scholarly journals 5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia In Neuropathic Pain Via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation

2021 ◽  
Author(s):  
Long-Qing Zhang ◽  
Ya-Qun Zhou ◽  
Jia-Yan Li ◽  
Jia Sun ◽  
Shuang Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mitochondrial Biogenesis ◽  
Mechanical Allodynia ◽  
Receptor Agonist ◽  
Therapeutic Option ◽  
Pain Modulation ◽  
Sprague Dawley ◽  
Mtdna Copy Number ◽  
Withdrawal Threshold

Abstract Background: Neuropathic pain is a devastating disease affecting millions of people worldwide. Serotonin (5-hydroxytryptamine, 5-HT) has long been involved in pain modulation. Several lines of evidence indicate that 5-HT1F receptor agonists are potent inducers of mitochondrial biogenesis. In this study, we tested the hypothesis that 5-HT1F receptor agonist ameliorates mechanical allodynia in neuropathic pain via induction of mitochondrial biogenesis and suppression of neuroinflammation. Methods: Male Sprague-Dawley rats were used to establish neuropathic pain via spared nerve injury (SNI). Paw withdrawal threshold was used to evaluate mechanical allodynia. Real time polymerase chain reaction was used to examine the mitochondrial DNA (mtDNA) copy number. Western blot and immunofluorescence were used to examine the expression of target proteins. Results: Our results showed that mitochondrial biogenesis was impaired in the spinal cord of SNI rats. Moreover, activation of PGC-1α, the master regulator of mitochondrial biogenesis, attenuated established mechanical allodynia in neuropathic pain rats. Besides, neuronal 5-HT1F receptor was significantly downregulated in the spinal cord of neuropathic pain rats. Furthermore, selective 5-HT1F receptor agonist Lasmiditan attenuated established mechanical allodynia in neuropathic pain rats. Finally, Lasmiditan treatment restored mitochondrial biogenesis and suppressed neuroinflammation in the spinal cord of SNI rats. Conclusion: These results provide the first evidence that Lasmiditan ameliorates mechanical allodynia in neuropathic pain via induction of mitochondrial biogenesis and suppression of neuroinflammation in the spinal cord. Mitochondrial biogenesis inducers may become encouraging therapeutic option for the management of neuropathic pain.

scholarly journals Hydrogen-Rich Saline Activated Autophagy via HIF-1α Pathways in Neuropathic Pain Model

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Huixing Wang ◽  
Xiaodong Huo ◽  
Hongguang Chen ◽  
Bo Li ◽  
Jingzhi Liu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Intractable Pain ◽  
Sprague Dawley ◽  
Pain Model ◽  
Withdrawal Threshold ◽  
Downstream Target ◽  
Cord Injury ◽  
Neuropathic Pain Model ◽  
Regulatory Effects

Background. Neuropathic pain is a chronic and intractable pain, with very few effective analgesics. It involves an impaired cell autophagy process. Hydrogen-rich saline (HRS) reportedly reduces allodynia and hyperalgesia in a neuropathic pain model; however, it is unknown whether these effects involve autophagy induction. Methods. We investigated the relationship between HRS and cell autophagy in a neuropathic pain model generated by chronic constriction injury (CCI) in Sprague–Dawley rats. Rats received an intraperitoneal injection of HRS (10 mL/kg daily, from 1 day before until 14 days after CCI), 3MA (autophagy inhibitor), 2ME2 (HIF-1α inhibitor), or EDHB (HIF-1α agonist). The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were tested 1 day before and 1, 3, 7, 10, and 14 days after the operation. HIF-1α and cell autophagy markers in the spinal cord were evaluated by western blotting and real-time PCR assays at 14 days after CCI. Autophagosomes with double membranes were identified by transmission electron microscopy. Results. CCI caused behavioral hypersensitivity to mechanical and thermal stimulation in the hind-paw of the injured side. HRS improved MWT and TWL, activated autophagy, and increased autophagosomes and autolysosomes in CCI rats. 3-MA aggravated hyperalgesia and allodynia and suppressed autophagy, while EDHB attenuated hyperalgesia and activated the autophagy procedure and the HIF-1α downstream target gene BNIP3. HIF-1α inhibitors reversed the regulatory effects of HRS on autophagy in CCI rats at 14 days after spinal cord injury. Conclusion. HRS reduced mechanical hyperalgesia and activation of cell autophagy in neuropathic pain through a HIF1-dependent pathway.

scholarly journals N-Acetylcysteine Attenuates Hyperalgesia in Rats with Diabetic Neuropathic Pain: Role of Oxidative Stress and Inflammatory Mediators and CXCR4

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Sisi Li ◽  
Xuying Li ◽  
Xiangbin Xie ◽  
Xiao Wei ◽  
Cong Yu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Prefrontal Cortex ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Diabetic Neuropathic Pain ◽  
Withdrawal Threshold ◽  
Sprague Dawley Rats ◽  
Therapeutic Value ◽  
Tnf Α

Objectives. CXCR4 plays critical roles in the development of diabetic neuropathic pain (DNP) in rats, and its mechanism is unknown. This study was aimed at evaluating the potential therapeutic value of the antioxidant N-acetylcysteine (NAC) against DNP in rats and how CXCR4 participates in the formation of DNP. Methods. Control or streptozotocin- (STZ-) induced diabetic Sprague-Dawley rats received vehicle or NAC for four weeks starting one week after STZ injection. Von Frey and Hargreaves Apparatus were used to analyze the behavioral changes of mechanical allodynia and heat hyperalgesia. CXCR4, p-CXCR4, interleukin- (IL-) 6, and tumor necrosis factor- (TNF-) α in the spinal cord and the prefrontal cortex were detected by western blotting. Plasma IL-6, TNF-α, superoxide dismutase- (SOD-) 1, SOD-2, and lipid peroxidation products malondialdehyde (MDA) and 15-F2t-Isoprostane were detected by ELISA. Results. The values of paw withdrawal threshold (PWT) and paw withdrawal latencies (PWL) were reduced in diabetic rats compared to control rats that were concomitant with significant increases of CXCR4, p-CXCR4, IL-6, and TNF-α protein expressions in the spinal cord and prefrontal cortex. The treatment with NAC decreased the IL-6 and TNF-α protein expression and further increased CXCR4 and p-CXCR4 in the spinal cord and the cortex of diabetic rats that were accompanied with enhancement of PWT and PWL. NAC also significantly attenuated or reverted the increases of plasma IL-6, TNF-α, SOD-1, SOD-2, MDA, and 15-F2t-Isoprostane in diabetic rats. Conclusion. It is concluded that NAC treatment could effectively alleviate DNP and that induction of CXCR4 and p-CXCR4 may represent a mechanism whereby NAC attenuates DNP.

scholarly journals Inhibition of miR-665 alleviates neuropathic pain by targeting SOCS1

2020 ◽  
Vol 19 (8) ◽  
pp. 1591-1597
Author(s):  
Yongqiang Lin ◽  
Mengjia Li ◽  
Gaofeng Rao ◽  
Wenfu Zhang ◽  
Xuyan Chen
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Thermal Hyperalgesia ◽  
Luciferase Assay ◽  
Cytokine Signaling ◽  
Sprague Dawley ◽  
Down Regulation ◽  
Withdrawal Threshold ◽  
Promising Therapeutic Target ◽  
Neuropathic Pain Model

Purpose: To investigate the effect of miR-665 in neuropathic pain and the possible molecular mechanism involved.Methods: A neuropathic pain model was established using chronic constriction injury (CCI) methods in Sprague Dawley (SD) rats. Mechanical and thermal hyperalgesia were measured using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), respectively. The inflammation response was determined by assessing the production of inflammation factors. The target relationship of miR-665 and suppressor of cytokine signaling 1 (SOCS1) was verified by luciferase assay.Results: In the CCI rat model, PWT and PWL decreased following treatment with miR-665 (p < 0.01). MiR-665 was elevated in the spinal cord and microglia of CCI rats at different time points (p < 0.01). Down-regulation of miR-665 increased PWT and PWL and inhibited the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in CCI rats (p < 0.01). Luciferase assay results indicate that SOCS1 was the target of miR-665 (p < 0.01). SOCS1 decreased in CCI rats (p < 0.01) after treatment with miR-665. MiR-665 negatively regulated the expression of SOCS1 (p < 0.01). Down-regulation of SOCS1 reversed the alleviating effect of decreased miR-665 on pain sensitivity and inflammationresponse (p < 0.01).Conclusion: Down-regulation of miR-665 alleviates neuropathic pain by targeting SOCS1, and hence making miR-665 a promising therapeutic target for neuropathic pain. Keywords: MiR-665, SOCS1, Neuropathic pain, CCI, Spinal cord

scholarly journals EGCG Prevents the Loss of Pontine Noradrenergic Neurons Induced by Diabetes: A Role in Diabetic Neuropathic Pain

2012 ◽  
Vol 18 (S5) ◽  
pp. 5-6 ◽  
Author(s):  
Carla Morgado ◽  
João Silva ◽  
André Miranda ◽  
Patrícia Pereira-Terra ◽  
Diogo Raposo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Diabetic Rats ◽  
Pain Modulation ◽  
Diabetic Patients ◽  
Spontaneous Pain ◽  
Noradrenergic Neurons ◽  
Diabetic Neuropathic Pain ◽  
Descending Pain Modulation ◽  
Pain Responses

Diabetes is a major health problem with an alarming increasing prevalence, and is the most frequent cause of neuropathy worldwide. Neuropathy affects 50–60% of diabetic patients, being a major life-quality impairment for a quarter of these patients. Diabetic neuropathic pain (DNP) is characterized by spontaneous pain, mechanical hyperalgesia and tactile allodynia and is accompanied by functional and neurochemical changes at the peripheral nerves, spinal cord and supraspinal pain control areas. Regarding the effects of diabetic neuropathy in the central somatossensory system, it was shown that streptozotocin (STZ)-diabetic rats present spontaneous hyperactivity and hyperexcitability of spinal nociceptive neurons, which may be subserving the exacerbated pain responses. The spinal functional changes and pain may be due to increased peripheral input(2), changes in spinal nociceptive modulatory mechanisms and altered supraspinal descending pain modulation. Noradrenergic descending pain modulation seems to be impaired since STZ-diabetic rats present decreased numbers of noradrenergic neurons at the A5 and A7 pontine cell groups, along with lower levels of noradrenaline at the spinal cord and higher behavioral responses to pain. This is consistent with the strong noradrenergic projection from A5 and A7 neurons to the spinal dorsal horn and the modulation of nociceptive transmission by local release of noradrenaline. The mechanisms underlying the decrease in noradrenergic neurons in the brainstem during diabetes remain unclear. Our recent findings that diabetes induces oxidative stress damage in neurons from those areas, lead us to hypothesize that it may contribute to their loss. Thereafter, with the present study we aimed to evaluate the effects of Epigallocathechin Gallate (EGCG), a potent antioxidant present in green tea, on spinal noradrenaline levels, on A5 and A7 noradrenergic neurons and on behavioral pain responses of STZ-diabetic rats.

scholarly journals Intrathecal Injection of the ς1Receptor Antagonist BD1047 Blocks Both Mechanical Allodynia and Increases in Spinal NR1 Expression during the Induction Phase of Rodent Neuropathic Pain

2008 ◽  
Vol 109 (5) ◽  
pp. 879-889 ◽  
Author(s):  
Dae-Hyun Roh ◽  
Hyun-Woo Kim ◽  
Seo-Yeon Yoon ◽  
Hyoung-Sig Seo ◽  
Young-Bae Kwon ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Maintenance Phase ◽  
Spinal Cord Dorsal Horn ◽  
Induction Phase ◽  
Receptor Subunit ◽  
Aspartate Receptor ◽  
Spinal Cord Dorsal

Background Selective blockade of spinal sigma(1) receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. Methods Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. Results BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation. Conclusions These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.

Sortilins in neuropathic pain

2012 ◽  
Vol 3 (3) ◽  
pp. 183-184
Author(s):  
M. Richner ◽  
O.J. Bjerrum ◽  
Y. De Koninck ◽  
A. Nykjaer ◽  
C.B. Vaegter
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Mechanical Allodynia ◽  
Molecular Mechanisms ◽  
Intrathecal Injection ◽  
Ion Concentration ◽  
Down Regulation

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation

2008 ◽  
Vol 109 (3-5) ◽  
pp. 286-293 ◽  
Author(s):  
A.G. Mensah-Nyagan ◽  
C. Kibaly ◽  
V. Schaeffer ◽  
C. Venard ◽  
L. Meyer ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Pain Modulation ◽  
Steroid Production ◽  
Endogenous Steroid

Increased Expression of Cyclooxygenase and Nitric Oxide Isoforms, and Exaggerated Sensitivity to Prostaglandin E2, in the Rat Lumbar Spinal Cord 3 Days after L5–L6 Spinal Nerve Ligation

2006 ◽  
Vol 104 (2) ◽  
pp. 328-337 ◽  
Author(s):  
Darren D. O’Rielly ◽  
Christopher W. Loomis
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Glutamate Release ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Withdrawal Threshold ◽  
Enhanced Sensitivity ◽  
Sham Surgery ◽  
Inducible Nos

Background Spinal prostaglandins seem to be important in the early pathogenesis of experimental neuropathic pain. Here, the authors investigated changes in the expression of cyclooxygenase and nitric oxide synthase (NOS) isoforms in the lumbar, thoracic, and cervical spinal cord and the pharmacologic sensitivity to spinal prostaglandin E2 (PGE2) after L5-L6 spinal nerve ligation (SNL). Methods Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery 3 days before experimentation. Paw withdrawal threshold was monitored for up to 20 days. Immunoblotting, spinal glutamate release, and behavioral testing were examined 3 days after SNL. Results Allodynia (paw withdrawal threshold &lt; or = 4 g) was evident 1 day after SNL and remained stable for 20 days. Paw withdrawal threshold was unchanged (P &gt; 0.05) from baseline (&gt; 15 g) after sham surgery except for a small but significant decrease on day 20. Cyclooxygenase 2, neuronal NOS, and inducible NOS were significantly increased in the ipsilateral lumbar dorsal horn after SNL. Expression in the contralateral dorsal horn and ventral horns (lumbar segments) or bilaterally (thoracic and cervical segments) was unchanged from sham controls. This was accompanied by a significant decrease in both the EC50 of PGE2-evoked glutamate release and the ED50 of PGE2 on brush-evoked allodynia. Enhanced sensitivity to PGE2 was localized to lumbar segments of SNL animals and attenuated by SC-51322 or S(+)-ibuprofen, but not R(-)-ibuprofen (100 mum). Conclusion The increased expression of cyclooxygense-2, neuronal NOS, and inducible NOS and the enhanced sensitivity to PGE2 in spinal segments affected by SNL support the hypothesis that spinal prostanoids play an early pathogenic role in experimental neuropathic pain.

scholarly journals Spinal Cord Stimulation for Neuropathic Pain: Current Trends and Future Applications

2018 ◽  
Vol 8 (8) ◽  
pp. 138 ◽  
Author(s):  
Ivano Dones ◽  
Vincenzo Levi
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Spinal Cord Stimulation ◽  
Therapeutic Option ◽  
Neural Pathways ◽  
Chronic Neuropathic Pain ◽  
Pain Medications ◽  
Epidural Spinal Cord Stimulation ◽  
Pain Therapists ◽  
Effective Drugs

The origin and the neural pathways involved in chronic neuropathic pain are still not extensively understood. For this reason, despite the wide variety of pain medications available on the market, neuropathic pain is challenging to treat. The present therapeutic alternative considered as the gold standard for many kinds of chronic neuropathic pain is epidural spinal cord stimulation (SCS). Despite its proved efficacy, the favourable cost-effectiveness when compared to the long-term use of poorly effective drugs and the expanding array of indications and technical improvements, SCS is still worldwide largely neglected by general practitioners, neurologists, neurosurgeons and pain therapists, often bringing to a large delay in considering as a therapeutic option for patients affected by neuropathic chronic pain. The present state of the art of SCS in the treatment of chronic neuropathic pain is here overviewed and speculations on whether to use a trial period or direct implant, to choose between percutaneous leads or paddle electrodes and on the pros and cons of the different patterns of stimulation presently available on the market (tonic stim, high-frequency stim and burst stim) are described.

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