Allodynia in rats infected with varicella zoster virus—a small animal model for post-herpetic neuralgia

The most common complication of herpes zoster is post-herpetic neuralgia (PHN), which has been defined as severe pain occurring 1 month after rash onset or persisting for greater than 3 months. PHN is classed as a neuropathic pain that is associated with mechanical allodynia where normally innocuous tactile stimuli are perceived as painful. The development of therapies to treat PHN has been hampered by the lack of animal models, which mimic the clinical situation. We have previously reported that varicella zoster virus (VZV) infection in the rat results in mechanical allodynia and thermal hyperalgesia. Here, we report that following VZV infection of the left footpad rats develop a chronic mechanical allodynia, which is present for longer than 60 days post-infection and which resolves by 100 days PI. The model is robust and reproducible with animals consistently developing allodynia by 3 days PI and continuing to present with symptoms for at least 30 days. The reproducible nature of the induction and course of the allodynia allows the use of this model to determine the effect of various compounds on, and to investigate the pathogenic mechanisms underlying the development of VZV-induced allodynia. Comparative studies using HSV-1 show that the induction of the chronic allodynia is VZV-specific and is not a result is of virus replication-induced tissue damage or accompanying inflammation.Therefore, we propose that the rat VZV infection model could prove useful in studying the mechanisms underlying post-herpetic neuralgia.     

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.     

Possible involvement of oxido-nitrosative stress induced neuro-inflammatory cascade and monoaminergic pathway: Underpinning the correlation between nociceptive and depressive behaviour in a rodent model

Background

Pain and depression are frequent co-morbid disorders. The prevalence rate of depression is several times higher in patients with chronic pain than in the general population but the mechanism underlying this association is unknown. A combination of interactions between neurotransmitters, neuropeptides, oxidative and nitrosative stress and cytokines are thought to take part in pathogenesis of pain as well as depression. Thus, the aim of the present study was two-fold, first to investigate the interplay between nociception and associated depression and second to investigate the protective potential of berberine against the reserpine-induced nociceptive and depressive behaviour and further to explore the role of oxidative–nitrosative stress mediated inflammatory cascade and apoptotic signalling pathway in this dyad.

Methods and results

Nociception and associated depression were induced by administration of reserpine (1 mg/kg subcutaneous daily) for three consecutive days. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, oxidative–nitrosative stress, inflammatory cytokines, NF-κβ and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats.

Limitation

More studies are still warranted in similar rodent models of pain and depression, so, that the present findings can be further substantiated to establish the clinical effectiveness of berberine in a subset of patients suffering from pain as well as depression.

Conclusion

The findings from the current study suggested that reserpine-induced neurochemical alterations and dysregulation of oxidative–nitrosative stress induced inflammatory cascade underlies the co-morbidity of nociceptive behaviour and associated depression in rats.     

Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice

The reactivity of microglia within the spinal cord in response to nerve injury, has been associated with the development and maintenance of neuropathic pain. However, the temporal changes in microglial reactivity following nerve injury remains to be defined. Importantly, the magnitude of behavioural allodynia displayed and the relationship to the phenotypic microglial changes is also unexplored. Using a heterozygous CX₃CR₁ ^gfp+ transgenic mouse strain, we monitored microglial activity as measured by cell density, morphology, process movement and process length over 14 days following chronic constriction of the sciatic nerve via in vivo confocal microscopy. Uniquely this relationship was explored in groups of male mice which had graded nerve injury and associated graded behavioural mechanical nociceptive sensitivity. Significant mechanical allodynia was quantified from the ipsilateral hind paw and this interacted with the extent of nerve injury from day 5 to day 14 (p < 0.009). The extent of this ipsilateral allodynia was proportional to the nerve injury from day 5 to 14 (Spearman rho = −0.58 to −0.77; p < 0.002). This approach allowed for the assessment of the association of spinal microglial changes with the magnitude of the mechanical sensitivity quantified behaviourally. Additionally, the haemodynamic response in the somatosensory cortex was quantified as a surrogate measure of neuronal activity. We found that spinal dorsal horn microglia underwent changes unilateral to the injury in density (Spearman rho = 0.47; p = 0.01), velocity (Spearman rho = −0.68; p = 0.00009), and circularity (Spearman rho = 0.55; p = 0.01) proportional to the degree of the neuronal injury. Importantly, these data demonstrate for the first time that the mechanical allodynia behaviour is not a binary all or nothing state, and that microglial reactivity change proportional to this behavioural measurement. Increased total haemoglobin levels in the somatosensory cortex of higher-grade injured animals was observed when compared to sham controls suggesting increased neuronal activity in this brain region. The degree of phenotypic microglial changes quantified here, may explain how microglia can induce both rapid onset and sustained functional changes in the spinal cord dorsal horn, following peripheral injury.     

Intrathecal Gabapentin Increases Interleukin-10 Expression and Inhibits Pro-Inflammatory Cytokine in a Rat Model of Neuropathic Pain

We examined the possible anti-inflammatory mechanisms of gabapentin in the attenuation of neuropathic pain and the interaction between the anti-allodynic effects of gabapentin and interleukin-10 (IL-10) expression in a rat model of neuropathic pain. The anti-allodynic effect of intrathecal gabapentin was examined over a 7-day period. The anti-allodynic effects of IL-10 was measured, and the effects of anti-IL-10 antibody on the gabapentin were assessed. On day 7, the concentrations of pro-inflammatory cytokines and IL-10 were measured. Gabapentin produced an anti-allodynic effect over the 7-day period, reducing the expression of pro-inflammatory cytokines but increasing the expression of IL-10 (TNF-α, 316.0 ± 69.7 pg/mL vs 88.8 ± 24.4 pg/mL; IL-1β, 1,212.9 ± 104.5 vs 577.4 ± 97.1 pg/mL; IL-6, 254.0 ± 64.8 pg/mL vs 125.5 ± 44.1 pg/mL; IL-10, 532.1 ± 78.7 pg/mL vs 918.9 ± 63.1 pg/mL). The suppressive effect of gabapentin on pro-inflammatory cytokine expression was partially blocked by the anti-IL-10 antibody. Expression of pro-inflammatory cytokines was significantly attenuated by daily injections of IL-10. The anti-allodynic effects of gabapentin may be caused by upregulation of IL-10 expression in the spinal cord, which leads to inhibition of the expression of pro-inflammatory cytokines in the spinal cords.     

Decline in attentional inhibition among migraine patients: an event‐related potential study using the Stroop task

BackgroundAs a disorder of brain dysfunction, migraine has been associated with cognitive decline. However, no consistent results with respect to the attention function in migraineurs have been found, and the relationship between attentional inhibition and migraine is also unclear. In this study, the attentional inhibition function was evaluated using event-related potentials (ERPs) while migraine patients and healthy controls were performing the color–word Stroop task.MethodsIn this study, 75 migraine patients and 41 age-, gender-, and education-matched healthy controls were enrolled. The Stroop task was performed, and both behavioral and ERP data were analyzed.ResultsAs to the behavioral data, the migraine group had a longer reaction time compared to the control group, but no difference in Stroop effect was observed. With respect to ERP components, the amplitudes of both early and late medial frontal negativity (MFN) were decreased in the migraine group. Additionally, obvious differences in the early MFN and sustained potential (SP) amplitudes were found between patients with and without allodynia.ConclusionsAt the behavioral level, migraine patients exhibited decreased executive ability but no obvious decline in inhibition. By contrast, a decline in attentional inhibition during the migraine interictal phase was confirmed by the analysis of ERP components, mainly those associated with changes in the conflict-monitoring stage, independent of confounding factors such as age, education, medication and mood disorders. Migraine patients with allodynia exhibited some significant differences in early MFN and SP compared to those without, supporting the hypothesis that migraine chronification aggravates the decline in attentional inhibition.     

Andrographolide relieved pathological pain generated by spared nerve injury model in mice

Context: Andrographolide (Andro), found in large quantities in Andrographis paniculata Nees (Acanthaceae), is anti-inflammatory, especially in the central nervous system (CNS) glia.

Objective: The objective of this study is to test Andro’s ability to reduce allodynia in a spared nerve injury model.

Material and methods: Male 30?g BalbC mice were divided into four groups: (1) Sham-operated control (Sham-group); (2) nerve injured and treated with saline (Saline-group); (3) nerve injured and treated with Andro (Andro-group); (4) nerve injured and treated with non-steroidal anti-inflammatory drugs (NSAIDS) (NSAIDS-group). Andro or NSAIDS (diclofenac salt) were injected intraperitoneally at 5?mg/kg body weight daily. Mechanical allodynia was assessed by von Frey tests at 3, 7, and 14?d. For immunohistochemical analysis, samples were collected at 7?d.

Results: The threshold for inducing allodynia increased and the response percentage reduced in the Andro-group when compared with the Saline-group, as well as when compared with NSAIDS groups throughout 3–14?d. The ratio of threshold for OP-Andro/OP-saline and for OP-Andro/OP-NSAIDS groups was 20.42 and 11.67 at 14?d, respectively. The ratio of response percentage for OP-Andro/OP-saline and for OP-Andro/OP-NSAIDS was 0.32 and 0.39 at 14?d, respectively. Interleukin-1 (IL-1) immunostaining in the spinal cord was reduced in the Andro-group. Astrocytic activities were not significantly reduced in the Andro-group compared with the Saline-group at 7?d post-operation (PO)

Conclusions: Andro reduced mechanical allodynia more than NSAIDS at the same concentration, and the observed behaviour was associated with a reduction in inflammatory cytokine produced in the spinal cord.     

痛觉过敏的中枢敏感化机制及其分子基础

痛觉过敏一向被归咎于外周伤害性感受器的敏感化。新近有证据表明，中枢神经元的敏感化和高兴奋性在痛觉过敏的发生发展中具有至关重要的作用，并主要由ＮＭＤＡ受体－ＰＣＫ－ＮＯ等一系列受体－胞内分子过程参与。中枢敏感化及其分子基础的发现可望对疼痛临床防治提供新的对策。     

CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy

Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3 × 8 mg/kg, cumulative dose 24 mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.