Macrophage-T Cell Interactions Mediate Neuropathic Pain through the Glucocorticoid-induced Tumor Necrosis Factor Ligand System

Peripheral neuroinflammation caused by activated immune cells can provoke neuropathic pain. Herein, we investigate the actions of macrophages and T cells through glucocorticoid-induced tumor neurosis factor receptor ligand (GITRL) and its receptor (GITR) in neuropathic pain. After partial sciatic nerve ligation (PSL) in enhanced green fluorescent protein (eGFP) chimeric mice generated by the transplantation of eGFP⁺ bone marrow cells, eGFP⁺ macrophages, and T cells markedly migrated to the injured site after PSL. Administration of agents to deplete macrophages (liposome-clodronate and Clophosome-A^TM) or T cells (anti-CD4 antibody and FTY720) could suppress PSL-induced thermal hyperalgesia and tactile allodynia. The expression levels of co-stimulatory molecules GITRL and GITR were increased on infiltrating macrophages and T cells, respectively. The perineural injection of a GITRL neutralizing antibody that could inhibit the function of the GITRL-GITR pathway attenuated PSL-induced neuropathic pain. Additionally, the induction of inflammatory cytokines and the accumulation of GITR⁺ T cells in the injured SCN were abrogated after macrophage depletion by Clophosome-A^TM. In conclusion, GITRL expressed on macrophages drives cytokine release and T cell activation, resulting in neuropathic pain via GITR-dependent actions. The GITRL-GITR pathway might represent a novel target for the treatment of neuropathic pain.     

Estimated human absorbed dose of a new 153Sm bone seeking agent based on biodistribution data in mice: Comparison with 153Sm-EDTMP

PurposeThe main goal in radiotherapy is to deliver the absorbed dose within the target organs in highest possible amount, while the absorbed dose of the other organs, especially the critical organs, should be kept as low as possible. In this work, the absorbed dose to human organs for a new ¹⁵³Sm bone-seeking agent was investigated.Methods¹⁵³Sm-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (¹⁵³Sm-BPAMD) complex was successfully prepared. The biodistribution of the complex was investigated in male Syrian mice up to 48 h post injection. The human absorbed dose of the complex was estimated based on the biodistribution data of the mice by radiation absorbed dose assessment resource (RADAR) method. The target to non-target absorbed dose ratios for ¹⁵³Sm-BPAMD were compared with these ratios for ¹⁵³Sm-EDTMP.ResultsThe highest absorbed dose for ¹⁵³Sm-BPAMD was observed in bone surface with 5.828 mGy/MBq. The dose ratios of the bone surface to the red marrow and to the total body for ¹⁵³Sm-BPAMD were 5.3 and 20.0, respectively, while these ratios for ¹⁵³Sm-EDTMP were 4.4 and 18.3, respectively. This means, for a given dose to the bone surface as the target organ, the red marrow (as the main critical organ) and the total body would receive lesser absorbed dose in the case of ¹⁵³Sm-BPAMD.ConclusionsGenerally, the human absorbed dose estimation of ¹⁵³Sm-BPAMD indicated that all other tissues approximately received insignificant absorbed dose in comparison with bone surface and therefore can be regarded as a new potential agent for bone pain palliation therapy.     

Discovery of a novel series of selective HCN1 blockers

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.     

Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor

Two new series of EP₄ antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP₄ receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.     

神经病理痛大鼠DRG神经元GABAA受体激活电流的变化

目的：观察坐骨神经慢性压榨损伤（CCI）致神经病理痛后,大鼠背根节神经元GABAA受体（γ-氨基丁酸A受体）激活电流的变化。方法：运用全细胞膜片钳技术记录CCI模型手术侧、手术对侧及假手术组大鼠背根神经节细胞GABAx受体激活电流,比较坐骨神经慢性压榨损伤后GABAA受体激活电流的变化。结果：①CCI模型组大鼠手术侧DRG神经元在不同浓度（0．1-1000μmol／L）GABAA受体激活电流幅值均显著小于假手术组。②CCI模型组大鼠手术对侧DRG神经元在不同浓度（0．01-1000μmol／L）GABAA受体激活电流幅值均显著大于手术同侧及假手术组。结论：在坐骨神经慢性压榨损伤的过程中,不仅损伤侧的DRG神经元GABAA受体激活电流显著减小,这种损伤同时还引起了手术对侧的DRG神经元GABA激活电流代偿性的增强,GABAA受体功能的改变导致的突触前抑制作用的减弱可能是神经病理痛产生的根本原因之一。     

Altered activity of the serratus anterior during unilateral arm elevation in patients with cervical disorders

Altered activity in the axioscapular muscles is considered to be an important feature in patients with neck pain. The activity of the serratus anterior (SA) and trapezius muscles during arm elevation has not been investigated in these patients. The objectives of this study was to investigate whether there is a pattern of altered activity in the SA and trapezius in patients with insidious onset neck pain (IONP) (n = 22) and whiplash associated disorders (WAD) (n = 27). An asymptomatic group was selected for baseline measurements (n = 23).Surface electromyography was used to measure the onset of muscle activation and duration of muscle activity of the SA as well as the upper, middle, and lower trapezius during unilateral arm elevation in the three subject groups. Both arms were tested.With no interaction, the main effect for the onset of muscle activation and duration of muscle activity for serratus anterior was statistically significant among the groups. Post hoc comparison revealed a significantly delayed onset of muscle activation and less duration of muscle activity in the IONP group, and in the WAD group compared to the asymptomatic group. There were no group main effects or interaction effects for upper, middle and lower trapezius.This finding may have implications for scapular stability in these patients because the altered activity in the SA may reflect inconsistent or poorly coordinated muscle activation that may reduce the quality of neuromuscular performance and induce an increased load on the cervical and the thoracic spine.     

Electrophysiological Measurements and Analysis of Nociception in Human Infants

Pain is an unpleasant sensory and emotional experience. Since infants cannot verbally report their experiences, current methods of pain assessment are based on behavioural and physiological body reactions, such as crying, body movements or changes in facial expression. While these measures demonstrate that infants mount a response following noxious stimulation, they are limited: they are based on activation of subcortical somatic and autonomic motor pathways that may not be reliably linked to central sensory processing in the brain. Knowledge of how the central nervous system responds to noxious events could provide an insight to how nociceptive information and pain is processed in newborns.The heel lancing procedure used to extract blood from hospitalised infants offers a unique opportunity to study pain in infancy. In this video we describe how electroencephalography (EEG) and electromyography (EMG) time-locked to this procedure can be used to investigate nociceptive activity in the brain and spinal cord.This integrative approach to the measurement of infant pain has the potential to pave the way for an effective and sensitive clinical measurement tool.     

慢性非细菌性前列腺炎/慢性骨盆疼痛综合征患者的尿动力学检查

目的:探讨尿动力学检查在了解慢性非细菌性前列腺炎/慢性骨盆疼痛综合征(Chronicabacterialprostatitis/chronicpelvicpain syndrome,CPPS)患者中下尿路症状(LUTS)产生原因的作用。方法:对36例难治性慢性前列腺炎/盆腔疼痛综合征患者行尿流动力学压力-流率测定,同步测定膀胱压、逼尿肌压、同步肌电图测定,了解其症状产生的原因。结果:36例患者中,尿动力学证实膀胱出口梗阻14例(39%);逼尿肌过度活动者8例,其中有7例与BOO同时存在;假性逼尿肌尿道外括约肌协同失调6例(16.7%);逼尿肌收缩力低下者5例(13.9%)。结论:对难治性CPPS患者进行尿动力学检查有助于对此类患者LUTS产生的原因进行鉴别,从而可以采取有针对性的治疗。     

Rho-kinase mediates spinal nitric oxide formation by prostaglandin E2 via EP3 subtype

Prostaglandin E2 (PGE2), the principal pro-inflammatory prostanoid, is known to play versatile roles in pain transmission via four PGE receptor subtypes, EP1-EP4. We recently demonstrated that continuous production of nitric oxide (NO) by neuronal NO synthase (nNOS) following phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) and NMDA receptor NR2B subunits is essential for neuropathic pain. These phosphorylation and nNOS activity visualized by NADPH-diaphorase histochemistry were blocked by indomethacin, a PG synthesis inhibitor. To clarify the interaction between cyclooxygenase and nNOS pathways in the spinal cord, we examined the effect of EP subtype-selective agonists on NO production. NO formation was stimulated in the spinal superficial layer by EP1, EP3, and EP4 agonists. While the EP1- and the EP4-stimulated NO formation was markedly blocked by MK-801, an NMDA receptor antagonist, the EP3-stimulated one was completely inhibited by H-1152, a Rho-kinase inhibitor. Phosphorylation of MARCKS and NADPH-diaphorase activity stimulated by the EP3 agonist were also blocked by H-1152. These results suggest that PGE2 stimulates NO formation by Rho-kinase via EP3, a mechanism(s) different from EP1 and EP4.