Thoracic spinous process nonunion as an unusual cause of back pain: a case report and review of the literature.

BACKGROUND: Purely isolated spinous processes fractures are rare and are usually treated conservatively, although a few authors have reported cases of nonunion that ultimately required surgical resection. CASE PRESENTATION: We present a case of an isolated T6 spinous process pseudoarthrosis that was treated by surgical resection of the tip of the spinous process. A 34-year-old Caucasian male patient was complaining of mid-thoracic back pain without neurologic impairment more than 2 years after an isolated spinous process fracture. Magnetic Resonance Imaging (MRI) and Single Photon Emission Computed Tomography (SPECT) revealed a nonunion. We performed a resection without further complication. CONCLUSION: Although spinous process nonunions may in some cases be well tolerated, surgical resection appears to be a reliable option in case of persistent symptoms. This illustrated case shows the description of an isolated thoracic spinous process nonunion and its surgical treatment.

Influence of Normal Aging and Multisensory Data Fusion on Cybersickness and Postural Adaptation in Immersive Virtual Reality.

Immersive Virtual Reality (VR) systems are expanding as sensorimotor readaptation tools for older adults. However, this purpose may be challenged by cybersickness occurrences possibly caused by sensory conflicts. This study aims to analyze the effects of aging and multisensory data fusion processes in the brain on cybersickness and the adaptation of postural responses when exposed to immersive VR. METHODS: We repeatedly exposed 75 participants, aged 21 to 86, to immersive VR while recording the trajectory of their Center of Pressure (CoP). Participants rated their cybersickness after the first and fifth exposure. RESULTS: The repeated exposures increased cybersickness and allowed for a decrease in postural responses from the second repetition, i.e., increased stability. We did not find any significant correlation between biological age and cybersickness scores. On the contrary, even if some postural responses are age-dependent, a significant postural adaptation occurred independently of age. The CoP trajectory length in the anteroposterior axis and mean velocity were the postural parameters the most affected by age and repetition. CONCLUSIONS: This study suggests that cybersickness and postural adaptation to immersive VR are not age-dependent and that cybersickness is unrelated to a deficit in postural adaptation or age. Age does not seem to influence the properties of multisensory data fusion.

Proenkephalin deletion in hematopoietic cells induces intestinal barrier failure resulting in clinical feature similarities with irritable bowel syndrome in mice.

Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer's patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.

Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life.

BACKGROUND: Perinatal exposure to titanium dioxide (TiO2), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel disease (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO2 exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO2 until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2'-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis. RESULTS: In pregnant and lactating mice, foodborne TiO2 was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO2 early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO2 also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO2 exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO2-induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring. CONCLUSIONS: Our findings indicate that foodborne TiO2 consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.

Tolerance of immersive head-mounted virtual reality among older nursing home residents.

Introduction: Virtual Reality (VR) is a tool that is increasingly used in the aging population. Head-Mounted Displays (HMDs) are stereoscopic vision devices used for immersive VR. Cybersickness is sometimes reported after head-mounted display (HMD) VR exposure. Cybersickness severity and anxiety state reflect VR low tolerance. We aimed to evaluate HMD VR tolerance among older nursing home residents through cybersickness and anxiety state. Methods: A total of 36 participants were included in this preliminary study, 33 of whom (mean age: 89.33 ± 5.48) underwent three individual HMD VR sessions with three different contents. Cybersickness occurrence and severity were scored by the Simulator Sickness Questionnaire (SSQ) after each session. Anxiety state was assessed by the State-Trait Anxiety Inventory form Y-A before and after each session. Anxiety trait (using State-Trait Anxiety Inventory form Y-B) was also evaluated before and after the experiment. In total, 92% (33/36) of patients completed all three sessions, of which 61% (20/33) did not report any cybersickness symptoms (SSQ = 0). Six participants reported significant cybersickness (defined by an SSQ score ⩾10) in at least one session. Discussion: Only two participants stopped the study after the first exposure because of cybersickness. Age, cognitive function, anxiety trait, and well-being were not associated with cybersickness. The mean anxiety state decreased significantly from pre- to post-session. This immersive HMD VR experience was well tolerated among nursing home dwellers. Further larger studies in this population aiming to identify CS determinants are needed in order to use HMD VR on a standard basis.

Influence of smoking on the healing of conservatively treated displaced midshaft clavicle fractures.

Aims: Tobacco, in addition to being one of the greatest public health threats facing our world, is believed to have deleterious effects on bone metabolism and especially on bone healing. It has been described in the literature that patients who smoke are approximately twice as likely to develop a nonunion following a non-specific bone fracture. For clavicle fractures, this risk is unclear, as is the impact that such a complication might have on the initial management of these fractures. Methods: A systematic review and meta-analysis were performed for conservatively treated displaced midshaft clavicle fractures. Embase, PubMed, and Cochrane Central Register of Controlled Trials (via Cochrane Library) were searched from inception to 12 May 2022, with supplementary searches in Open Grey, ClinicalTrials.gov, ProQuest Dissertations & Theses, and Google Scholar. The searches were performed without limits for publication date or languages. Results: The meta-analysis included eight studies, 2,285 observations, and 304 events (nonunion). The random effects model predicted a pooled risk ratio (RR) of 3.68 (95% confidence interval 1.87 to 7.23), which can be considered significant (p = 0.003). It indicates that smoking more than triples the risk of nonunion when a fracture is treated conservatively. Conclusion: Smoking confers a RR of 3.68 for developing a nonunion in patients with a displaced middle third clavicle fracture treated conservatively. We know that most patients with pseudarthrosis will have pain and a poor functional outcome. Therefore, patients should be informed of the significantly higher risks of nonunion and offered smoking cessation efforts and counselling. Moreover, surgery should be considered for any patient who smokes with this type of fracture.

Significant Reduction of Radiation Exposure Using Specific Settings of the O-Arm for Percutaneous Cementoplasty in Accordance With the ALARA Principle.

BACKGROUND: Three-dimensional (3D) navigation has become routinely used in spine surgery, allowing more accurate and safe procedures. However, radiation exposure related to the use of imaging is an unresolved issue, and information about it is relatively scarce. The "as low as reasonably achievable" (ALARA) principle aims to reduce the radiation exposure for the patients as low as possible. The objective of this study was to compare the effective dose related to the use of the O-arm in standard settings with adapted features for dose reduction during percutaneous cementoplasty. METHODS: From March 2021 to October 2022, all consecutive patients who underwent navigated percutaneous cementoplasty with the use of the O-arm were prospectively included. Demographic, operative, irradiation, and radiological data were collected. The main outcome was the effective dose (E) in millisievert (mSv). Secondary outcomes were the absolute risk of cancer (AR) in percent equivalent to a whole-body exposition, operative time, and radiological results according to Garnier. In group A, patients were operated on with standard settings of the O-arm, whereas in group B, navigation on the field of view, collimation, and low-dose settings were used. RESULTS: A total of 70 patients were included in the study: 43 in group A and 27 in group B. Also, 109 vertebrae were operated: 59 in group A and 50 in group B. Mean E was significantly higher in group A than in group B (9.94 and 4.34 mSv, respectively; P < 0.01). The 3D-related E followed the same trend (7.82 and 3.97 mSv, respectively), as did 2-dimensional-related E (2.12 and 0.37 mSv, respectively; P < 0.01). Average AR was also significantly higher in group A than in group B (5.10-4% and 2.10-4% respectively; P < 0.01). Operative time was similar in both groups, but the rate of satisfactory radiological results was higher in group A than in group B (95% and 84%, respectively; P = 0.11), and we found similar rates of cement leakage (22% and 24%, respectively; P = 0.71). CONCLUSIONS: The application of settings of the O-arm in accordance with the ALARA principle helped to significantly reduce the radiation exposure and should be routinely used for O-arm-assisted cementoplasty procedures. CLINICAL RELEVANCE: This study details technical aspects and settings that may help users of the O-arm to decrease radiation exposure to patients and surgeons alike, especially in cementoplasty procedures, as well as in other procedures performed under O-arm guidance.

Identification of bacterial lipopeptides as key players in IBS.

OBJECTIVES: Clinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA). DESIGN: We developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity. RESULTS: Prenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance of Ligilactobacillus murinus, in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs. CONCLUSION: PS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood.

Major acetabular prosthetic protrusion following total hip arthroplasty: a case report of a reconstruction challenge.

Background: Acetabular protrusion is an acetabular defect caused by the shift of the femoral head through the pelvic bone. Because of bone loss, usual anatomical landmarks may be confusing or absent, leading to a particularly high demanding surgical reconstruction in case of total hip arthroplasty (THA) implantation, without adequate support of the acetabulum due to major acetabular defect. To our knowledge, no article has dealt with acetabular defects to this extent and associated femoral osteolysis, which we will attempt to do in this case report. That's why we would like to share this case in order to propose an interesting alternative for the management of these challenging pathologies. Case Description: We hereby present the case of a rare pattern of severe acetabular prosthetic protrusion through the pelvic ring on a 77-year-old patient without any trauma. He was surgically treated with acetabular metal augment and a wide femoral modular reconstruction prosthesis. An instability was revealed after 6 weeks, so he underwent an early surgical revision with a constraint cup, overwhelming the absence of abductor apparatus. After this, his recovery was complete and uneventful, with effective function of the reconstructed hip joint and adequate stability of the prosthesis. Conclusions: Although acetabular protrusion is a rare complication in total hip replacement patients, we would like to draw attention to the challenging nature of this complication, both in terms of initial assessment and surgical management. The described strategy showed effective function of the reconstructed hip joint and final adequate stability of the prosthesis despite the absence of a competent abductor apparatus.

Isolated Femoral LCL Avulsion Fracture in the Adult Knee: Two Patient Cases and Literature Review.

Avulsion injuries of the LCL most commonly occur at the fibular insertion. Femoral LCL avulsion injuries have only been previously described in pediatric patients or as multiligament knee injury components among adults. This case series with comprehensive literature review describes for the first time 2 cases of isolated LCL femoral avulsion fractures in adults including conservative treatment outcomes. Both patients sustained a strong varus stress mechanism to their right knee, following sport injury or road traffic accident. For both patients, a complete radiographic evaluation including X-rays, MRI, and CT scan confirmed no other associated knee lesions. The femoral LCL avulsion fractures that were observed were minimally displaced and noncomminuted. Furthermore, imagery suggested preserved integrity at the superior lateral genicular artery, adjacent articular capsule, and IT band. Based on clinical and imaging evaluations, the decision was made to follow conservative treatment. By 10 weeks postinjury, both patients were asymptomatic with early radiological fracture healing evidence. Comparative varus stress radiographs at 20° knee flexion revealed no side-to-side differences and clinical exam showed no posterolateral rotatory instability. The second patient case presented with mild femoral LCL attachment calcification on follow-up CT-scan. Following a detailed analysis of anatomic injury characteristics, we suggest that patients with isolated femoral LCL avulsion fractures have low secondary displacement risk provided SLGA, articular capsule, and IT band integrity are present. In contrast to high-grade ligamentous and distal avulsion LCL injuries, we recommend conservative treatment for patients who sustain these lesions.

Conservative management of a specific subtype of Maisonneuve fractures: a report of two cases.

Background: Maisonneuve fractures are most commonly characterised by a specific pattern with a medial malleolar fracture or deltoid ligament rupture, a disruption of the ankle syndesmosis ligaments and a fracture of the proximal fibula. Case Description: We hereby describe for the first time two cases of conservative therapy of Maisonneuve fracture with intact medial structures and with associated posterior malleolus fracture. Patients were assessed with ankle radiographs and magnetic resonance imaging (MRI). The distal fibula was anatomically positioned in its notch and the deltoid ligament and interosseous membrane (IOM) were intact. In addition, the posterior malleolus fracture was not associated with talar subluxation or articular impaction, and the mortise remained anatomically positioned on the initial radiographs. Based on clinical and imaging evaluations, the decision was made to follow conservative treatment. Follow-up showed stability criteria on standing radiographs, and their evolution was clinically uneventful with a good AOFAS score after 1 year. Conclusions: The discussion emphasized the scarce description of conservative therapy of Maisonneuve fractures for which surgical treatment is considered to be the gold standard. The good results of these two cases are in favour with conservative therapy, avoiding adverse events and complications related to surgery, and showed that conservative therapy should be also considered as an effective therapeutic option in selected cases. We also emphasize that the results of our two cases are, moreover, in favor of an early weight-bearing protocol.

Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis.

BACKGROUND: Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. METHODS: The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. RESULTS: Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. CONCLUSION: The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.

Chemically diverse activity-based probes with unexpected inhibitory mechanisms targeting trypsin-like serine proteases.

Activity-based probes (ABP) are molecules that bind covalently to the active form of an enzyme family, making them an attractive tool for target and biomarker identification and drug discovery. The present study describes the synthesis and biochemical characterization of novel activity-based probes targeting trypsin-like serine proteases. We developed an extensive library of activity-based probes with "clickable" affinity tags and a diaryl phosphonate warhead. A wide diversity was achieved by including natural amino acid analogs as well as basic polar residues as side chains. A detailed enzymatic characterization was performed in a panel of trypsin-like serine proteases. Their inhibitory potencies and kinetic profile were examined, and their IC50 values, mechanism of inhibition, and kinetic constants were determined. The activity-based probes with a benzyl guanidine side chain showed the highest inhibitory effects in the panel. Surprisingly, some of the high-affinity probes presented a reversible inhibitory mechanism. On the other hand, probes with different side chains exhibited the expected irreversible mechanism. For the first time, we demonstrate that not only irreversible probes but also reversible probes can tightly label recombinant proteases and proteases released from human mast cells. Even under denaturing SDS-PAGE conditions, reversible slow-tight-binding probes can label proteases due to the formation of high-affinity complexes and slow dissociation rates. This unexpected finding will transform the view on the required irreversible nature of activity-based probes. The diversity of this library of activity-based probes combined with a detailed enzyme kinetic characterization will advance their applications in proteomic studies and drug discovery.

Peripheral Opioid Receptor Blockade Enhances Epithelial Damage in Piroxicam-Accelerated Colitis in IL-10-Deficient Mice.

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.

Multiple primary malignancies: synchronous lymphoma, pancreatic neuroendocrine tumour and colorectal cancer.

A 67-year-old woman underwent a medical check-up by her general practitioner after complaining of atypical pain in the shoulder girdle. Due to the important inflammatory syndrome noticed on blood testing, a polymyalgia rheumatica was suspected and she was started on corticosteroid treatment with good clinical response, but no impact on inflammation. She underwent extensive imaging with a thoraco-abdominal CT scanner that demonstrated a pancreatic mass, then later a PET-CT showed 3 different hyperactive lesions. Biopsies then revealed simultaneous diffuse large B-cell lymphoma (DLBCL), colorectal adenocarcinoma and pancreatic neuroendocrine tumour. She benefited from low rectal endoscopic excision of the colorectal tumour, R-CHOP chemotherapy for DLBCL and laparoscopic left pancreatectomy. Successful treatment required a good multidisciplinary collaboration between the different specialists. The patient made a good recovery and achieved complete remission at 1 year. This an unusual presentation of multiple primary malignancies.

Colitis Linked to Endoplasmic Reticulum Stress Induces Trypsin Activity Affecting Epithelial Functions.

BACKGROUND AND AIMS: Intestinal epithelial cells [IECs] from inflammatory bowel disease [IBD] patients exhibit an excessive induction of endoplasmic reticulum stress [ER stress] linked to altered intestinal barrier function and inflammation. Colonic tissues and the luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown. We aimed to study the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions. METHODS: The impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cell lines or organoids. Moreover, treating human intestinal cells with protease-activated receptor antagonists allowed us to investigate ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology. RESULTS: Colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apical trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 [CXCL8]. The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of protease-activated receptors 2 and 4. CONCLUSIONS: Excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, promoting the development of inflammatory process.

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice.

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.

Pain Management in a Model of Interstitial Cystitis/Bladder Pain Syndrome by a Vaccinal Strategy.

Current analgesic treatments for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) are limited. Here, we propose a novel antinociceptive strategy exploiting the opioid-mediated analgesic properties of T lymphocytes to relieve from bladder pain. In a chronic model of IC/BPS in rats, we show that a secondary T cell response against intravesically administered ovalbumin prevents from visceral pain in OVA-primed animals. The analgesic effect is associated with the recruitment of T lymphocytes within the inflamed mucosa and is reversed by naloxone-methiodide, a peripheral opioid receptor antagonist. Similarly, intravesical instillation of BCG or tetanus toxoid antigens in vaccinated rats protects from pain in the same model. We show opioid-dependent analgesic properties of local vaccine antigen recall in a preclinical rat model of chronic cystitis. Since BCG bladder instillation is regularly used in humans (as anticancer therapy), our results open it as a new therapeutic positioning for a pain management indication for IC/BPS patients.

Endothelin-1 Exhibiting Pro-Nociceptive and Pro-Peristaltic Activities Is Increased in Peritoneal Carcinomatosis.

Background: Peritoneal carcinomatosis often results in alterations in intestinal peristalsis and recurrent abdominal pain. Pain management in these patients is often unsatisfactory. This study aimed to investigate whether endothelin-1 (EDN1) was involved in pain mediation in peritoneal carcinomatosis, and thus whether the EDN1 pathway could be a new therapeutic target for peritoneal carcinomatosis-associated pain. Methods: EDN1 plasma levels and abdominal pain severity were assessed in patients with abdominal tumors, with or without peritoneal carcinomatosis, and in healthy donors. The effects of EDN1 on the visceromotor response to colorectal distension, and on colonic contractions were then examined in mice, and the mechanism of action of EDN1 was then investigated by measuring the impact of EDN1 exposure on calcium mobilization in cultured neurons. Inhibition studies were also performed to determine if the effects of EDN1 exposure could be reversed by EDN1-specific receptor antagonists. Results: A positive correlation between EDN1 plasma levels and abdominal pain was identified in patients with peritoneal carcinomatosis. EDN1 exposure increased visceral sensitivity and the amplitude of colonic contractions in mice and induced calcium mobilization by direct binding to its receptors on sensory neurons. The effects of EDN1 were inhibited by antagonists of the EDN1 receptors. Conclusions: This preliminary study, using data from patients with peritoneal carcinomatosis combined with data from experiments performed in mice, suggests that EDN1 may play a key role mediating pain in peritoneal carcinomatosis. Our findings suggest that antagonists of the EDN1 receptors might be beneficial in the management of pain in patients with peritoneal carcinomatosis.