice with low-dose interleukin-2 (ld-IL2) injections or adoptive transfer of Treg cells. METHODS: Female Swiss Webster mice received daily injections of ld-IL2 (1 µg/mouse, intraperitoneally) either before or after unilateral spared nerve injury (SNI). Male C57BL/6J mice received adoptive transfer of 1 x 106 Treg cells 3 weeks post-SNI. The responses to punctate and dynamic mechanical stimuli on the hindpaw were monitored before and up to 4-6 weeks post-SNI. We also compared the distribution of Treg cells and CD3+ total T cells after SNI and/or ld-IL2 treatment. RESULTS: Ld-IL2 pretreatment in female Swiss Webster mice completely blocked the development of SNI-induced dynamic mechanical allodynia and reduced the magnitude of punctate allodynia. Delayed ld-IL2 treatment in female mice significantly attenuated the morphine-resistant punctate and dynamic allodynia at 3-5 weeks post-SNI. Adoptive transfer of Treg cells to male C57BL/6J mice 3 weeks post-SNI effectively reversed the persistent punctate and dynamic allodynia, supporting that the effect of ld-IL2 is mediated through endogenous Treg cells, and is likely independent of mouse strain and sex. Neither ld-IL2 treatment nor Treg transfer affected the basal responses to punctate or brush stimuli. Ld-IL2 significantly increased the frequency of Treg cells among total CD3+ T cells in the injured sciatic nerves but not in the uninjured nerves or the dorsal root ganglia, suggesting the injured nerve as ld-IL2's site of action. CONCLUSION: Collectively, results from the present study supports Treg as a cellular target and ld-IL2 as a potential therapeutic option for nerve injury-induced persistent punctate and dynamic mechanical allodynia.

Memantine selectively prevented the induction of dynamic allodynia by blocking Kir2.1 channel and inhibiting the activation of microglia in spinal dorsal horn of mice in spared nerve injury model.

BACKGROUND: Memantine is one of the important clinical medications in treating moderate to severe Alzheimer disease. The effect of memantine on preventing or treating punctate allodynia has been thoroughly studied but not on the induction of dynamic allodynia. The aim of this study is to investigate whether memantine could prevent the induction of dynamic allodynia and its underlying spinal mechanisms. RESULTS: (1) In in vivo spared nerve injury pain model, pretreatment with memantine at a lower dose (10 nmol, intrathecal; memantine-10) selectively prevented the induction of dynamic allodynia but not the punctate allodynia. (2) Pretreatment with either MK801-10 (MK801-10 nmol, intrathecal) or higher dose of memantine (30 nmol, intrathecal; memantine-30) prevented the induction of both dynamic and punctate allodynia. (3) Memantine-10 showed significant effect on the inhibition of the spared nerve injury-induced overactivation of microglia in spinal dorsal horn. (4) In contrast, in complete freund's adjuvant (CFA) model, memantine-10 neither affected the CFA injection-induced activation of microglia in spinal dorsal horn nor the induction of dynamic allodynia. (5) Immunohistological studies showed Kir2.1 channel distributed widely and co-localized with microglia in the spinal dorsal horn of mice. (6) Pretreatment with either minocycline, a microglia inhibitor, or ML133, a Kir2.1 inhibitor, both selectively prevented the overactivation of microglia in spinal dorsal horn and the induction of dynamic allodynia following spared nerve injury. CONCLUSION: The selective inhibitory effect on the induction of dynamic allodynia in spared nerve injury model by low dose of the memantine (memantine-10) was tightly correlated with the blockade of microglia Kir2.1 channel to suppress the microglia activation.

Kir2.1 Channel Regulation of Glycinergic Transmission Selectively Contributes to Dynamic Mechanical Allodynia in a Mouse Model of Spared Nerve Injury.

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABAA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.

Kir2.1 Channel Regulation of Glycinergic Transmission Selectively Contributes to Dynamic Mechanical Allodynia in a Mouse Model of Spared Nerve Injury / 神经科学通报·英文版

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.