IL-18 Contributes to Bone Cancer Pain by Regulating Glia Cells and Neuron Interaction
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Abstract MicroRNAs (miRNAs) have been shown to participate in development of neuropathic pain. However, the role of microRNA‐144 (miR‐144) in neuropathic pain remains unclear. In the present study, we established a neuropathic pain mouse model via chronic constriction injury (CCI)‐induction. The successful establishment of this model was confirmed via evaluation of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). By using this model, we found that miR‐144 was significantly downregulated in CCI‐induced neuropathic pain mice. In addition, intrathecal injection of miR‐144 agomiR alleviated mechanical and thermal hyperalgesia in neuropathic pain mice as shown by the increased of PWT and PWL. Moreover, miR‐144 negatively regulated neuroinflammation by decreasing the expression of proinflammatory mediators, including TNF‐α (tumor necrosis factor‐α), IL (interleukin)‐1β, and IL‐6, thus facilitating the inhibition of neuropathic pain development. Mechanistically, RASA1 (RAS P21 Protein Activator 1) was downregulated following the injection of agomiR‐144, and was verified to be a target of miR‐144. Furthermore, overexpression of RASA1 reversed the inhibitory effect of miR‐144 on neuropathic pain. Therefore, the present study suggested that miR‐144 has the potential to be explored as therapeutic target for treatment of neuropathic pain.
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Neuropathic pain is a type of spontaneous pain that causes damage to the central nervous system. Long noncoding RNAs (lncRNAs) participate in the progression of various nervous system diseases, including neuropathic pain. However, the biological function of GAS5 in neuropathic pain remains unclear. Our findings revealed that GAS5 was downregulated in chronic constriction injury (CCI) rats. Besides, ELISA showed that the concentration of IL‐6, TNF-α, and IL‐1β were reduced by overexpressed GAS5 in spinal cord homogenates of CCI rats. Moreover, mechanical allodynia and thermal hyperalgesia in CCI rats were inhibited by GAS5 overexpression, suggesting that GAS5 overexpression attenuated neuropathic pain. Subsequently, we found that GAS5 served as a sponge for miR-452-5p in CCI rats and CELF2 was the downstream target of miR-452-5p. Finally, through a rescue assay, we found that GAS5 ameliorated neuropathic pain in CCI rats by sponging miR-452-5p to regulate CELF2 expression. Our study confirmed that GAS5 ameliorated neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis, which may provide some clues for neuropathic pain treatment.
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Neuropathic pain (NP) is among the most intractable comorbidities of spinal cord injury. Dysregulation of non-coding RNAs has also been implicated in the development of neuropathic pain. Here, we identified a novel lncRNA, PKIA-AS1, by using lncRNA array analysis in spinal cord tissue of spinal nerve ligation (SNL) model rats, and investigated the role of PKIA-AS1 in SNL-mediated neuropathic pain. We observed that PKIA-AS1 was significantly upregulated in SNL model rats and that PKIA-AS1 knockdown attenuated neuropathic pain progression. Alternatively, overexpression of PKIA-AS1 was sufficient to induce neuropathic pain-like symptoms in uninjured rats. We also found that PKIA-AS1 mediated SNL-induced neuropathic pain by directly regulating the expression and function of CDK6, which is essential for the initiation and maintenance of neuroinflammation and neuropathic pain. Therefore, our study identifies PKIA-AS1 as a novel therapeutic target for neuroinflammation related neuropathic pain.
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It was identified that microRNAs were involved in the regulation of chronic neuropathic pain. However, the role of miR-206-3p in neuropathic pain was still unclear. In the current study, the role of miR-206-3p, a type of mature miR-206, in neuropathic pain was investigated. The potential mechanisms were also explored. We found that the expression of miR-206-3p decreased in the dorsal root ganglion (DRG) of chronic constriction sciatic nerve injury (CCI) rats, whereas the While histone deacetylase 4 (HDAC4) level increased. Further exploration showed that administration of a miR-206-3p mimic alleviated neuropathic pain and reduced the level of HDAC4, a predicted target of miR-206-3p. Overexpression of HDAC4 attenuated the effects of miR-206-3p on neuropathic pain. Our data revealed a miR-206-3p-HDAC4 signal that played a potentially important role in CCI-induced neuropathic pain.
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1) To determine if the neuropathic pain scale (NPS) can be used to classify chronic pain patients (CPPs) as having primarily neuropathic vs non-neuropathic pain, and furthermore; 2) to determine what, if any, cut-off score can be used to reliably make this determination.A total of 305 CPPs consecutive admissions to The Rosomoff Pain Center were administered the NPS and were assigned a diagnosis according to the physical examination and all available test results. CPPs with a diagnosis of chronic radiculopathy and spondylolysis/degenerative arthritis were segregated into two groups for the purposes of having a group representative of neuropathic pain (chronic radiculopathy) and non-neuropathic pain (spondylolysis/degenerative arthritis). Applying neuropathic pain criteria to each "of these two groups": a neuropathic pain "subtype" was identified within the chronic radiculopathy group; and, a non-neuropathic pain "subtype" was identified within the spondylolysis/degenerative arthritis group. This step was performed in order to assure that the CPPs selected for further analysis were truly representative of neuropathic and non-neuropathic pain. Discriminant function analysis was then employed to determine if NPS scoring could differentiate between these two "subtypes." Results from the discriminant function analysis model were utilized to derive an NPS cut-off score above which CPPs would be classified as having neuropathic pain. For the diagnoses of myofascial pain syndromes, spinal stenosis, epidural fibrosis, fibromyalgia, complex regional pain syndromes 1 and 2, and failed back surgery syndrome, a predicted NPS score was calculated and compared with the cut-off score.Multidisciplinary pain facility.Chronic pain patients.The NPS appeared to be able to separate CPPs into neuropathic pain vs non-neuropathic pain subtypes. The derived cut-off score from the model was 5.53. Myofascial pain syndrome and spinal stenosis had predictive scores lower than this cut-off score at 3.81 and 4.26, respectively. Epidural fibrosis, fibromyalgia, complex regional pain syndromes 1 and 2, and failed back surgery syndrome had predictive scores higher than the cut-off score at 6.15, 6.35, 6.87, 9.34, and 7.19, respectively.The NPS appears to be able to discriminate between neuropathic and non-neuropathic pain. A debate is currently raging as to whether diagnoses, such as fibromyalgia and complex regional pain syndrome 1, can be classified as neuropathic. Our NPS cut-off score results suggest that these diagnoses may have a neuropathic pain component. The reliability and validity of our NPS method will need to be tested further in other neuropathic pain models, such as diabetic peripheral neuropathic pain.
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Background Despite the suggestion of a neuropathic component to sickle cell disease (SCD) pain, there are minimal data on the systematic assessment of neuropathic pain in patients with SCD. Neuropathic pain is defined as pain primarily initiated by dysfunction of the peripheral or central nervous system. Procedure In a cross-sectional study, we used the painDETECT questionnaire, a one-page validated neuropathic pain screening tool, to determine the presence of neuropathic pain in patients with SCD and to evaluate the relationship between neuropathic pain, age, and gender. We hypothesized that 20% of patients with SCD will experience neuropathic pain and that neuropathic pain will be associated with older age and female gender. The completed painDETECT questionnaire yields a total score between 0 and 38 (≥19 = definite neuropathic pain, 13–18 = probable neuropathic pain, ≤12 = no neuropathic pain). Scores ≥13 were designated as having evidence of neuropathic pain. Results A total of 56 patients participated. Median age was 20.3 years and 77% were female. We found 37% of patients had evidence of neuropathic pain. Age was positively correlated with total score (r = 0.43; P = 0.001) suggesting older patients experience more neuropathic pain. Females had higher mean total scores (13 vs. 8.4; P = 0.04). Significantly more patients with neuropathic pain were taking hydroxyurea (90% vs. 59%; P = 0.015). Despite 37% of patients experiencing neuropathic pain, only 5% were taking a neuropathic pain drug. Conclusions Neuropathic pain exists in SCD. Valid screening tools can identify patients that would benefit from existing and future neuropathic pain therapies and could determine the impact of these therapies. Pediatr Blood Cancer 2014;61:512–517. © 2013 Wiley Periodicals, Inc.
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Neuropathic pain is an intractable comorbidity of spinal cord injury. Increasing noncoding RNAs have been implicated in neuropathic pain development. lncRNAs have been recognized as significant regulators of neuropathic pain. lncRNA Small Nucleolar RNA Host Gene 4 (SNHG4) is associated with several tumors. However, the molecular mechanisms of SNHG4 in neuropathic pain remain barely documented. Here, we evaluated the function of SNHG4 in spinal nerve ligation (SNL) rat models. We observed that SNHG4 was significantly upregulated in SNL rat. Knockdown of SNHG4 was able to attenuate neuropathic pain progression via regulating behaviors of neuropathic pain including mechanical and thermal hyperalgesia. Moreover, knockdown of SNHG4 could repress the neuroinflammation via inhibiting IL-6, IL-12, and TNF-α while inducing IL-10 levels. Additionally, miR-423-5p was predicted as the target of SNHG4 by employing bioinformatics analysis. miR-423-5p has been reported to exert significantly poorer in several diseases. However, the role of miR-423-5p in the development of neuropathic pain is needed to be clarified. Here, in our investigation, RIP assay confirmed the correlation between miR-423-5p and SNHG4. Meanwhile, we found that miR-423-5p was significantly decreased in SNL rat models. SNHG4 regulated miR-423-5p expression negatively. As exhibited, the loss of miR-423-5p contributed to neuropathic pain progression, which was rescued by the silence of SNHG4. Therefore, our study indicated SNHG4 as a novel therapeutic target for neuropathic pain via sponging miR-423-5p.
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Abstract Astrocyte activation is involved in the neuropathic pain. As a glutamate scavenger, the glutamate transporter‐1 (GLT‐1) is exclusively expressed on the astrocytes and probably correlates with astrocyte activation. In the present study, we attempted to clarify the temporal changing courses of astrocyte activation and GLT‐1 expression, as well as their correlations induced by a neuropathic pain model, namely, spinal nerve ligation (SNL) in which rapidly appearing (<3 days) and persistent (>21 days) mechanical allodynia and thermal hyperalgesia were presented. Immunofluorescent staining showed that GLT‐1 was expressed exclusively in most (not all) of the astrocytes, even when the GLT‐1 expression reached its peak. The expression of GLT‐1 displayed an interesting biphasic change, with an initial up‐regulation followed by a down‐regulation after SNL. Our results also demonstrated that SNL induced a marked and long‐term (>21 days) activation of astrocytes in the ipsilateral spinal dorsal horn. These results suggest that astrocyte activation, the change of GLT‐1 expression and the potential relationship between them might play key roles in the induction and/or maintenance of neuropathic pain. The present results provide novel clues in understanding the mechanisms underlying the involvement of astrocytes and GLT‐1 in the neuropathic pain. Anat Rec, 291:513–518, 2008. © 2008 Wiley‐Liss, Inc.
Allodynia
Spinal nerve
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Dorsal root ganglion
Nerve Injury
Sciatic nerve injury
Peripheral nerve injury
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