BACKGROUND: Endometriosis is a chronic inflammatory disease that affects ∼ 10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis.
OBJECTIVE: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice.
METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT).
RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain.
CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

One of the most common concerns of patients undergoing surgery is preoperative anxiety, with a prevalence of up to 48%. The effects of preoperative anxiety continue beyond the preoperative period and are associated with more severe postoperative pain and poorer treatment outcomes. Treatment options for preoperative anxiety are often limited as sedatives cause side effects and their efficacy remains controversial. Placebo research has shown that optimization of positive treatment expectations, as can be achieved through placebo administration and education, has clinically relevant effects on preoperative anxiety, pain and treatment outcomes. As the administration of masked placebos raises ethical questions, clinical studies have increasingly focused on the use of open, non-deceptive placebo administration (open-label placebo, OLP). The use of OLPs to reduce preoperative anxiety and modify clinically relevant postoperative outcomes has not yet been investigated. This bicentric, prospective, randomized-controlled clinical trial (PATE Trial; German Registry for Clinical Studies DRKS00033221), an associated project of the Collaborative Research Center (CRC) 289 \"Treatment Expectation\", aims to alleviate preoperative anxiety by optimizing positive treatment expectations facilitated by OLP. Furthermore, this study examines a potential enhancement of these effects through aspects of observational learning, operationalized by a positive expectation-enhancing video. In addition, patient\'s perspective on the self-efficacy and appropriateness of OLPs prior to surgery will be assessed. To achieve these objectives, female patients will be randomized into three groups before undergoing gynecological laparoscopic surgery. One group receives the OLP with a positive rationale conveyed by a study physician. A second group receives the same intervention, OLP administration and rationale provided by a physician, and additionally watches a video on OLP presenting a satisfied patient. A third group receives standard treatment as usual (TAU). Outcome measures will be effects on preoperative anxiety and postoperative experience, particularly visceral and somatic postoperative pain. As the non-deceptive administration of placebos; when indicated; may yield positive outcomes without side effects, and as current treatment of preoperative anxiety is limited, evidence from clinical placebo research has the potential to improve outcomes and patient experience in the surgical setting.

BACKGROUND: The aim of this study was to investigate the frequency dependence of electroacupuncture (EA) in alleviating chronic visceral pain in patients with irritable bowel syndrome (IBS) and the differences in the gut microbiota and metabolites as potential mechanisms to explain frequency dependence.
METHODS: A visceral hyperalgesia model was established by colorectal instillation of 2,4,6-trinitrobenzene sulfonic acid in rats, and EA treatment at 2/10 Hz, 2/50 Hz and 2/100 Hz was applied at ST25. Visceral sensation was quantified by the abdominal withdrawal reflex score and the area under the curve of the rectus abdominis electromyogram in response to colorectal distension. Ultrastructural morphological damage of colonic tissue of the rats was examined by transmission electron microscopy. 16S rRNA gene sequencing and 1H-nuclear magnetic resonance spectroscopy were applied to study the differences in the gut microbiota and to perform metabonomic profiling of the colonic tissue.
RESULTS: EA at ST25 at different frequencies attenuated chronic visceral pain, ultrastructural morphological damage to colonic tissue and disruption of the gut microbiota in IBS rats. The frequency of 2/100 Hz has more regulatory pathways than 2/10 Hz and 2/50 Hz. In addition, IBS rats exhibited colonic metabolic disorders, and pantothenate was significantly upregulated after EA treatment at different frequencies. Very low-density lipoprotein and 2-hydroxybutyrate were significantly increased in the 2/10 Hz group, while low density lipoprotein, very low-density lipoprotein, 2-hydroxybutyrate, methylmalonate and alpha-hydroxyisobutyric acid were significantly increased in the 2/100 Hz group.
CONCLUSIONS: EA at ST25 at different frequencies attenuated chronic visceral pain through different gut microbiota and metabolic pathways.

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.

Inflammatory bowel disease (IBD) is a morbid condition characterized by relapsing-remitting inflammation of the colon, accompanied by persistent gut dysmotility and abdominal pain. Different reports demonstrated biological activities of aged black garlic (ABG), including anti-inflammatory and antioxidant effects. We aimed to investigate beneficial effects exerted by ABGE on colon inflammation by using ex vivo and in vivo experimental models. We investigated the anti-inflammatory effects of an ABG water extract (ABGE) on rat colon specimens exposed to E. coli lipopolysaccharide (LPS), a known ex vivo experimental model of ulcerative colitis. We determined gene expression of various biomarkers involved in inflammation, including interleukin (IL)-1β, IL-6, nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α. Moreover, we studied the acute effects of ABGE on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) injection in rats. ABGE suppressed LPS-induced gene expression of IL-1β, IL-6, NF-kB, and TNF-α. In addition, the acute administration of ABGE (0.03-1 g kg-1) dose-dependently relieved post-inflammatory visceral pain, with the higher dose (1 g kg-1) able to significantly reduce both the behavioral nociceptive response and the entity of abdominal contraction (assessed by electromyography) in response to colorectal distension after the acute administration in DNBS-treated rats. Present findings showed that ABGE could represent a potential strategy for treatment of colitis-associated inflammatory process and visceral pain. The beneficial effects induced by the extract could be related to the pattern of polyphenolic composition, with particular regard to gallic acid and catechin.

UNASSIGNED: We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain during elective cesarean section under combined spinal-epidural anesthesia (CSEA).
UNASSIGNED: A total of 269 parturients scheduled for elective cesarean section under CSEA between May 2023 and August 2023 were assessed. The parturients were randomly allocated to receiving either intravenous infusion of 0.3-mg/kg esketamine combined with 0.5-μg/kg dexmedetomidine (group ED, n=76), 0.5-μg/kg dexmedetomidine (group D, n=76), or normal saline (group C, n=76) after umbilical cord clamping. The primary outcome was intraoperative visceral pain. Secondary outcomes included the visual analog scale (VAS) score for pain evaluation and other intraoperative complications.
UNASSIGNED: The incidence of visceral pain was lower in group ED [9 (12.7%)] than in group D [32 (43.8%)] and group C [36 (48.6%), P <0.0001]. The VAS score was also lower in group ED when exploring abdominal cavity [0 (0), P <0.0001] and suturing the muscle layer [0 (0), P =0.036]. The mean arterial pressure was higher in group D [83 (9) mmHg] and group ED [81 (11) mmHg] than in group C [75 (10) mmHg, P <0.0001] after solution infusion. The heart rate after infusion of the solution was lower in group D [80 (12) bpm] than in group C [86 (14) bpm] and group ED [85 (12) bpm, P = 0.016]. The incidence of transient neurologic or mental symptoms was higher in group ED compared to group C and group D (76.1% vs 18.9% vs 23.3%, P<0.0001).
UNASSIGNED: During cesarean section, 0.3-mg/kg esketamine combined with 0.5-μg/kg dexmedetomidine can alleviate visceral traction pain and provide stable hemodynamics. Parturients receiving this regimen may experience transient neurologic or mental symptoms that can spontaneously resolve at the end of the surgery.
Some parturients endure experience indescribable pain and discomfort during fetal delivery. Esketamine combined with dexmedetomidine can alleviate this pain during cesarean section under combined spinal-epidural anesthesia. However, after intravenous injection of esketamine and dexmedetomidine, the parturients may experience nightmares, dizziness, hallucinations, and drowsiness, etc.

The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT2A, 5-HT6, and 5-HT7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se, supporting the concept that 5-HT2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT2A and 5-HT6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT7 receptor. Considering previous studies showing that 5-HT6 receptor inhibition, but not activation, and 5-HT7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT2A receptor activation.

Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1β levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In in vitro studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1β axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1β axis inhibition.

UNASSIGNED: Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery.
UNASSIGNED: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1.
UNASSIGNED: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups.
UNASSIGNED: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner.
UNASSIGNED: Chinese Clinical Trial Registry (ChiCTR2100052085).

UNASSIGNED: Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs.
UNASSIGNED: Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested.
UNASSIGNED: Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure.
UNASSIGNED: We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.