Guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL), part II: Management of recurrent pleomorphic adenoma of the parotid gland.

INTRODUCTION: The authors present the guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL) for the management of recurrent pleomorphic adenoma (RPA) of the parotid gland. METHOD: A review of the literature was performed by a multidisciplinary task force. Guidelines were drafted, based on the articles retrieved and the work group members' individual experience. There were then read and re-edited by an independent reading group. The proposed recommendations were graded A, B or C on decreasing levels of evidence. RESULTS: Complete resection under neuromonitoring is recommended in case of RPA. The risks of progression and malignant transformation, which are higher the younger the patient, have to be taken into consideration. The risk of functional sequelae must be explained to the patient. MRI is recommended ahead of any surgery for parotid RPA, to determine extension and detect subclinical lesions. Radiotherapy should be considered in case of multi-recurrent pleomorphic adenoma after macroscopically complete revision surgery at high risk of new recurrence (microscopic residual disease), in case of RPA after incomplete resection, and in non-operable RPA.

Guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL), part I: Primary treatment of pleomorphic adenoma.

INTRODUCTION: The authors present the guidelines of the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL) for the diagnosis and treatment of pleomorphic adenoma (PA) of the salivary glands. METHOD: A review of the literature was performed by a multidisciplinary task force. Guidelines were drafted based on the articles retrieved and the workgroup members' individual experience. Guidelines were graded A, B, C or expert opinion by decreasing level of evidence. RESULTS: In clinically suspected salivary gland PA, MRI should be performed, including head and neck lymph node levels. Fine needle aspiration cytology is particularly recommended for tumours difficult to characterise by MRI. Frozen section biopsy should be performed to confirm diagnosis and adapt the surgical procedure in case of intraoperative findings of malignancy. Complete resection of the parotid PA should be performed en bloc, including margins, when feasible according to tumour location, while respecting the facial nerve. Enucleation (resection only in contact with the tumour) is not recommended. For the accessory salivary and submandibular glands, complete en bloc resection should be performed.

Basal Ti level in the human placenta and meconium and evidence of a materno-foetal transfer of food-grade TiO2 nanoparticles in an ex vivo placental perfusion model.

BACKGROUND: Titanium dioxide (TiO2) is broadly used in common consumer goods, including as a food additive (E171 in Europe) for colouring and opacifying properties. The E171 additive contains TiO2 nanoparticles (NPs), part of them being absorbed in the intestine and accumulated in several systemic organs. Exposure to TiO2-NPs in rodents during pregnancy resulted in alteration of placental functions and a materno-foetal transfer of NPs, both with toxic effects on the foetus. However, no human data are available for pregnant women exposed to food-grade TiO2-NPs and their potential transfer to the foetus. In this study, human placentae collected at term from normal pregnancies and meconium (the first stool of newborns) from unpaired mothers/children were analysed using inductively coupled plasma mass spectrometry (ICP-MS) and scanning transmission electron microscopy (STEM) coupled to energy-dispersive X-ray (EDX) spectroscopy for their titanium (Ti) contents and for analysis of TiO2 particle deposition, respectively. Using an ex vivo placenta perfusion model, we also assessed the transplacental passage of food-grade TiO2 particles. RESULTS: By ICP-MS analysis, we evidenced the presence of Ti in all placentae (basal level ranging from 0.01 to 0.48 mg/kg of tissue) and in 50% of the meconium samples (0.02-1.50 mg/kg), suggesting a materno-foetal passage of Ti. STEM-EDX observation of the placental tissues confirmed the presence of TiO2-NPs in addition to iron (Fe), tin (Sn), aluminium (Al) and silicon (Si) as mixed or isolated particle deposits. TiO2 particles, as well as Si, Al, Fe and zinc (Zn) particles were also recovered in the meconium. In placenta perfusion experiments, confocal imaging and SEM-EDX analysis of foetal exudate confirmed a low transfer of food-grade TiO2 particles to the foetal side, which was barely quantifiable by ICP-MS. Diameter measurements showed that 70 to 100% of the TiO2 particles recovered in the foetal exudate were nanosized. CONCLUSIONS: Altogether, these results show a materno-foetal transfer of TiO2 particles during pregnancy, with food-grade TiO2 as a potential source for foetal exposure to NPs. These data emphasize the need for risk assessment of chronic exposure to TiO2-NPs during pregnancy.

Symptomatic head and neck lipomas.

INTRODUCTION: Lipomas are very common benign lumps that could be encountered in any part of the body but with limited proportion being present in the head and neck region. CASE SUMMARY: In this article, three different cases of symptomatic cervical lipomas were illustrated, with their different diagnostic as well as therapeutic approaches and will be discussed in light of medical literature. DISCUSSION: These cervical tumors tend to grow slowly giving variable signs that include dysphagia, dyspnea, dysphonia due to the mass effect of surrounding structures or can be present as simple as a cosmetic concern. Clinicians must bear in mind the malignant transformation of lipomas, which can be challenging to diagnose. With this article, authors will try to highlight the importance of maintaining a good communication between surgeons, pathologists and radiologists as an essential part of the medical management.

Endoscopic transnasal transseptal pituitary surgery.

Pituitary surgery is performed via a transsphenoidal approach in the vast majority of cases according to various methods that have changed over the years. A microscopic transseptal approach via a sublabial mucosal incision or a nasal mucosal incision has also been extensively used. An endoscopic transnasal approach was first described in the 1990's, followed by the concept of a microscopic transseptal approach and an endoscopic strictly endonasal approach. We use an entirely endoscopic transseptal transsphenoidal approach via an incision in the nasal mucosa for both access and tumour resection. This procedure has a number of advantages: strictly midline approach to the sella turcica, large operative field, no interference between instruments and a low rate of nasal complications.

Early life stress in mice is a suitable model for Irritable Bowel Syndrome but does not predispose to colitis nor increase susceptibility to enteric infections.

Neonatal period is characterized by an immature intestinal barrier. Scattered evidence suggests that early life stressful events induce long lasting alterations of intestinal homeostasis mimicking Irritable Bowel Syndrome (IBS). Those observations highlighting defect of intestinal barrier by early life stress questioned its potential role as a risk factor for gastrointestinal disorders such as colitis and infections. In this study, we aimed to analyze if maternal separation (MS) in mice mimicks IBS main features. We next addressed whether MS could trigger or exacerbate colitis in genetically predisposed mice and/or enhance susceptibility to gastrointestinal infections in wild type mice. MS induced main features of IBS in adult wild type male mice i.e. intestinal hyperpermeability, visceral hypersensitivity, microbiota dysbiosis, bile acid malabsorption and low grade inflammation in intestine associated with a defect of Paneth cells and the ILC3 population. This breach in mucosal barrier functions in adults was associated with a systemic IgG response against commensal E. coli and increased IFNγ secretion by splenocytes. However, in IL10-/- mice, MS did not trigger nor worsen colitis. Furthermore, wild type mice submitted to MS did not show increase susceptibility to gastrointestinal infections (S. Typhimurium, L. monocytogenes or T. gondii) compared to controls. Altogether, our results identify MS in mice as a good experimental model for IBS mimicking all the main features. In addition, early life stress, even though it has long lasting consequences on intestinal homeostasis, does not constitute a facilitating factor to colitis in predisposed individuals nor to gastrointestinal infections in wild type mice.

Daily allergic multimorbidity in rhinitis using mobile technology: A novel concept of the MASK study.

BACKGROUND: Multimorbidity in allergic airway diseases is well known, but no data exist about the daily dynamics of symptoms and their impact on work. To better understand this, we aimed to assess the presence and control of daily allergic multimorbidity (asthma, conjunctivitis, rhinitis) and its impact on work productivity using a mobile technology, the Allergy Diary. METHODS: We undertook a 1-year prospective observational study in which 4 210 users and 32 585 days were monitored in 19 countries. Five visual analogue scales (VAS) assessed the daily burden of the disease (i.e., global evaluation, nose, eyes, asthma and work). Visual analogue scale levels <20/100 were categorized as "Low" burden and VAS levels ≥50/100 as "High" burden. RESULTS: Visual analogue scales global measured levels assessing the global control of the allergic disease were significantly associated with allergic multimorbidity. Eight hypothesis-driven patterns were defined based on "Low" and "High" VAS levels. There were <0.2% days of Rhinitis Low and Asthma High or Conjunctivitis High patterns. There were 5.9% days with a Rhinitis High-Asthma Low pattern. There were 1.7% days with a Rhinitis High-Asthma High-Conjunctivitis Low pattern. A novel Rhinitis High-Asthma High-Conjunctivitis High pattern was identified in 2.9% days and had the greatest impact on uncontrolled VAS global measured and impaired work productivity. Work productivity was significantly correlated with VAS global measured levels. CONCLUSIONS: In a novel approach examining daily symptoms with mobile technology, we found considerable intra-individual variability of allergic multimorbidity including a previously unrecognized extreme pattern of uncontrolled multimorbidity.

Transfer of innovation on allergic rhinitis and asthma multimorbidity in the elderly (MACVIA-ARIA) - EIP on AHA Twinning Reference Site (GARD research demonstration project).

The overarching goals of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) are to enable European citizens to lead healthy, active and independent lives whilst ageing. The EIP on AHA includes 74 Reference Sites. The aim of this study was to transfer innovation from an app developed by the MACVIA-France EIP on AHA reference site (Allergy Diary) to other reference sites. The phenotypic characteristics of rhinitis and asthma multimorbidity in adults and the elderly will be compared using validated information and communication technology (ICT) tools (i.e. the Allergy Diary and CARAT: Control of Allergic Rhinitis and Asthma Test) in 22 Reference Sites or regions across Europe. This will improve the understanding, assessment of burden, diagnosis and management of rhinitis in the elderly by comparison with an adult population. Specific objectives will be: (i) to assess the percentage of adults and elderly who are able to use the Allergy Diary, (ii) to study the phenotypic characteristics and treatment over a 1-year period of rhinitis and asthma multimorbidity at baseline (cross-sectional study) and (iii) to follow-up using visual analogue scale (VAS). This part of the study may provide some insight into the differences between the elderly and adults in terms of response to treatment and practice. Finally (iv) work productivity will be examined in adults.

Gardner's syndrome presenting with a fibromatous tumour of the parotid.

INTRODUCTION: Gardner's syndrome is the association of familial adenomatous polyposis (FAP) with an anaphase promoting complex (APC) gene mutation and several extradigestive manifestations: osteomas, epidermal cysts and desmoid tumours. Only 2 cases of FAP associated with parotid tumour have been reported in the literature: one carcinoma and one pleomorphic adenoma. CASE REPORT: We report the case of a 23-year-old man with Gardner's syndrome presenting with a fibromatous tumour of the left parotid gland. The other clinical manifestations were an osteoma of the skull base and a mesentery desmoid tumour. Left total parotidectomy was performed, followed by gastroscopy and colonoscopy, demonstrating numerous colonic adenomas. Genetic analysis revealed an APC gene mutation, confirming the diagnosis. Total prophylactic colectomy was performed. CONCLUSIONS: This is the first reported case of Gardner's syndrome associated with a fibromatous tumour of the parotid. Early management of FAP is essential to prevent colorectal cancer that occurs in 100% of untreated cases. The rarity of this syndrome and the parotid site can lead to delayed diagnosis.

Interest of video-assisted minimally invasive surgery in primary hyperparathyroidism.

INTRODUCTION: Surgery is the only radical and definitive treatment for primary hyperparathyroidism. Exploration of the four parathyroid sites is giving way to minimally invasive techniques. The present study sought to compare two minimally invasive parathyroidectomy techniques, by classical cervicotomy (MIP-C) and by video-assistance (MIP-VA), in terms of success rate, complications rate, operating time, and patient and community physician satisfaction. MATERIALS AND METHOD: A non-randomized retrospective comparative study included 112 patients presenting with primary hyperparathyroidism with identified parathyroid adenoma, operated on between January 2005 and October 2010. The two groups were constituted according to the surgeons' habitual practice: 54 cases of MIP-VA and 58 of MIP-C. RESULTS: Results for MIP-VA and MIP-C were respectively: success, 96.3% vs. 100% (P=0.09); mean scar size, 1.47 vs. 3.43cm (P<0.01); hypocalcemia, 2 vs. 3 cases (P=0.1); theater time, 94.25 vs. 76min (P=0.02); and postoperative stay, 1.08 vs. 1.37 days (P=0.07). Patient satisfaction was comparable between groups, while 93.3% of community physicians found MIP-VA preferable to MIP-C, although only 39.3% had known the MIP-VA technique. CONCLUSION: With efficacy, morbidity and patient satisfaction comparable to classical surgery, MIP-VA significantly reduced cervicotomy size and hospital stay. Community physicians considered it to be preferable to MIP-C.

Nodular recurrence and hypothyroidism following partial thyroidectomy for benign nodular thyroid disease in children and adolescents.

OBJECTIVES: Diagnostic and therapeutic processing of a thyroid nodule in children and adolescents may require lobectomy-isthmusectomy (LI) or nodule-resection (NR). Very few data in the literature report the long-term evolution of the remaining thyroid lobe in a defined pediatric population. In this study, we aimed to answer the following questions: Does a nodule recurrence occur in the remainder lobe? Is a post-operative thyroxine treatment necessary? MATERIAL AND METHODS: This retrospective study describes 28 patients under 18 who underwent LI (22 cases) or NR (6 cases) from January 2004 to March 2012. Ten of them were lost to follow up, 18 could be assessed (4 NR (22%) and 14 LI (78%) - mean follow-up 45±31 months). All patients benefited of post-operative thyroid ultrasonography, and regular endocrinologic follow-up. The following data were analysed: emergence of new thyroid nodules, evolution of pre-existing nodules, occurrence of post-operative hypothyroidism and requirement for completion thyroidectomy. RESULTS: The mean age at the time of surgery was 14.3±1.9 years. Two patients (11%) had pre-existing nodules in the remaining thyroid gland, none of which showed an increase in size after surgery. De novo nodules developed in five patients (27.8%). Three patients who underwent LI (21.4%) needed thyroxine treatment for post-operative hypothyroidism. One patient (5.5%) needed completion thyroidectomy. CONCLUSIONS: In this children and adolescents population, after performing LI or NR, remaining thyroid tissue stays free of nodules in 72.2% of the cases. A post-operative thyroxin treatment is necessary in 21.4% of cases after LI.

Thyroid surgery in children and adolescents: a series of 65 cases.

OBJECTIVES: To describe the specificities and complications of thyroid surgery in children and adolescents. MATERIAL AND METHODS: This retrospective study was based on 64 patients under the age of 18 who underwent thyroid surgery between January 2004 and March 2012, with two operations in one case. The following data were analysed: anatomical variants of the recurrent laryngeal nerve, postoperative recurrent laryngeal nerve paralysis rate, postoperative hypoparathyroidism rate, and histological results. RESULTS: Two cases of right non-recurrent inferior laryngeal nerve were observed (2.2% of the 93 recurrent laryngeal nerves dissected). One case of persistent left recurrent laryngeal nerve paralysis was observed (1.1%) despite intraoperative recurrent laryngeal nerve monitoring. Eight cases of immediate postoperative hypocalcaemia were observed (23.5% of the 34 total thyroidectomies) and permanent hypocalcaemia was observed in 5 cases (14.7%) with a significantly lower immediate postoperative serum calcium than in the case of transient hypocalcaemia (P=0.035). Among the 11 patients operated for familial medullary thyroid carcinoma (MTC), 36.3% presented one or more sites of C-cell carcinoma. Among the 32 patients operated for thyroid nodule, 6.3% presented papillary adenocarcinoma. Histological results were benign in all other cases. CONCLUSIONS: Thyroid surgery in children and adolescents is part of global multidisciplinary management of thyroid disorders in children. Recurrent laryngeal nerve paralysis is a rare complication, but may occur despite the use of intraoperative recurrent laryngeal nerve monitoring. Permanent hypoparathyroidism is the most common complication and is correlated with immediate postoperative serum calcium. Systematic prophylactic total thyroidectomy in patients with a RET proto-oncogene mutation allowed early diagnosis of MTC in one-third of cases. In view of the low rate of malignant nodules in our series, the malignant thyroid nodule rates reported in children in the literature may be overestimated.

Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice.

BACKGROUND: A probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 combination, Probio'Stick(®) ) displays anxiolytic-like activity and reduces apoptosis in the lymbic system in animal models of depression. Based on the hypothesis that modulation of gut microbiota by this probiotic formulation has beneficial effects on brain activity in stress conditions, we report a set of probiotic-evoked physiological, cellular, and molecular events in the brain of Probio'Stick(®) pretreated mice submitted to chronic psychological stress. METHODS: Water avoidance stress (WAS) was applied or not (sham). Hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses to the chronic stress were assessed through plasma corticosterone and catecholamine measurements. Specific markers for neuronal activity, neurogenesis, and synaptic plasticity were used to assess brain activity. In addition, gut permeability and tight junction (TJ) proteins levels were also determinated. KEY RESULTS: We observed that a pretreatment with the probiotic formulation attenuated HPA axis and ANS activities in response to WAS, and reduced cFos expression in different brain areas but Lactobacillus salivarius (a negative control) treatment was ineffective on these parameters. Moreover, probiotic pretreatment prevented the WAS-induced decrease hippocampal neurogenesis and expression changes in hypothalamic genes involved in synaptic plasticity. These central effects were associated with restoration of TJ barrier integrity in stressed mice. CONCLUSIONS & INFERENCES: These data suggest that chronic stress-induced abnormal brain plasticity and reduction in neurogenesis can be prevented by a pretreatment with the Probio'Stick(®) formulation, suggesting that probiotics modulate neuroregulatory factors and various signaling pathways in the central nervous system involved in stress response.

Reduced infections with perioperative immunonutrition in head and neck cancer: exploratory results of a multicenter, prospective, randomized, double-blind study.

BACKGROUND & AIMS: Head and neck cancer surgery is affected by complications in 20-60% of cases, with risk factors being malnutrition, alcoholism and immunosuppression due to cancer. The aim of the study was to investigate whether preoperative or perioperative immunonutrition could reduce postoperative infectious complications (IC) and surgical-site infections (SSI) in this population. METHODS: This was a multicenter, prospective, randomized, double-blind study. Patients with oropharyngeal and pharyngolaryngeal tumour were randomly allocated to three groups: a) perioperative formula of Impact(®) without immune nutrients, named "reference diet" (group A, control); b) preoperative Impact(®) and "reference diet" postoperatively (group B); c) Impact(®) perioperatively (group C). Products were available in oral and enteral formula and were given 7 days before surgery and for 7-15 days postoperatively. The primary and secondary endpoints were the incidence of IC and SSI, respectively. RESULTS: Of 312 randomized patients, 205 were evaluable for ITT analysis. There was no significant difference in IC and SSI. However out of this population, only 64 patients had taken at least 75% of the theoretical intake from surgery to day 10 (per-protocol population). In this condition, a significant difference in IC (OR = 0.24, p = 0.05), SSI (OR = 0.17, p = 0.04) and also in the median length of postoperative stay (18 vs. 25 days, p = 0.05) was demonstrated between groups A and C. CONCLUSIONS: In the ITT population, no significant difference in IC, SSI and LOS was demonstrated. Positive exploratory results on the perioperative Impact(®) per-protocol population, encourage further study in head and neck cancer patients. Registered under ClinicalTrials.gov Identifier no. NCT00765440.

The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota.

BACKGROUND: Alterations of intestinal microbiota and hypersensitivity to colonic distension are two features of the irritable bowel syndrome (IBS). However, the role of intestinal microbiota in visceral hypersensitivity of IBS patients is far to be established. The aim of our study was to determine whether the intestinal microbiota is involved in the visceral hypersensitivity in IBS. METHODS: The painful response to colorectal distension and colonic mucosal parameters were assessed in gnotobiotic rats. Germfree (GF) rats were inoculated with the fecal microbiota from IBS patients characterized by hypersensitivity to colorectal distension (IBS HMA rats) or from non-hypersensitive healthy volunteers (Healthy HMA rats). Conventional rats were studied as normosensitivity control. Fecal microbial analyses were carried out in human and HMA rats fecal samples using cultural and molecular approaches. KEY RESULTS: The microbial dysbiosis of the IBS gut microbiota (more sulfate-reducing bacteria and Enterobacteriaceae and less bifidobacteria) could be maintained in gnotobiotic rats. The number of abdominal contractions in response to colorectal distensions was significantly higher in IBS HMA rats than in healthy HMA rats. No difference was observed between healthy HMA and conventional rats. Colorectal compliance, epithelial paracellular permeability, and density of colonic mucosal mast cells were similar in the three groups of rats. CONCLUSIONS & INFERENCES: We herein showed that sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota. Mucosal alterations associated with microbiota transfer are not involved in this hypersensitivity. The altered IBS microbiota may have important role in the hypersensitivity characterizing IBS patients through specific bacterial metabolites.

Positron emission tomography-computed tomography evaluation for recurrent differentiated thyroid carcinoma.

OBJECTIVES: Recurrence is observed in 15-20% of patients under surveillance following treatment of differentiated thyroid cancer (DTC). However, due to cell dedifferentiation, the recurrence may be iodine-negative, thereby compromising detection. For this reason, new methods of exploration are indispensable to enable localization of such recurrences. The purpose of this work is to review the contribution of positron emission tomography-computed tomography (PET-CT) in the exploration of iodine-negative recurrent DTC. METHOD: A comprehensive review and discussion of the medical literature was carried out. RESULTS: Depending on the report, the sensitivity of PET-CT ranged from 70% to 85%, with up to 90% specificity. However, the large number of false negatives, which can reach 40%, is the disadvantage of this examination. PET-CT results lead to change in the therapeutic strategy in approximately 50% of patients with isolated raised serum thyroglobulin levels, and surgical exploration of a precise anatomical area in the neck. CONCLUSION: As post-treatment recurrence of a DTC can affect patient survival, a thorough diagnostic work-up is required in these cases. Where thyroglobulin levels are elevated with no uptake on 131-iodine scans, PET-CT can be a useful complementary exploration, especially for localizing the site of recurrence.

A marketed fermented dairy product containing Bifidobacterium lactis CNCM I-2494 suppresses gut hypersensitivity and colonic barrier disruption induced by acute stress in rats.

BACKGROUND: Fermented milk (FM) containing Bifidobacterium lactis CNCM I-2494 and yogurt strains improves irritable bowel syndrome (IBS) symptoms in constipated IBS patients. In rats, stressful events exacerbate IBS symptoms and result in the alteration of gut sensitivity and permeability via epithelial cell cytoskeleton contraction. In a stress model, we aimed at evaluating the effect of B. lactis CNCM I-2494 as a pure strain or contained in an FM product on visceral sensitivity and the impact of this FM on intestinal barrier integrity. METHODS: Visceral sensitivity was analyzed in rats subjected to partial restraint stress (PRS). Rats received during 15 days the B. lactis as a pure strain (10(6) to 10(10) CFU mL(-1)), B. lactis in an FM product (10(8) CFU g(-1), diluted or not), or a control product. Gut paracellular permeability, colonic occluding and Jam-A proteins, and blood endotoxin levels were determined in rats receiving B. lactis in an FM product submitted or not to a PRS. KEY RESULTS: The FM product showed a dose-dependent inhibitory effect on stress-induced visceral hypersensitivity. A similar antihyperalgesic effect was observed at 10(10) CFU mL(-1) of pure B. lactis administration. The FM product prevented the increase in intestinal permeability induced by PRS and restored occludin and JAM-A expressions to control levels. The FM product abolished the increase concentration of blood endotoxin induced by PRS. CONCLUSIONS & INFERENCES: This study illustrates that a probiotic food containing B. lactis CNCM I-2494 strain reduces visceral hypersensitivity associated with acute stress by normalizing intestinal epithelial barrier via a synergistic interplay with the different probiotic strains and/or metabolites contained in this product.

Proteinase-activated receptor-4 evoked colorectal analgesia in mice: an endogenously activated feed-back loop in visceral inflammatory pain.

BACKGROUND: Activation of proteinase-activated receptor-4 (PAR-4) from the colonic lumen has an antinociceptive effect to colorectal distension (CRD) in mice in basal conditions. We aimed to determine the functional localization of the responsible receptors and to test their role in two different hyperalgesia models. METHODS: Mice received PAR-4 activating peptide (PAR-4-AP, AYPGKF-NH(2)) or vehicle intraperitoneally (IP), and abdominal EMG response to CRD was measured. The next group received PAR-4-AP intracolonically (IC) with or without 2,4,6-triaminopyrimidine, a chemical tight junction blocker, before CRD. The SCID mice were used to test the role of lymphocytes in the antihyperalgesic effect. The effects of PAR-4-AP and PAR-4-antagonist (P4pal-10) were evaluated in water avoidance stress (WAS) model and low grade 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis. Spinal Fos protein expression was visualized by immunohistochemistry. KEY RESULTS: The antinociceptive effect of PAR-4-AP disappeared when was administrered IP, or with the blockade of colonic epithelial tight junctions, suggesting that PAR-4-AP needs to reach directly the nerve terminals in the colon. The CRD-induced spinal Fos overexpression was reduced by 43% by PAR-4-AP. The PAR-4-AP was antihyperalgesic in both hyperalgesia models and in mice with impaired lymphocytes. The PAR-4-antagonist significantly increased the TNBS, but not the WAS-induced colonic hyperalgesia. CONCLUSIONS & INFERENCES: The antinociceptive effect of PAR-4-AP depends on its penetration to the colonic mucosa. The PAR-4 activation is endogenously involved as a feedback loop to attenuate inflammatory colonic hyperalgesia to CRD.