Transmission Of Nociceptive Information Research Articles

Spinal circRNA-9119 Suppresses Nociception by Mediating the miR-26a-TLR3 Axis in a Bone Cancer Pain Mouse Model.

Altered expression of circular RNA (circRNA) is recognized as a contributor to malignant pain where microRNA (miRNA) exerts an essential effect. We generated a murine model for bone malignancy pain in which 2472 osteolytic sarcoma cells were injected into the femurs of mice. CircRNA microarray and quantitative PCR (qPCR) and revealed that circ9119 expression was repressed in the spinal cord of bone malignancy pain model mice, which is the first relay site involved in the transmission of nociceptive information to the cerebrum of mice that receive spinal analgesics for malignancy pain. Overexpression of circ9119 by plasmid injection in the model mice reduced progressive thermal hyperalgesia and mechanical hyperalgesia. Bioinformatics prediction and dual-luciferase reporter assay showed that circ9119 functions as a sponge of miR-26a, which targets the TLR3 3'-untranslated region. Furthermore, expression of miR-26a was elevated and TLR3 level was repressed in bone malignancy pain model mice, which were counteracted by circ9119 in the spinal cord of tumor-bearing mice. Moreover, excessive expression of miR-26a was involved in the recovery of mice from progressive thermal hyperalgesia and mechanical hyperalgesia triggered via circ9119. TLR3 knockdown in bone malignancy pain model mice thoroughly impaired pain in the initial stages and reduced the effects of circ9119 on hyperalgesia. Our research findings indicate that targeting the circ9119-miR-26a-TLR3 axis may be a promising analgesic strategy to manage malignancy pain.

Galanin plays a role in antinociception via binding to galanin receptors in the nucleus accumbens of rats with neuropathic pain

Galanin and galanin receptors (GalRs) play important roles in the transmission and modulation of nociceptive information. Our previous research has shown that the expression of GalR1 is upregulated and that GalR1 activation in the nucleus accumbens (NAc) of rats with neuropathic pain has an antinociceptive effect. However, the antinociceptive effect of NAc galanin in neuralgia remains unclear. The present study aimed to explore the antinociceptive effect induced by galanin in rats with neuropathic pain and the underlying mechanism. The results showed that the intra-NAc injection of galanin induced a dose-dependent increase in hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in mononeuropathic rats and that this effect was stronger than that in intact rats. The intra-NAc injection of the non-selective GalR antagonist galantide reduced HWL in the rats with neuropathic pain, but there was no influence of galantide on HWL in intact rats. Moreover, galanin expression in the NAc was upregulated after sciatic nerve ligation. All of these results demonstrate that galanin plays a role in antinociception via binding to GalRs in the NAc of rats and that endogenous galanin is involved in the antinociception after peripheral nerve injury.

Collateral Projections from the Medullary Dorsal Horn to the Ventral Posteromedial Thalamic Nucleus and the Parafascicular Thalamic Nucleus in the Rat

Medullary dorsal horn (MDH), the homolog of spinal dorsal horn, plays essential roles in processing of nociceptive signals from orofacial region toward higher centers, such as the ventral posteromedial thalamic nucleus (VPM) and parafascicular thalamic nucleus (Pf), which belong to the sensory-discriminative and affective aspects of pain transmission systems at the thalamic level, respectively. In the present study, in order to provide morphological evidence for whether neurons in the MDH send collateral projections to the VPM and Pf, a retrograde double tracing method combined with immunofluorescence staining for substance P (SP), SP receptor (SPR) and Fos protein was used. Fluoro-gold (FG) was injected into the VPM and the tetramethylrhodamine-dextran (TMR) was injected into the Pf. The result revealed that both FG- and TMR-labeled projection neurons were observed throughout the entire extent of the MDH, while the FG/TMR double-labeled neurons were mainly located in laminae I and III. It was also found that some of the FG/TMR double-labeled neurons within lamina I expressed SPR and were in close contact with SP-immunoreactive (SP-ir) terminals. After formalin injection into the orofacial region, 41.4% and 34.3% of the FG/TMR double-labeled neurons expressed Fos protein in laminae I and III, respectively. The present results provided morphological evidence for that some SPR-expressing neurons within the MDH send collateral projections to both VPM and Pf and might be involved in sensory-discriminative and affective aspects of acute orofacial nociceptive information transmission.

Galanin receptor 1 plays an antinociceptive effect via inhibiting PKA activation in the nucleus accumbens of rats with neuropathic pain.

Galanin and galanin receptors (GalRs) have been reported to be involved in the transmission and modulation of nociceptive information in the central nervous system (CNS). However, the underlying mechanism of the antinociception of GalRs in neuropathic pain remains unclear. This study investigated the antinociception induced by galanin receptor 1 (GalR1) via protein kinase A (PKA) signaling pathway in the nucleus accumbens (NAc) of rats with neuropathic pain. A mononeuropathy model was replicated by ligation of the left sciatic nerve, following which the expression of phospho-PKA (p-PKA) in the NAc were markedly up-regulated at 14(th) and 28(th) day after ligation of sciatic nerve, and p-PKA expression was down-regulated by intra-NAc injection of GalR1 agonist M617, but the GalR1 antagonist M35 did not have an effect. We also found that M35 in the NAc blocked the M617-induced increase in the hind paw withdrawal latencies (HWLs) of rats with mononeuropathy, but M35 alone had no effect on HWLs, and PKA inhibitor H-89 attenuated the M617-induced an increase in the HWLs. These results suggested that GalR1 induced an antinociception via inhibiting PKA activation, implying that GalR agonists may be potential and potent therapeutic options to treat chronic neuropathic pain.

Progress in renin-angiotensin system and pain in the central nervous system

Recent studies have shown that angiotensin Ⅱ (AngⅡ) may act as a neurotransmitter or neuromodulator in the spinal transmission of nociceptive information. This review illustrated the action site of AngⅡ, the localization of AngⅡ receptors and the mechanism of angiotensin peptides involved in pain in the central nervous system, to review the relationship between renin-angiotensin system (RAS) and pain in the central nervous system and provide reference for the treatment of postoperative pain. RAS will become new targets for the treatment of postoperative pain, which needs to be further investigated. Key words: Angiotensin Ⅱ; Pain; Spinal cord

Inhibition on acid-sensing ion channels and analgesic activities of flavonoids isolated from dragon's blood resin.

Acid-sensing ion channel (ASIC) serves important roles in the transmission of nociceptive information. To confirm the analgesic mechanism of dragon's blood resin, patch-clamp technique, in vivo animal experiments, and immunohistochemical staining were used to observe the effects of the three flavonoids (loureirin B, cochinchinemin A, and cochinchinemin B) isolated from dragon's blood resin on ASIC. Results showed that the three flavonoids exerted various inhibitory effects on ASIC currents in rat dorsal root ganglion (DRG) neurons. The combination of the three flavonoids with total concentration of 6.5μM could decrease (53.8±4.3%) of the peak amplitude and (45.8±4.5%) of the sustained portion of ASIC currents. The combination of the three flavonoids was fully efficacious on complete Freud's adjuvant (CFA)-induced inflammatory thermal hyperalgesia at a dose of 6.5mM similar with amiloride at 10mM. The analgesic effects of the combination could be weakened by an ASIC activator 2-guanidine-4-methylquinazoline. CFA-induced hyperalgesia was accompanied by c-Fos up-regulation in DRG neurons, and the combination rescued thermal hyperalgesia through down-regulation of c-Fos and ASIC3 expression in CFA-induced inflammation. These collective results suggested that the flavonoids isolated from dragon's blood resin could be considered as the chemical compounds that exert analgesic effects on inflammatory thermal pain due to action on ASIC.

Collateral Projections from the Lateral Parabrachial Nucleus to the Central Amygdaloid Nucleus and the Ventral Tegmental Area in the Rat.

ABSTRACTLateral parabrachial nucleus (LPB) is a critical region in the integration and transmission of peripheral nociceptive information. The parabrachio‐amygdaloid (P‐Amy) pathway and parabrachio‐ventral tegmental area (P‐VTA) pathway is thought to be significant in regulation of pain‐related negative emotions. In present study, retrograde tract tracers Fluoro‐gold (FG) and tetramethylrhodramine‐dextran (TMR) were stereotaxically injected into the right central amygdaloid nucleus (CeA) and right VTA, respectively. Then, part of these rats were performed with the spare nerve injury (SNI) in the controlateral side of FG and TMR injection. Afterwards, double‐ or triple‐immunofluorescent histochemistry was used to examine FG/TMR double‐ and FG/TMR/FOS or FG/TMR/CGRP triple‐labeled neurons in the LPB. The results showed that all of FG, TMR single‐ and FG/TMR double‐labeled neurons were distributed in the LPB bilaterally with an ipsilateral predominance. The proportion of FG/TMR double‐labeled neurons to the total number of FG‐ and TMR‐labeled neurons was 10.78% and 13.07%, respectively. Nearly all of the FG/TMR double‐labeled neurons (92.67%) showed calcitonin gene‐related peptide (CGRP) immunopositive. On the other hand, in the SNI rats, about 89.49% and 77.87% of FG‐ and TMR‐labeled neurons were FG/FOS‐ and TMR/FOS‐positive neurons; about 93.33% of the FG/TMR double‐labeled neurons were FOS‐LI. Our results suggest that the part of CGRP immunopositive neurons in the LPB send projection fibers to both the CeA and VTA by the way of axon collaterals, which are activated by the nociceptive stimulation in the SNI condition, and may play an important role in the transmission of peripheral nociceptive information. Anat Rec, 302:1178–1186, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Electroacupuncture Treatment Alleviates the Remifentanil-Induced Hyperalgesia by Regulating the Activities of the Ventral Posterior Lateral Nucleus of the Thalamus Neurons in Rats.

Mechanisms underlying remifentanil- (RF-) induced hyperalgesia, a phenomenon that is generally named as opioid-induced hyperalgesia (OIH), still remain elusive. The ventral posterior lateral nucleus (VPL) of the thalamus, a key relay station for the transmission of nociceptive information to the cerebral cortex, is activated by RF infusion. Electroacupuncture (EA) is an effective method for the treatment of pain. This study aimed to explore the role of VPL in the development of OIH and the effect of EA treatment on OIH in rats. RF was administered to rats via the tail vein for OIH induction. Paw withdrawal threshold (PWT) in response to mechanical stimuli and paw withdrawal latency (PWL) to thermal stimulation were tested in rats for the assessment of mechanical allodynia and thermal hyperalgesia, respectively. Spontaneous neuronal activity and local field potential (LFP) in VPL were recorded in freely moving rats using the in vivo multichannel recording technique. EA at 2 Hz frequency (pulse width 0.6 ms, 1–3 mA) was applied to the bilateral acupoints “Zusanli” (ST.36) and “Sanyinjiao” (SP.6) in rats. The results showed that both the PWT and PWL were significantly decreased after RF infusion to rats. Meanwhile, both the spontaneous neuronal firing rate and the theta band oscillation in VPL LFP were increased on day 3 post-RF infusion, indicating that the VPL may promote the development of RF-induced hyperalgesia by regulating the pain-related cortical activity. Moreover, 2 Hz-EA reversed the RF-induced decrease both in PWT and PWL of rats and also abrogated the RF-induced augmentation of the spontaneous neuronal activity and the power spectral density (PSD) of the theta band oscillation in VPL LFP. These results suggested that 2 Hz-EA attenuates the remifentanil-induced hyperalgesia via reducing the excitability of VPL neurons and the low-frequency (theta band) oscillation in VPL LFP.

Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing.

Pain is a prevalent symptom of Parkinson's disease, and is effectively treated by deep brain stimulation of the subthalamic nucleus (STN). However, the link between pain and the STN remains unclear. In the present work, using in vivo electrophysiology in rats, we report that STN neurons exhibit complex tonic and phasic responses to noxious stimuli. We also show that nociception is altered following lesions of the STN, and characterize the role of the superior colliculus and the parabrachial nucleus in the transmission of nociceptive information to the STN, physiologically from both structures and anatomically in the case of the parabrachial nucleus. We show that STN nociceptive responses are abnormal in a rat model of PD, suggesting their dependence on the integrity of the nigrostriatal dopaminergic system. The STN-linked nociceptive network that we reveal is likely to be of considerable clinical importance in neurological diseases involving a dysfunction of the basal ganglia.

Contribution of membrane receptor signalling to chronic visceral pain

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.

Metabotropic Glutamate Receptor 7 (mGluR7) as a Target for Modulating Pain-evoked Activities of Neurons in the Hippocampal CA3 Region of Rats.

Metabotropic glutamate could contribute to the development of neuropathic pain-related behaviors. Previously, we have confirmed that the glutamic acid and dizocilpine maleate in the hippocampal CA3 region are involved in the modulation of noxious stimulation. However, whether the metabotropic glutamate receptor 7 (mGluR7) can modulate the pain-evoked electrical activities of pain-excited neurons and pain-inhibited neurons in the hippocampal CA3 region is not clear. The study aimed to examine the effects of mGluR7 allosteric agonist N,N'-dibenzhydrylethane- 1,2-diamine dihydrochloride (AMN082) and antagonist 6-(4-methoxyphenyl)-5-methyl-3- pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) on the pain-evoked electrical activities of pain-excited neurons and pain-inhibited neurons in the CA3 region of rats. A train of electric impulses applied to the sciatic nerve were used for noxious stimulation. The bio-electrical activities of pain-excited neuron or pain-inhibited neuron in the CA3 region were recorded by a glass microelectrode. Our results exhibited that intra-CA3 region administration of the glutamic acid or AMN082 increased the pain-evoked discharged frequency and shortened the latency of pain-excited neuron, while decreased the pain-evoked discharged frequency and prolonged the inhibitory duration of paininhibited neuron in the CA3 region. The intra-CA3 region microinjection of MMPIP produced the opposite response. These findings demonstrated that the glutamic acid and mGluR7 in hippocampal CA3 region are involved in the modulation of nociceptive information transmission by regulating pain-evoked electric activities of pain-excited neurons and pain-inhibited neurons.

Spontaneous Synaptic Activity in Projection Neurons of Lamina I of the Isolated Rat Lumbar Spinal Cord: Effect of Peripheral Inflammation

Spino-cerebral (projection) neurons localized in lamina I of the spinal gray substance play an important role in the transmission of pain-related information to the brain. We examined spontaneous excitatory postsynaptic currents (sEPSC) recorded from lamina I spino-pontine neurons in isolated preparations of the rat lumbar spinal cord; the respective neurons were retrogradely labeled by a fluorescent dye. We tried to find out how experimentally induced peripheral inflammation affects the amplitude/time characteristics of these currents. It was found that, in preparations obtained from animals with inflammation of hind limb tissues, the frequency and (to a lesser extent) amplitude of sEPSC in projection neurons are, on average, higher than those measured in neurons of the control animals. It is belived that such changes result mostly from plastic modifications of neuron-to-neuron interactions in neuronal networks of lamina II, which form main synaptic inputs to neurons of lamina I. Increased frequency and amplitude of sEPSC in lamina I neurons should lead to some facilitation of transmission of nociceptive information to the cerebral structures. Such hyperexcitability of lamina 1 projection neurons can provide a notable contribution to the development of hyperalgesia in chronic inflammatory states and to facilitation of generation of pain-related emotions.

Reticular Formation and Pain: The Past and the Future.

The involvement of the reticular formation (RF) in the transmission and modulation of nociceptive information has been extensively studied. The brainstem RF contains several areas which are targeted by spinal cord afferents conveying nociceptive input. The arrival of nociceptive input to the RF may trigger alert reactions which generate a protective/defense reaction to pain. RF neurons located at the medulla oblongata and targeted by ascending nociceptive information are also involved in the control of vital functions that can be affected by pain, namely cardiovascular control. The RF contains centers that belong to the pain modulatory system, namely areas involved in bidirectional balance (decrease or enhancement) of pain responses. It is currently accepted that the imbalance of pain modulation towards pain facilitation accounts for chronic pain. The medullary RF has the peculiarity of harboring areas involved in bidirectional pain control namely by the existence of specific neuronal populations involved in antinociceptive or pronociceptive behavioral responses, namely at the rostroventromedial medulla (RVM) and the caudal ventrolateral medulla (VLM). Furthermore the dorsal reticular nucleus (also known as subnucleus reticularis dorsalis; DRt) may enhance nociceptive responses, through a reverberative circuit established with spinal lamina I neurons and inhibit wide-dynamic range (WDR) neurons of the deep dorsal horn. The components of the triad RVM-VLM-DRt are reciprocally connected and represent a key gateway for top-down pain modulation. The RVM-VLM-DRt triad also represents the neurobiological substrate for the emotional and cognitive modulation of pain, through pathways that involve the periaqueductal gray (PAG)-RVM connection. Collectively, we propose that the RVM-VLM-DRt triad represents a key component of the “dynamic pain connectome” with special features to provide integrated and rapid responses in situations which are life-threatening and involve pain. The new available techniques in neurobiological studies both in animal and human studies are producing new and fascinating data which allow to understand the complex role of the RF in pain modulation and its integration with several body functions and also how the RF accounts for chronic pain.

POSTOPERATIVE ANALGESIA IN CHILDREN. ARE THERE ANY METHODS AVAILABLE TODAY?

This review presents the current state of postoperative pain in children. Based on the fundamental studies that have shown the presence of a newborn neurophysiological and neurochemical nociceptive information transmission mechanisms, provides information about the negative impact of pain on the body of the child. Presented neurophysiological aspects of pain perception in children, pain assessment methods, the basic principles of modern post-operative analgesia. Particular attention is given to drugs permitted for use in the Russian Federation. in children

Activation of N‐methyl‐D‐aspartate Receptor Inhibits Enkephalinergic Neurons in Mouse Spinal Superficial Dorsal Horn

Enkephalin (Enk)‐containing neurons are distributed at high concentration in the spinal cord superficial dorsal horn (SDH), where they play an important role in the transmission and modulation of nociceptive information. Recently, we performed physiological characterization of Enk‐containing neurons identified by green fluorescent protein fluorescence expressed under the control of the preproenkephalin gene promoter. We observed that Enk‐containing neurons in the SDH express the N‐methyl‐D‐aspartate receptor (NMDAR) 2B (NR2B) subunit and large conductance calcium activated potassium (BK) channels. In the present experiments, we investigated the involvement of NMDAR and BK channels in the regulation of the activity of Enk‐containing neurons in the SDH.The experiments were performed in 5‐ to 8‐week‐old male ICR mice. Under ketamine/xylazine anesthesia, the lumbar spinal cord was dissected, and transverse slices were prepared. Tight‐seal whole‐cell recordings were obtained from neurons in the SDH. L‐glutamate (Glu) was applied by pressure ejection through a glass pipette placed near the recorded neurons. After the electrophysiological experiments, the recorded neurons were sampled, and single cell real‐time RT‐PCR was performed to analyze the expression profile of genes of interest in single SDH neurons. In some experiments, the left sciatic nerve was partially ligated, and mechanical allodynia was assessed by von Frey test.Puff‐applied Glu evoked an inward current at a holding potential of −70 mV. Depolarizing the holding potential to 0 mV, outward current of long duration appeared subsequent to initial inward current. The NMDAR antagonist AP‐V abolished the outward current. The NR2B‐selective NMDAR antagonist ifenprodil reduced the outward current. The outward current was also abolished by the selective BK channels antagonist iberiotoxin. Single cell real‐time RT‐PCR analysis revealed that the neurons generating the outward current showed a significant tendency to express BK channels α‐subunit mRNA, which is consistent with the pharmacological results of a BK channels antagonist. Furthermore, single SDH neurons expressing the preproenkephalin mRNA also expressed the BK channel α‐subunit, NR1, and NR2B subunit mRNAs. The expression of NR2B increased significantly in sciatic nerve‐ligated mice.Our results suggest that Ca2+ influx through NMDAR may activate BK channels and thus inhibit Enk‐containing neurons in the SDH. NMDAR‐mediated inhibition of Enk‐containing neurons is speculated to be one of the possible cellular mechanisms of chronic pain induced by peripheral nerve injury.

NMDA receptor 2B Subunit and BK Channel May Affect Mechanical Allodynia by Regulating the Activity of Enkephalinergic Neurons in the Spinal Dorsal Horn

Enkephalin (ENK)‐containing neurons in the spinal superficial dorsal horn (SDH) play an important role in regulating the transmission of nociceptive information. Using BAC transgenic mice, in which ENK‐containing neurons can be identified by green fluorescent protein expressed under the control of preproenkephalin gene promoter, we have observed that ENK‐containing neurons in the SDH express the NMDA receptor 2B (NR2B) subunit and large conductance calcium‐activated potassium (BK) channels. In experiments, we investigated the effects on nociceptive behavior of intrathecally administrating NR2B subunit antagonist and BK channel antagonist in peripheral nerve‐injured mice.The experiments were performed in 6‐ to 8‐week‐old male ICR mice. Partial sciatic nerve ligation was performed as described previously (PSL, Seltzer model). To assess the development of mechanical allodynia, we measured the frequency of withdrawal responses to 10 repetitive stimuli with von Frey filaments. Behavioral assessments were performed beginning 3 days prior to the ligation surgery. On post‐surgical day 7, effects on nociceptive behavior of the BK channel antagonist, charybdotoxin (CTX), and the NR2B antagonist, ifenprodil (IFN), were analyzed. Additionally, in order to clarify whether the actions of CTX and IFN are mediated by an alteration in the release of enkephalin, we investigated the effect of the selective δ‐opioid receptor antagonist naltrindole (NTI).CTX (1 pmol/10 μL per mouse), IFN (50 nmol/10 μL per mouse) and saline as a control (10 μL per mouse) was intrathecally injected according to the modified method originally described by Hylden. All behavioral experiments were performed in double‐blind fashion.PSL significantly increased the occurrence of withdrawal reflex to von Frey stimuli being indicative of the development of mechanical allodynia. Intrathecal CTX significantly reduced the occurrence of withdrawal reflex as compared to saline group. Additionally, intraperitoneal administration of NTI at the dose of 5 mg/kg body weight attenuated the effect on nociceptive behavior of CTX. Intrathecal IFN significantly reduced the occurrence of withdrawal reflex. This effect was also blocked by intraperitoneal NTI.These behavioral observations might suggest that NMDA receptors and BK channels inhibit the activity of enkephalin‐containing neurons in the spinal dorsal horn, which is speculated to be involved in peripheral nerve injury‐induced chronic pain state.Support or Funding InformationThis work was supported by Dokkyo Medical University Endowment Fund.

Identifying brain nociceptive information transmission in patients with chronic somatic pain.

Recent advances regarding mechanisms of chronic pain emphasize the role of corticolimbic circuitry in predicting risk for chronic pain, independently from site of injury-related parameters. These results compel revisiting the role of peripheral nociceptive signaling in chronic pain. We address this issue by examining what brain circuitry transmit information regarding the intensity of chronic pain and how this information may be related to a common co-morbidity, depression. Resting state functional MRI was used in a large group of chronic pain patients (n=40 chronic back pain, CBP, and n=44 osteoarthritis, OA patients), and in comparison to healthy subjects (n=88). We used a graph theoretical measure, degree count, to investigate voxel-wise information sharing/transmission in the brain. Degree count, a functional connectivity based measure, identifies the number of voxels functionally connected to every given voxel. Subdividing the chronic pain cohort into discovery, replication, and also for overall group we show that only degree counts of diencephalic voxels centered in the ventral lateral thalamus reflected intensity of chronic pain, independently of depression. Pain intensity was reliably associated with degree count of the thalamus, which was correlated negatively with components of the default mode network and positively with the periaqueductal grey (in contrast to healthy controls). Depression scores were not reliably associated with regional degree count. Collectively the results suggest that, across two types of chronic pain, nociceptive specific information is relayed through the spinothalamic pathway to the lateral thalamus, potentiated by pro-nociceptive descending modulation, and interrupting cortical cognitive processes.

Altered T-UCRs expression profile in the spinal cord of mice with neuropathic pain

Spinal cord plays an important role in the transmission and modulation of nociceptive information. Global changes in gene expression in the spinal cord contribute to the induction and maintenance of neuropathic pain. Transcribed Ultraconserved Regions (T-UCRs), a novel class of long noncoding RNAs, can regulate gene expression at both transcriptional and post-transcriptional levels and are related to many human diseases such as cancer, Alzheimer's disease, and heart diseases. In this study, we screened abnormal T-UCRs expression in the spinal cord under spinal nerve ligation (SNL)-induced neuropathic pain condition. Microarray data showed the alternation of T-UCRs at the transcriptional level in the spinal cord 10 days after SNL. Among 78 altered T-UCRs, 23 T-UCRs were upregulated by more than 1.5-fold and 55 ones downregulated by less than 0.5-fold after SNL. Hierarchical cluster analysis of T-UCRs expression profiles showed the opposite expression pattern between SNL and sham-operated mice. The quantitative real-time reverse transcription polymerase chain reaction analysis further confirmed the expression patterns of uc.305, uc.189, uc.46, and uc.217 after SNL. The gene ontology annotation and signaling pathway analysis for the T-UCRs host genes indicated that differentially expressed T-UCRs were involved in several intracellular activities and signaling pathways, including Ephrin receptor activity, soluble NSF attachment protein receptor (SNARE) interactions in vesicular transport pathway, and WNT signaling pathway. Collectively, the current data suggest the possible role of T-UCR in the pathogenesis of neuropathic pain. T-UCRs may serve as a new kind of target for the treatment of neuropathic pain.

Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.

Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine.

ABSTRACTMigraine is a highly prevalent headache disorder, especially in women. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinases (TrkB), as well as extracellular signal-regulated kinase (ERK) and its downstream target c-AMP-responsive element binding protein (CREB) are strongly associated with the transmission of nociceptive information. However, the involvement of these substances in migraine has rarely been examined. In the present study, intraperitoneal injection of nitroglycerin (NTC) successfully induced rat migraine attack, as evidenced by behavioral testing. The location and abundance of these substances in the migraine model were determined by immunohistochemistry, real-time polymerase chain reaction (RT-PCR), western blot and enzyme-linked immunosorbant assays (ELISA). Results showed that BDNF, TrkB, phosphor(p)-ERK and p-CREB were up-regulated in the brain neurons of both male and female rats with NTG-induced migraine compared to non-migraine control, whereas their expression levels were decreased in headache-free intervals of the migraine compared to migraine attacks. Estrogen is an important contributor to migraine. Female ovariectomized rats showed significant reduction in the expression of BDNF, TrkB, p-CREB and p-ERK in both attacks and intervals of NTG-induced migraine, relative to rats that have their ovaries. But, intraperitoneal administration of exogenous estrogen recovered their expression in ovariectomized rats. Collectively, this study unveiled a positive correlation of BDNF/TrkB and ERK/CREB axes in NTG-induced migraine and promoting effects of estrogen on their signals in the migraine. These findings contribute to further understanding the pathogenesis of migraine in the molecular basis.