Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 g for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naive, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.

/pdf/transcriptional-profiling-of-non-injured-nociceptors-after-2v7o0vomw9.pdf

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis, and they are thus implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia. We present structure of the full-length human TRPC3, a lipid-gated TRPC member, in a lipid-occupied, closed state at 3.3 Angstrom. TRPC3 has an acorn-like shape with four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism. The third transmembrane helix S3 is remarkably long, resulting in a windmill-like transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. We identified two lipid binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located.

https://www.biorxiv.org/content/early/2018/03/21/286153.full.pdf

Structure of the human lipid-sensitive cation channel TRPC3

Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons distal to the site of injury may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15g for 1 minute. Alterations in gene expression produce long-term sensory changes, therefore we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting. RNA was extracted from sorted sensory neurons of naive, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain. Contribution to the field Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain. Much of the pain seems to emanate from tissues further away from the brain than the site of injury. Chronic pain develops weeks to months after injury, which means that patients are frequently treated only after enduring pain has developed. Nociceptors are the specialized sensory neurons central to chronic pain. We were interested in studying SCI-induced gene transcript (RNA) changes before the onset of chronic pain, in the hope of identifying mechanisms which could become therapeutic targets. Nociceptors below the site of spinal injury were isolated and their RNAs were sequenced. The results identified a unique pattern of gene expression in the subpopulation of nociceptors projecting to the relevant peripheral tissue. Particularly interesting were sets of genes crucial to synapse formation and maturation – the ability of neurons to talk to each other – and genes involved in inflammatory responses, since treatment of inflammation of nervous tissue could also be important for therapeutic approaches. It is evident that the transition from acute to chronic pain occurs in distinct steps that involve numerous signaling pathways, providing a host of potential new drug targets.

/pdf/transcriptional-profiling-of-non-injured-nociceptors-after-1kyh7zgabn.pdf

Transcriptional profiling of non-injured nociceptors after spinal cord injury reveals diverse molecular changes

886a Spinal Microglia Mediates the Initiation/Maintanence of Visceral Hyperalgesia in Rats With Chronic Pancreatitis

Endogenous TRPC channels mediate Ca2+ signals and trigeminal synaptic plasticity induced by mGluR5.

Chronic visceral pain is a typical condition associated with inflammation. The mechanism of visceral pain in chronic abdominal pain syndromes, such as irritable bowel syndrome and chronic pancreatitis, is poorly understood and its treatment has been largely empirical, with an outcome that is variable and frequently unsatisfactory. Human and experimental studies have indicated a critical role of neuronal mechanisms that result in peripheral and central sensitization.1–3 The nociceptive sensitization, literally meaning sensitization to noxious stimuli, begins with the primary afferent nociceptor, a nerve whose cell body lies in the dorsal root ganglia (DRG). DRG is located next to the spinal cord and has 2 branches: a long peripheral one terminating in the target tissue and a shorter central process that ends in the dorsal horn of the spinal cord. The peripheral process of these neurons senses tissue injury via a variety of receptors that respond to specific physical or chemical factors in the injured environment. In studying visceral pain, several visceral nociceptors have been identified as significant factors in inflammatory condition. For instance, A-type potassium channel is downregulated in chronic pancreatitis.2 Others, including transient receptor potential vanilloid 1,4 nerve growth factor,5 the protease activated receptor 2 (PAR2),6 and transforming growth factor beta1,7 are upregulated. In a further mechanism study on those nociceptors in thoracic/lumbar DRG, a prolonged intracellular calcium elevation is commonly associated with the neuronal hyper-excitability or hyper-sensitivity, contributing to nociception and chronic pain (hyperalgesia or allodynia).

There are 2 distinct mechanisms proposed in modulating the intracellular calcium level when noxious stimuli activating the cognate membrane receptors at the surface of nociceptors.8 Store-operated calcium entry (SOCE) involves in activation of calcium channels by inositol 1,4,5-trisphosphate which is the key for calcium depletion from endoplasmic reticulum calcium stores; receptor-operated calcium entry (ROCE) involves in activation of calcium permeable channels directly by DAG.9,10 It remains unknown whether ROCE mechanism sensitizes the sensory neuron, however, SOCE component participates in calcium homeostasis and plays a significant role in chronic pain pathologies.

Recently, Alkhani et al11 published “Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors” in Molecular Pain. This study reveals a major contribution of transient receptor potential cation channels (TRPC) to neuronal calcium homeostasis in somatosensory pathways. These channels are non-selectively permeable to cations, with a selectivity of calcium over sodium variable among the different members. Here, TRPC engages in both SOCE and ROCE in control of calcium influx that triggers calcium-dependent pathways and peripheral sensitization. Therefore TRPC is functionally coupled to several inflammatory transductions, including UTP/P2Y2 and proteases/PAR2 signaling complexes. Logically, this unique dual contribution to SOCE and ROCE defines the calcium-permeable TRPC3 channel as a key regulator of calcium homeostasis in DRG neurons in normal or pathological pain conditions. Therefore, TRPC3 is a new target for therapeutic strategies in chronic pain.

TRPC3: A New Target for Therapeutic Strategies in Chronic Pain-DAG-mediated Activation of Non-selective Cation Currents and Chronic Pain (Mol Pain 2014;10:43).

c 2022 The Korean Society of Neurogastroenterology and Motility J Neurogastroenterol Motil, Vol. 28 No. 2 April, 2022 www.jnmjournal.org TO THE EDITOR: Factors that can contribute to bile reflux gastritis are generally categorized as primary biliary reflux and secondary biliary reflux after gastric resection with ablation of the pylorus. Primary biliary reflux is excessive bile in the duodenum retrograding to the stomach. Risk factors include gallbladder dyskinesia, gastric or duodenal dysmotility, and surgical resection such as cholecystectomy and sphincterotomy. Recently, a new analysis for the old problem of primary bile reflux gastropathy has been reported, in which a total of 262 patients with functional dyspepsia (FD) were stratified into 3 cohorts: bile gastropathy (BG), non-bile gastropathy (NBG), and no gastropathy (NG). The evaluations based on phenotype, symptoms, endoscopic and histological changes, etc. were compared using chi-square test for continuous data, Kruskal– Wallis test (one-way analysis of variance) for continuous data, and multivariate regression for 2 binary modeling. The findings of this study are mainly featured or established with some characteristics to BG, in contrast to BNG and NG. Following aspects from BG, versus to BNG and NG, are significantly more severe or increased: (1) abdominal pain, (2) prevalence of cholecystectomy, (3) prevalence of gastric erythema in endoscopic examination, (4) prevalence of gastritis, (5) edema, and (6) chronic active inflammation on pathological examination. Indeed, this is a more comprehensive study, and its cohort analysis could be potentially informative in the diagnosis of bile reflux gastritis in clinical practice though it is not the criteria. However, a few of concerns raised from this study may be worth to further discussing for clarification and understanding. First, the subjects included in the study were patients with FD, therefore, delayed gastric emptying was crucial and expected. In the literature, significantly longer delayed gastric emptying and higher bilirubin concentrations were observed in patients with bile reflux gastritis. The validation of the wireless motility capsule testing used in the study may need to adjust/compare with traditional or universally accepted measurements, since the supplementary results showing delayed gastric emptying in BG, NBG, and NG are respectively 38.6%, 40.4%, and 39.1% (P = 0.981), as seen in Table. At least, a further explanation on why there is no correlation with the degree of bile reflux among cohorts is expected by audiences. Second, the differential of heartburn was not discernable among the cohorts as seen in Figure. In the contrary, the amplitude of that from BG is obviously lower than other cohorts which looks different enough to be statistically significant. Then, the patients who did not have cholecystectomy could be more informative if such cohorts could be analyzed. Since the diagnosis of bile reflux gastritis is very challenging, any difference from BG, NBG, and NG may be guides for the diagnosis, treatment, and prognosis. As commented, “role of bile reflux in functional dyspepsia: areas that need further research,” there are few studies on the association of bile reflux, FD, the severity of symptoms, and response to Table. Assessment of Motility

https://www.jnmjournal.org/journal/download_pdf.php?doi=10.5056/jnm21207

A New Analysis for Old Problem of Bile Reflux

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TRPC3: A New Target for Therapeutic Strategies in Chronic Pain-DAG-mediated Activation of Non-selective Cation Currents and Chronic Pain (Mol Pain 2014;10:43).

A New Analysis for Old Problem of Bile Reflux