Intracardiac and Cerebral Thrombosis Complicated With Mycoplasma Pneumonia.

A seven-year-old girl developed multiposition thrombosis after fever and respiratory symptoms. Chest computed tomography (CT) scan demonstrated bilateral infiltrates, consolidation of the right lower lobe, and pleural effusion in the right lung field. Brain magnetic resonance imaging (MRI) showed multiple abnormal signals in the brain with limited diffusion, and cerebral infarction could not be excluded. Echocardiography revealed hypoechoic mitral valve tips, which are likely to be suspected as vegetation. Mycoplasma pneumoniae infection was clarified by a four-fold increase in IgG antibodies to M. pneumoniae sera. D-dimer levels were elevated increasingly. We found and reported this rare pediatric case of an M. pneumoniae-induced severe pneumonia complicated with intracardiac and cerebral thrombosis. We investigate the clinical characteristics, diagnosis, and treatment of refractory mycoplasma pneumonia complicated with intracardiac and cerebral thrombosis in children.

[Clinical and genetic characteristics of children with primary dilated cardiomyopathy]. / å„¿ç«¥åŽŸå‘æ€§æ‰©å¼ åž‹å¿ƒè‚Œç— çš„ä¸´åºŠç‰¹å¾åŠé—ä¼ å­¦åˆ†æž.

OBJECTIVES: To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM). METHODS: A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data. RESULTS: Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05). CONCLUSIONS: There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.

Kawasaki disease: lncRNA Slco4a1 regulates the progression of human umbilical vein endothelial cells by targeting the miR-335-5p/POU5F1 axis.

Background: Kawasaki disease (KD) is an autoimmune disease with systemic vasculitis as the main pathological change, and is most common in children under 5. The role of long non-coding RNAs (lncRNAs) in human diseases has been highlighted. LncRNA Slco4a1 was reported to promote cell growth and act as an oncogenic regulator in cancer. However, the role of lncRNA Slco4a1 in KD remains unclear. This study aimed to investigate the role and mechanism of lncRNA Slco4a1 in KD. Methods: Enzyme linked immunosorbent assay (ELISA), qRT-PCR, Western blot, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining were conducted to explore the function of lncRNA Slco4a1. The interaction between POU5F1 and miR-335-5p was analyzed by the RIP assay and dual luciferase assay. Results: LncRNA Slco4a1 was significantly upregulated in the serum of KD patients compared with healthy controls. LncRNA Slco4a1 was upregulated in human umbilical vein endothelial cells (HUVECs) stimulated with KD serum. LncRNA Slco4a1 overexpression could promote the expression of inflammatory factors and apoptosis in HUVECs. The number of inflammatory cells and the infiltration area of the coronary artery in KD rats were decreased after lncRNA Slco4a1 silencing. Furthermore, lncRNA Slco4a1 is a sponge of miR-335-5p and negatively regulated the expression of miR-335-5p. POU5F1 was the downstream target of miR-335-5p, and miR-335-5p overexpression could upregulate the expression of POU5F1. Additionally, miR-335-5p overexpression could inhibit the expression of inflammatory factors and apoptosis in HUVECs. We further investigated the effect of lncRNA Slco4a1 on the mitogen-activated protein kinase (MAPK) signaling pathway, and the results showed that lncRNA Slco4a1 could promote the activation of the MAPK signaling pathway. Conclusions: Together, these results indicated that lncRNA Slco4a1 could regulate the progression of HUVECs in KD by targeting the miR-335-5p/POU5F1 axis, providing new insights for KD treatment.

Efficacy evaluation and mechanical study of short- and long-term antithrombotic therapy for Kawasaki disease.

BACKGROUND: Antithrombotic therapy was commonly applied in treating Kawasaki disease (KD) children; however, the effects and mechanisms of different plans were not fully elucidated. In this study, we aimed to evaluate different antithrombotic drugs. METHODS: Eighty-two children diagnosed with KD in Hebei Children's Hospital from January 2017 to January 2020 were recruited. For cohort study, KD children were divided into a series of groups according to whether they were complicated with coronary artery lesions (CAL), drug therapy plan, and the presence of liver damage. The thromboelastogram (TEG) indexes [clotting time (R), clot formation time (K), clot formation angle (α), maximum amplitude of the clot (MA), arachidonic acid (AA), and adenosine diphosphate (ADP)] were employed to evaluate the relationship between disease state and drug treatment efficacy. Meanwhile, children were divided into different therapy groups according to their degree of CAL, the treatment efficiency was evaluated by TEG indexes, and the bleeding ratio was recorded. In addition, the warfarin metabolic gene was detected to explain the changes of coagulation parameters in children treated with warfarin. RESULTS: The R value and coagulation index (CoI) were significantly lower (P<0.05) and MA value was significantly higher (P<0.05) in CAL group than those in non-coronary artery lesion (NCAL) group. There were significant individual differences in platelet inhibition between aspirin and dipyridamole groups. The AA% in aspirin group was 64% [95% confidence interval (CI): 49% to 74.3%] and the ADP% was 28.5% (95% CI: 26.2% to 37.2%) in dipyridamole group, and were significantly between groups. Warfarin and aspirin had a synergistic effect in anticoagulation. Warfarin metabolic gene detection was shown to be helpful for adjusting warfarin treatment dose, and shortening the initial attainment time of standard international normalized ratio (INR) index. The R value was significantly higher (P<0.05) in the liver injury group than that in the control group. CONCLUSIONS: KD Children complicated with CAL presented a hypercoagulable state, and the CAL was predictable with the R value. Warfarin metabolic gene detection and TEG can effectively evaluate and guide short- and long-term antithrombotic therapy in KD children.

Gabapentin and NMDA receptor antagonists interacts synergistically to alleviate allodynia in two rat models of neuropathic pain.

Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.

Delayed Imatinib Treatment for Acute Spinal Cord Injury: Functional Recovery and Serum Biomarkers.

With no currently available drug treatment for spinal cord injury, there is a need for additional therapeutic candidates. We took the approach of repositioning existing pharmacological agents to serve as acute treatments for spinal cord injury and previously found imatinib to have positive effects on locomotor and bladder function in experimental spinal cord injury when administered immediately after the injury. However, for imatinib to have translational value, it needs to have sustained beneficial effects with delayed initiation of treatment, as well. Here, we show that imatinib improves hind limb locomotion and bladder recovery when initiation of treatment was delayed until 4 h after injury and that bladder function was improved with a delay of up to 24 h. The treatment did not induce hypersensitivity. Instead, imatinib-treated animals were generally less hypersensitive to either thermal or mechanical stimuli, compared with controls. In an effort to provide potential biomarkers, we found serum levels of three cytokines/chemokines--monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-3α, and keratinocyte chemoattractant/growth-regulated oncogene (interleukin 8)--to increase over time with imatinib treatment and to be significantly higher in injured imatinib-treated animals than in controls during the early treatment period. This correlated to macrophage activation and autofluorescence in lymphoid organs. At the site of injury in the spinal cord, macrophage activation was instead reduced by imatinib treatment. Our data strengthen the case for clinical trials of imatinib by showing that initiation of treatment can be delayed and by identifying serum cytokines that may serve as candidate markers of effective imatinib doses.

N-terminal truncations of substance P 1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats.

Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the biodistribution and stability of the peptides. Most of the examined compounds alleviated mechanical allodynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by any of the compounds tested. Most of the amino acids in the heptapeptide structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapeptide and its N-terminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.

Analgesic effect of sinomenine in rodents after inflammation and nerve injury.

Sinomenine is an alkaloid originally isolated from the root of the plant Sinomenium acutum. It is used in traditional medicine in China to treat rheumatic arthritis. In the present study, we evaluated the potential antinociceptive effects of sinomenine in rodents with nociceptive, inflammatory and neuropathic pain. In normal rats and mice, systemic sinomenine produced moderate antinociceptive effect in the hot plate and tail flick tests. Sinomenine also exerted analgesic effects on mechanical and heat hypersensitivity in mice after carrageenan induced inflammation. Finally, sinomenine effectively alleviated mechanical and cold allodynia in rats and mice after injury to peripheral nerve or spinal cord. The analgesic effect of sinomenine is not associated with side effects and is not reversed by the opioid receptor antagonist naloxone. Our results showed that sinomenine has a wide spectrum analgesic effect in rodent models of nociceptive, inflammatory and neuropathic pain.

Quantitative test of responses to thermal stimulation in spinally injured rats using a Peltier thermode: a new approach to study cold allodynia.

In this work, we described a method of testing of responses of spinally injured rats to thermal stimulation (heating and cooling) to the flank area using a Peltier thermode. With a baseline holding temperature at 32°C and the temperature change rate of 0.5°C/s, we measured vocalization thresholds of rats to thermal stimulation in the flank area. While normal rats did not vocalize to temperatures changes ranging from 6°C to 50°C, the spinally injured rats exhibited significantly increased response to cooling with average response temperature above 15°C through the 70 day observation period after spinal cord injury. The response temperature to cooling in spinally injured rats is correlated with the magnitude of responses to cold stimulation scored after ethyl chloride spray and with the response threshold to mechanical stimulation. In contrast, we did not observe an increase in response to warm/heat stimuli. The results showed that ischemic spinal cord injury produced cold, but not heat, allodynia in rats. Furthermore, we showed that it is possible to quantitatively measure response of rats to thermal stimulation on the body using temperature as end points which may aid further studies on mechanisms and treatments of thermal stimulation, particularly cold, evoked pain.

Activation of TRPM8 cold receptor triggers allodynia-like behavior in spinally injured rats.

Aims Pain in response to innocuous cold stimulation (cold allodynia) is a common symptom in patients with neuropathic pain. Cold allodynia is difficult to treat and its mechanisms are poorly understood. Several transient receptor potential (TRP) channels have been shown to be the molecular sensors for cold stimulation in a temperature-dependent manner, but the contribution of various TRP channels in mediating cold allodynia in neuropathic pain is unclear. We have previously shown that spinally injured rats developed neuropathic pain-like behaviors, including marked cold allodynia. We now assessed the role of TRP channels in mediating cold allodynia in rats after ischemic spinal cord injury. Methods Methods: Spinal cord injury was produced using a photochemical method. The mechanical allodynia was assessed by examining the vocalization thresholds to graded mechanical touch/pressure applied with von Frey hairs. Temperature controlled cold stimulation was produced by a Peltier thermode (active surface 25 mm × 50 mm) connected to a MSA Thermal Simulator (Somedic, Sweden) with baseline temperature of 32 °C. The rate of temperature change was 0.5 °C/s. The temperature required to elicit cold allodynia was examined. The responses of the rats to topical application of icilin or menthol, agonists of transient receptor potential melastain 8 (TRPM8), were also studied. Results Normal rats did not exhibit nociceptive responses to cooling stimulation to the trunk and back area (minimal temperature +6°C) and they also did not react aversively to topical application of icilin or menthol. After spinal cord injury, the rats developed mechanical allodynia at the trunk and back just rostral to the dermatome of the injured spinal segments. In the same area, rats exhibited significant nociceptive responses to cooling from day 1 after injury, lasting for at least 70 days which is the longest time of observation. For the first two weeks after injury, the majority of spinally injured rats had a nociceptive response to cooling above 17°C. At day 70, about 50% of rats responded to cooling above 17 °C. Topical application of 400 µM icilin or 4mM menthol also elicited pain-like responses in spinally injured rats and these two cold mimetics also significantly exacerbated existing mechanical allodynia. Conclusion Our results showed that activation of the TRPM8 channel by menthol or icilin triggers allodynia in spinally injured rats and increases, rather than decreases, mechanical allodynia. TRPM8 channels which respond to cooling above 17 ° C may be involved at least in part in mediating cold allodynia in the rat model of neuropathic spinal cord injury pain. Implications The work introduced a method of quantitative testings of responses of rats to cold stimulation and may contribute to the understanding of mechanisms of cold allodynia after injury to the nervous system.

Meteorin reverses hypersensitivity in rat models of neuropathic pain.

Neuropathic pain is caused by a lesion or disease to the somatosensory nervous system and current treatment merely reduces symptoms. Here, we investigate the potential therapeutic effect of the neurotrophic factor Meteorin on multiple signs of neuropathic pain in two distinct rat models. In a first study, two weeks of intermittent systemic administration of recombinant Meteorin led to a dose-dependent reversal of established mechanical and cold hypersensitivity in rats after photochemically-induced sciatic nerve injury. Moreover, analgesic efficacy lasted for at least one week after treatment cessation. In rats with a chronic constriction injury (CCI) of the sciatic nerve, five systemic injections of Meteorin over 9 days dose-dependently reversed established mechanical and thermal hypersensitivity as well as weight bearing deficits taken as a surrogate marker of spontaneous pain. The beneficial effects of systemic Meteorin were sustained for at least three weeks after treatment ended and no adverse side effects were observed. Pharmacokinetic analysis indicated that plasma Meteorin exposure correlated well with dosing and was no longer detectable after 24 hours. This pharmacokinetic profile combined with a delayed time of onset and prolonged duration of analgesic efficacy on multiple parameters suggests a disease-modifying mechanism rather than symptomatic pain relief. In sciatic nerve lesioned rats, delivery of recombinant Meteorin by intrathecal injection was also efficacious in reversing mechanical and cold hypersensitivity. Together, these data demonstrate that Meteorin represents a novel treatment strategy for the effective and long lasting relief from the debilitating consequences of neuropathic pain.

Curcumin ameliorates hydrogen peroxide-induced epithelial barrier disruption by upregulating heme oxygenase-1 expression in human intestinal epithelial cells.

BACKGROUND: Disruption of epithelial tight junctions (TJ) followed by loss of barrier function is of crucial importance in the pathogenesis of a variety of gastrointestinal disorders. Heme oxygenase-1 (HO-1), which can be induced by curcumin (Cur), provides protection against various forms of oxidative stress. AIMS: The protective effect of Cur on oxidative stress-induced intestinal barrier disruption in human intestinal epithelial cells was elucidated in this study. METHODS: H(2)O(2)-induced Caco-2 enterocytic monolayers were incubated in the presence or absence of Cur and/or zinc protoporphyrin (ZnPP). The trans-epithelial electrical resistance (TEER) and the flux of sodium fluorescein in the filter-grown Caco-2 cell monolayers were measured. The expression and localization of the TJ protein occludin and zonula occluden-1 (ZO-1) were evaluated by western blot and immunofluorescence microscopy. The mRNA and protein levels of HO-1 were analyzed by real-time PCR and western blot. RESULTS: Cur attenuated H(2)O(2)-induced disruption of paracellular permeability (TEER 52.02 ± 10.15% vs 22.71 ± 3.11%; sodium fluorescein flux 12.41 ± 2.19% vs 32.00 ± 4.97%, P < 0.05) and induced HO-1 mRNA (6.64 ± 0.48 vs 3.22 ± 0.28, P < 0.05) and protein (291.00 ± 9.17% vs 99.00 ± 10.00%, P < 0.05) expression in Caco-2 cells. After administration of H(2)O(2), occludin and ZO-1 proteins were restored by Cur (occludin 175.67 ± 29.50% vs 53.67 ± 24.19%, P < 0.05; ZO-1 139.67 ± 33.71% vs 36.00 ± 15.88%, P < 0.05) and this effect was blocked by HO-1 inhibitor, ZnPP (occludin 54.67 ± 10.02% vs 168.33 ± 36.47%, P < 0.05; ZO-1 50.00 ± 15.13% vs 117.67 ± 38.81%, P < 0.05). CONCLUSION: Cur protects human intestinal epithelial cells against H(2)O(2)-induced disruption of TJ and barrier dysfunction via the HO-1 pathway.

Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice.

Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice.

Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse.

Transduction of pain following noxious stimuli is mediated by the activation of specialized ion channels and receptors expressed by nociceptive sensory neurons. A common early nociceptive sublineage expressing the nerve growth factor receptor TrkA diversifies into peptidergic and non-peptidergic nociceptors around birth. In this process, peptidergic neurons maintain TrkA expression, while non-peptidergic neurons downregulate TrkA and upregulate the common glial-derived neurotrophic factor family ligand receptor Ret and bind the isolectin B4 (IB4). Although Ret can have profound impacts on the molecular and physiological properties of nociceptive neurons, its role is not fully understood. Here we have deleted Ret in small- and medium-size sensory neurons, bypassing the early lethality of the full Ret knockout. We identify that Ret is expressed in two distinct populations of small-medium sized non-peptidergic neurons, an IB4(+) and an IB4(-) population. In these neurons, Ret is a critical regulator of several ion channels and receptors, including Nav1.8, Nav1.9, ASIC2a, P2X3, TrpC3, TrpM8, TrpA1, delta opioid receptor, MrgD, MrgA1 and MrgB4. Ret-deficient mice fail to respond to mustard oil-induced neurogenic inflammation, have elevated basal responses and a failure to terminate injury-induced sensitization to cold stimuli, hypersensitivity to basal but not injury-induced mechanical stimuli, while heat sensation is largely intact. We propose that elevated pain responses could be contributed by GPR35, which is dysregulated in adult Ret-deficient mice. Our results show that Ret is critical for expression of several molecular substrates participating in the detection and transduction of sensory stimuli, resulting in altered physiology following Ret deficiency.

Treatment of transected peripheral nerves with artemin improved motor neuron regeneration, but did not reduce nerve injury-induced pain behaviour.

Incomplete recovery of function and neuropathic pain are common problems after peripheral nerve injury. To develop new treatment strategies for peripheral nerve injuries we investigated whether the neurotrophic factor artemin could improve outcome after sciatic nerve injuries in rats. Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family and exerts neuroprotective effects on sensory neurons as well as influencing behavioural thermal sensitivity. We additionally evaluated if fibrin sealant, which is sometimes used as a nerve glue, had any effects on neuropathic pain-related behaviour. After the sciatic nerve had been transected, 30 animals were randomised to one of three groups: treatment with a fibrin sealant that contained artemin in conjunction with sutures; fibrin sealant with no artemin (sham) in conjunction with sutures; or sutures alone (n=10 in each group). Motor function, sensory function, and autotomy were evaluated from 1 to 12 weeks after injury. Retrograde flourogold tracing 12 weeks after injury showed that the addition of artemin increased the number of regenerating motor neurons. However, it did not improve their performance, as measured by the Sciatic Function Index, compared with sham or suture alone. Animals treated with artemin had a non-significant increase in motor nerve conduction velocity compared with sham. However, artemin did not reverse nerve injury-induced pain behaviour such as cold or heat hypersensitivity. Fibrin sealant in itself did not ameliorate motor performance, or regeneration of motor neurons, or give rise to nerve injury-induced pain behaviour. The results indicate that artemin is of value as a treatment for peripheral nerve injuries, although the effects were limited. As the artemin high-affinity receptor GFRalpha-3 is present in Schwann cells and not in motor neurons, the effect on motor neuron axon regeneration may result from an indirect effect through Schwann cells in the injured nerve.

Sex differences in the development of localized and spread mechanical hypersensitivity in rats after injury to the infraorbital or sciatic nerves to create a model for neuropathic pain.

BACKGROUND: Neuropathic pain after injury to the nervous system is a difficult clinical problem. Sex differences in the development of neuropathic pain have not been well established experimentally or clinically. OBJECTIVE: Rats were used to examine sex differences in localized and spread mechanical hypersensitivity after partial injury to their infraorbital or sciatic nerves in a model of neuropathic pain. METHODS: In adult female and male rats, partial nerve injury to the infraorbital and sciatic nerves was produced using a photochemical method. Mechanical hypersensitivity (allodynia) was examined and compared in the innervation territories of the nerves on the face or hind paw. The spread of hypersensitivity beyond the innervation territories of the injured nerves was also studied. The female and male rats were randomized to active and sham groups. The rats in the sham group had their sciatic or infraorbital nerve exposed, but not injured. RESULTS: A total of 67 rats (36 females, 31 males) were used. There was a marked sex difference in the response to infraorbital nerve injury: female rats developed more profound and long-lasting facial hypersensitivity than did male rats (P<0.001). Hypersensitivity of the hind paw after sciatic nerve injury did not, however, significantly differ between female and male rats. Spread mechanical hypersensitivity was noted in body areas outside the innervation territory of the injured nerve. This hypersensitivity was more profound after infraorbital than sciatic nerve injury and also displayed a significant sex difference (female>male, P < 0.001). Sham-group rats did not exhibit localized or spread mechanical hypersensitivity. CONCLUSION: Sex differences in the development of neuropathic painlike behaviors in rats were dependent on site of injury and site of testing, with female rats being more susceptible to the development of spread mechanical hypersensitivity, particularly after facial nerve injury, compared with male rats.

Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury.

Functional magnetic resonance imaging (fMRI) has been used to map cerebral activations related to nociceptive stimuli in rodents. Here, we used fMRI to investigate abnormally increased responses to noxious or innocuous stimuli, in a well-established rat model of chronic neuropathic pain induced by photochemical lumbar spinal cord injury. In this model, a subpopulation of rats exhibits allodynia-like hypersensitivity to mechanical and cold stimulation of the trunk area. In those rats that do not develop overt hypersensitivity after identical spinal cord injury (i.e. non-hypersensitive rats), touch evoked pain can be triggered by the opioid receptor antagonist, naloxone. We show that cerebral activations in contralateral primary somatosensory cortex (SI) are markedly correlated with different behavioural characteristics of these animals. Identical electrical stimulation, applied on trunks of spinally injured hypersensitive and non-hypersensitive rats, evoked significantly higher responses in SI of the former than the latter. Although levels of fMRI signals in SI of the trunk territory were not significantly different between normal and spinally injured non-hypersensitive rats, the administration of naloxone significantly increased fMRI signals in the non-hypersensitive rats, but not in the normal rats. We conclude that increased activation of contralateral SI is a key feature of behavioural neuropathic pain in spinally injured rats and that fMRI is an effective method to monitor experimental neuropathic pain in small animals.

Genetic analysis of neuropathic pain-like behavior following peripheral nerve injury suggests a role of the major histocompatibility complex in development of allodynia.

Neuropathic pain is a common consequence of damage to the nervous system. We here report a genetic analysis of development of neuropathic pain-like behaviors after unilateral photochemically-induced ischemic sciatic nerve injury in a panel of inbred rat strains known to display different susceptibility to autoimmune neuroinflammation. Pain behavior was initially characterized in Dark-Agouti (DA; RT1(av1)), Piebald Virol Glaxo (PVG; RT1(c)), and in the major histocompatibility complex (MHC)-congenic strain PVG-RT1(av1). All strains developed mechanical hypersensitivity (allodynia) following nerve injury. However, the extent and duration of allodynia varied significantly among the strains, with PVG displaying more severe allodynia compared to DA rats. Interestingly, the response of PVG-RT1(avRT1) was similar to that of DA, suggesting regulation by the MHC locus. This notion was subsequently confirmed in an F2 cohort derived from crossing of the PVG and PVG-RT1(av1)strains, where allodynia was reduced in homozygous or heterozygous carriers of the RT1(av1) allele in comparison to rats homozygous for the RT1(c) allele. These results indicate that certain allelic variants of the MHC could influence susceptibility to develop and maintain neuropathic pain-like behavior following peripheral nerve injury in rats.

Lacosamide, a new anti-epileptic, alleviates neuropathic pain-like behaviors in rat models of spinal cord or trigeminal nerve injury.

The effect of systemic administration of lacosamide, a newly developed anti-epileptic, on neuropathic pain-like behaviors was examined in rats after ischemic injury to the infraorbital nerve or spinal cord using a photochemical method. In rats with infraorbital nerve injury, lacosamide reduced mechanical hypersensitivity and the effect was markedly stronger in female than in male rats. In spinal cord injured female rats 10-20 mg/kg lacosamide dose-dependently alleviated the mechanical and cold allodynia-like behaviors without causing motor impairments or marked sedation. Administration of lacosamide twice daily at 20 mg/kg for 7 days totally alleviated the allodynia-like state in spinally-injured rats with no tolerance. Following treatment cessation the cold and the static allodynia reappeared but the effect on dynamic mechanical allodynia (brushing) was maintained until day 11. Lacosamide also produced hypothermia at antinociceptive doses in rats. It is suggested that this novel compound may be useful as an analgesic for treating central and trigeminal neuropathic pain. Furthermore, there may be a gender difference to the effect of lacosamide with female rats being more responsive to the treatments.

Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury.

Caffeine, used in many pain medications as an adjuvant analgesic, is an adenosine A1 and A2A receptor antagonist. Here we examined the effects of acute or chronic caffeine administration in rats after partial sciatic nerve injury. The hindpaw response to mechanical or cold stimulation was assessed following photochemically induced sciatic nerve injury which leads to hypersensitivity to these stimuli. Caffeine was administered i.p. acutely or in the drinking water chronically. The mechanical and cold hypersensitivity of sciatic nerve-injured rats was dose-dependently alleviated by acute systemic administration of caffeine (10-80 mg/kg). The effect of caffeine was, however, associated with side effects including locomotor stimulation or depression. Chronic oral administration (average daily doses 27.5 mg/kg/day or 61.5 mg/kg/day for 2 weeks) of caffeine starting at the time of nerve injury did not significantly affect the development of pain-like behaviors. Thus, acute, but not long term, caffeine intake reduced neuropathic pain state in nerve-injured rats, but only at very high doses. The potential hyperalgesic effect of chronic A1 adenosine receptor blockade may have been compensated for by an antinociceptive effect of caffeine through antagonism of A2A receptors and tolerance development.