The non-euphoric phytocannabinoid cannabidivarin counteracts intestinal inflammation in mice and cytokine expression in biopsies from UC pediatric patients.

Patients with ulcerative colitis (UC) using marijuana have been reported to experience symptomatic benefit. Cannabidivarin (CBDV) is a safe non-psychoactive phytocannabinoid able to activate and desensitize TRPA1, a member of the TRP channels superfamily, which plays a pivotal role in intestinal inflammation. Here, we have investigated the potential intestinal anti-inflammatory effect of CBDV in mice and in biopsies from pediatric patients with active UC. Colonic inflammation was induced in mice by dinitrobenzenesulfonic acid (DNBS). The effect of orally administered CBDV on macroscopic and microscopic damage, inflammatory parameters (i.e. myeloperoxidase activity, intestinal permeability and cytokine production) and faecal microbiota composition, was evaluated 3 days after DNBS administration. TRPA1 expression was studied by RT-PCR in inflamed colons of mice as well as in mucosal colonic biopsies of children with active UC, whose response to incubation with CBDV was also investigated. CBDV attenuates, in a TRPA1-antagonist sensitive manner, DNBS-induced signs of inflammation including neutrophil infiltration, intestinal permeability, and cytokine (i.e. IL-1ß, IL-6 and the chemokine MCP-1) production. CBDV also alters the dysregulation of gut microbiota associated to colitis. Finally, CBDV lessens cytokine expression in colonic biopsies from pediatric patients with ulcerative colitis, a condition in which TRPA1 was up-regulated. Our preclinical study shows that CBDV exerts intestinal anti-inflammatory effects in mice via TRPA1, and in children with active UC. Since CBDV has a favorable safety profile in humans, it may be considered for possible clinical trials in patients with UC.

Hypopharyngeal evaluation in obstructive sleep apnea with awake flexible laryngoscopy: Validation and updates to Cormack-Lehane and Modified Cormack-Lehane scoring systems.

OBJECTIVE: To validate the use of Cormack-Lehane and Modified Cormack-Lehane scoring systems to classify patterns of hypopharyngeal airway visualization seen during awake flexible laryngoscopy among patients with obstructive sleep apnoea. STUDY DESIGN: Validation study using samples collected from a prospective database. SETTING: University Medical Center. PARTICIPANTS: Data were obtained from a retrospective review of a prospective database of flexible fiberoptic examination recordings in 274 consecutive OSA subjects (Stanford Sleep Medicine/Surgery Clinic). MAIN OUTCOME MEASURES: Single still images from awake fiberoptic laryngoscopy examinations of the vocal cords from 90 different patients were presented to 2 experts and 4 novice raters. Raters used two grading systems (Cormack-Lehane scale and Modified Cormack-Lehane) to rate vocal cord visualization. Percent agreement and Cohen's kappa statistical analysis were used to evaluate inter-rater reliability and intrarater reliability for each grading system. Feedback from the participants was then used to propose updates to further improve upon the existing grading scales for their applicability to awake flexible endoscopy. RESULTS: The Cormack-Lehane and Modified Cormack-Lehane scale both communicate unobstructed and restricted views of the vocal cords reliably. Compared to the 4-grade scale, however, a modified 5-grade Vocal Cord Grading System allows for better objective communication of common variations in hypopharyngeal airway visualization. CONCLUSION: We propose a 5-Grade Vocal Cord Grading System that builds upon existing grading systems to allow for efficient and reliable communication of hypopharyngeal airway examination during awake fiberoptic laryngoscopy.

Impact of continuous positive airway pressure in patients with obstructive sleep apnea during drug-induced sleep endoscopy.

OBJECTIVES: The primary objective of the study was to understand the differential impact of continuous positive airway pressure (CPAP) on the location, degree and pattern of airway collapse in obstructive sleep apnea (OSA) patients utilizing drug-induced sleep endoscopy (DISE). STUDY DESIGN: Non-randomized trial. SETTING: University Medical Center. PARTICIPANTS: Fifteen consecutive OSA patients undergoing DISE. MAIN OUTCOMES AND MEASURES: The patterns of airway collapse were videorecorded at baseline and under differential application of nasal CPAP (nCPAP) at 5, 10 and 15 cm H2 O. For each modality, the pattern and degree of airway collapse were analyzed by three independent observers using the velum, oropharynx, tongue base, epiglottis (VOTE) classification system. RESULTS: The modest nCPAP pressures (10 cm H2 O) had the greatest impact on the lateral walls of the pharynx, followed by the palatal region. The collapsibility of the tongue base and epiglottis demonstrated significant resistance to nCPAP application, which was overcome by increasing nCPAP to 15 cm H2 O. Compared to 5 cm H2 O, nCPAP pressures of 10 and 15 cm H2 O improved complete collapse at least at one level of the upper airway (P=.016 and .001, respectively). Increased nCPAP pressures also led to changes in the configuration of airway collapse at the level of the velum. CONCLUSIONS: The differential nCPAP effects observed in this study may help to understand some of the mechanisms responsible for inadequate patient response and poor nCPAP compliance. The use of DISE in combination with CPAP may serve as a first step in optimizing patients that failed to adapt to treatment with CPAP. This approach can help the physician identify patterns of airway collapse that may require varying pressures different from the one the patient is using, as well as anatomical factors that may be corrected to help with compliance.

Dynamic evaluation of benign neoplasm of parotid glands with multidetector row CT.

AIM: The aim of this paper was to evaluate the role of net-enhancement (NE) of benign salivary glands with multiphase multidetector row CT (MDCT). METHODS: Forty-eight patients (M=27, F=21), aged 35-76 years old (mean =57) with benign parotid neoplasms were examinated with 4 MDCT, at 20'', 40'', 70'' e 9' after intravenous administration of contrast medium. NE was calculated after subtracting precontrast phase to postcontrast phases. Final data were compared to the histopathology. RESULTS: Thirty-six cases were pleomorphic adenomas (PA), 24 Warthin (WT). PA had a medium NE values of 23 HU, 74 HU, 53 HU e 34 HU at 20'', 40'', 70'' e 9' respectively. WT had a medium NE of 52 HU, 54 HU, 40 HU e 39 HU respectively at the same times. After subtracting precontrast phase to the delayed phase, with NE at 9' and cut-off of 34 HU, we have differenziate PA from WT and normal gland with specifity (SP) 87%, sensibility (SE) 60%, positive predictive value (PPV) and negative predictive value (NPV) of 75% and 59%; with NE at 20'' and cut-off of 54HU we have distingueshed WT from AP with SP 83%, SE 50%, PPV 75% and NPV 63%. CONCLUSION: The study of NE can allow the characterization of benign parotid gland tumors.

Pediatric maxillary expansion has a positive impact on hearing? A systematic review and meta-analysis.

OBJECTIVE: Hearing loss is a highly prevalent condition in the pediatric population. Pediatric maxillary expansion is a widespread treatment to address transverse maxillary deficiency. First reports describing an association between improvements for patients with HL and PME initiated in the 1960s. In this systematic review and meta-analysis we aim to review the role of maxillary expansion in reducing conductive hearing loss in pediatric population. REVIEW METHODS: Pubmed (Medline), the Cochrane Library, EMBASE and Trip Database were checked. Main outcome was expressed as the difference between air-bone gap, compliance, ear volume and conductive hearing thresholds before and after treatment and the 95% confidence interval. RESULTS: A total of 10 studies (218 patients) met inclusion criteria. The pooled data in the meta-analysis under a random effects model shows a statistically significant difference of 10.57dB mean reduction after palatal expansion. The air-bone gap was significantly reduced by 5.39dB (CI 95% 3.68, 7.10). Compliance and volume were assessed in three studies, with a non-significant positive difference in the compliance (0.14) and a statistically significant difference for volume (0.80) after palatal expansion. CONCLUSION: This systematic review and meta-analysis found a positive effect of pediatric maxillary expansion in conductive hearing loss in well-select children. However, results cannot be extrapolated for children with conductive hearing loss without an accompanying orthodontic indication (maxillary constriction). It showed that the existing prospective studies exhibited qualitative pitfalls, limiting the ability to obtain conclusive evidence about the role of pediatric maxillary expansion on conductive hearing loss in children.

Language testing in brain tumor patients.

Neuropsychological testing is not a luxury in the management of patients with brain tumors. Regardless of the therapeutic approach selected in each case (but, especially in the case of awake surgery), it provides information on the status of language and other cognitive functions. This information can be used preoperatively to identify eloquent areas and to provide a baseline against which further examinations can be evaluated, intraoperatively to identify eloquent areas, and post-operatively and at follow-up to ascertain the short-term and long-term consequences of surgery, as well as those of other treatments (chemotherapy and radiotherapy), and to plan and monitor rehabilitative treatments.

Cognitive outcome after awake surgery for tumors in language areas.

In surgery for tumors of the dominant hemisphere, the attention devoted to quality of resection and preservation of language function has not been accompanied by comparable interest in preservation of cognitive abilities which may affect quality of life. We studied 22 patients undergoing awake surgery for glioma removal in the language areas of the brain. Besides monitoring tumor variables (size, location, histology, edema), we used a multifaceted battery of tests to investigate mood, cognition, and language in an attempt to assess the burden of disease and treatment, and the relationships between these three dimensions. Baseline assessment showed that 45% of the patients were depressed and 23% anxious; some cognitive and language impairment was noted for 59 and 50%, respectively. A general decline in postoperative cognitive performance (significant for memory and attention only) and language function (significant for picture naming) was observed, whereas depression was unchanged and anxiety decreased. Tumor histology, but not demographic variables or extent of resection, correlated with postoperative cognitive changes: patients undergoing surgery for high-grade tumors were more likely to improve. No correlation was observed between scores for mood, cognition, and language function. A subset of patients with low-grade glioma was followed up for 3-6 months; although some improvement was observed they did not always regain their preoperative performance. In conclusion, we believe that cognitive assessment performed in conjunction with language testing is a necessary step in the global evaluation of brain tumor patients both before and after surgery.

Tissue-Sparing Uvulopalatopharyngoplasty for OSA: Conservative, Compassionate and Possibly just as Effective.

A common surgical treatment for obstructive sleep apnea (OSA) is uvulopalatopharyngoplasty (UPPP). Unfortunately, traditional UPPP can cause a foreign body sensation, chronic discomfort and in rare cases, nasopharyngeal stenosis or velopharyngeal insufficiency. Modifications to traditional UPPP have been developed over the years to help decrease side effects, while trying to maintain or improve OSA outcomes. Conservative, tissue-sparing UPPP techniques include preservation of soft palate tissues (muscle and/or mucosa), avoidance of plication or conservative plication of the uvula, partial instead of complete uvulectomy, and suture plication of the palatopharyngeus-superior pharyngeal constrictor-palatoglossus muscles with complete preservation of surrounding tissues after tonsillectomy.

Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice.

BACKGROUND AND PURPOSE: Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation. EXPERIMENTAL APPROACH: Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh. KEY RESULTS: In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB1 receptor antagonist rimonabant, but not by the cannabinoid CB2 receptor antagonist SR144528 (N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide), by the opioid receptor antagonist naloxone or by the alpha2-adrenergic antagonist yohimbine. Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice. CONCLUSIONS AND IMPLICATIONS: Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.

The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet.

BACKGROUND AND PURPOSE: Endocannabinoids (via cannabinoid CB(1) receptor activation) are physiological regulators of intestinal motility and food intake. However, their role in the regulation of gastric emptying is largely unexplored. The purpose of the present study was to investigate the involvement of the endocannabinoid system in the regulation of gastric emptying in mice fed either a standard diet (STD) or a high-fat diet (HFD) for 14 weeks. EXPERIMENTAL APPROACH: Gastric emptying was evaluated by measuring the amount of phenol red recovered in the stomach after oral challenge; CB(1) expression was analysed by quantitative reverse transcription-PCR; endocannabinoid (anandamide and 2-arachidonoyl glycerol) levels were measured by liquid chromatography-mass spectrometry. KEY RESULTS: Gastric emptying was reduced by anandamide, an effect counteracted by the CB(1) receptor antagonist rimonabant, but not by the CB(2) receptor antagonist SR144528 or by the transient receptor potential vanilloid type 1 (TRPV1) antagonist 5'-iodoresiniferatoxin. The fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine (but not the anandamide uptake inhibitor OMDM-2) reduced gastric emptying in a way partly reduced by rimonabant. Compared to STD mice, HFD mice exhibited significantly higher body weight and fasting glucose levels, delayed gastric emptying and lower anandamide and CB(1) mRNA levels. N-arachidonoylserotonin (but not rimonabant) affected gastric emptying more efficaciously in HFD than STD mice. CONCLUSIONS AND IMPLICATIONS: Gastric emptying is physiologically regulated by the endocannabinoid system, which is downregulated following a HFD leading to overweight.

Microsomal triglyceride transfer protein (MTP) -493G/T gene polymorphism contributes to fat liver accumulation in HCV genotype 3 infected patients.

SUMMARY: (A) A reduced activity of microsomal triglyceride transfer protein (MTP), a key enzyme of assembly/secretion of lipoproteins, is related to HCV steatosis. Host genetic background may influence development of steatosis. The aim of the study was to investigate the association between MTP-493 G/T gene polymorphism, fat liver accumulation and fibrosis progression in HCV infected patients. A total of 102 naïve patients with liver biopsy proven chronic hepatitis C were evaluated for MTP-493 G/T gene polymorphism, HCV RNA, HCV genotype, HOMA-IR, serum adiponectin, TNF-alpha and serum lipid levels. HCV genotype 3 infected patients carrying the T allele of the MTP gene polymorphism showed higher degree of steatosis than those carrying GG genotype (3.45 +/- 0.37 vs 1.30 +/- 0.45, respectively; P < 0.001). MTP'T' allele carriers also had higher HCV RNA serum levels (P < 0.01) and hepatic fibrosis (P < 0.001). Irrespective of MTP genotype, patients with HCV genotype 3 had lower levels of cholesterol, ApoB, HDL and LDL. In HCV genotype non-3 infected patients no parameters were associated with MTP gene polymorphism. In conclusion the presence of T allele of MTP-493G/T gene polymorphism predisposes patients infested with HCV genotype 3 to develop higher degree of fatty liver accumulation.

The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A reduce inflammation-induced hypermotility in mice.

The hallucinogenic plant Salvia divinorum has been used for medical treatments of gastrointestinal disorders. Here, we evaluated the effect of a standardized extract from the leaves of Salvia divinorum (SDE) and of its active ingredient salvinorin A on motility in vivo, both in physiological states and during croton oil-induced intestinal inflammation. SDE (1-100 mg kg(-1)) significantly inhibited motility only in inflamed, but not in control, mice. In control mice, salvinorin A (0.01-10 mg kg(-1)) significantly inhibited motility only at the highest doses tested (3 and 10 mg kg(-1)) and this effect was not counteracted by naloxone or by the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine. Inflammation significantly increased the potency of salvinorin A (but not of the KOR agonist U-50488) in reducing motility. The inhibitory effects of both salvinorin A and U-50488 in inflamed mice were counteracted by naloxone or by nor-binaltorphimine. We conclude that salvinorin A may reduce motility through activation of different targets. In physiological states, salvinorin A, at high doses, inhibited motility through a non-KOR mediated mechanism. Gut inflammation increased the potency of salvinorin A; this effect was mediated by KOR, but it was not shared by U-50488, thus suggesting that salvinorin A may have target(s) other than KOR in the inflamed gut.

Remediation of waters contaminated with ionic herbicides by sorption on polymerin.

This study investigated the sorption of paraquat and 2,4-D on polymerin, the humic acid-like fraction of olive mill wastewater. Effects of pH, contact time, initial concentration and sorbent dosage on the sorption of both herbicides were studied. The sorption mechanism of paraquat on polymerin was consistent with the ion exchange of this herbicide with Ca, Mg and K natively occurring in the sorbent; in contrast, 2,4-D was bound to polymerin by hydrogen bonding. Simulated wastewaters contaminated with paraquat were purified after three sorption cycles on polymerin renewed at each cycle, at a solid/liquid ratio of 0.5, whereas those containing 2,4-D showed a maximal residue removal of 44% after two sorption cycles at the same ratio. The possible application of this model to other water-soluble herbicides, as well as the possible exploitation of polymerin as a bio-filter for the decontamination of pollution point sources is briefly discussed.

The dissociation of color from form and function knowledge.

We report on two brain-damaged subjects who exhibit the uncommon pattern of loss of object color knowledge, but spared color perception and naming. The subject P.C.O., as in previously reported patients, is also impaired in processing other perceptual and functional properties of objects. I.O.C., in contrast, is the first subject on record to have impaired object color knowledge, but spared knowledge of object form, size and function. This pattern of performance is consistent with the view that semantic information about color and other perceptual properties of objects is grounded in modality-specific systems. Lesion analysis suggests that such grounding requires the integrity of the mesial temporal regions of the left hemisphere.

Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells.

The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively.

Recovery and characterization of the humate-like salified polymeric organic fraction (lignimerin) from Kraft cellulose mill wastewater.

A dark and complex salified organic polymeric mixture, named lignimerin, was for the first time recovered from Kraft cellulose mill wastewater (KCMW) and characterized by chemical, spectroscopic and relative molecular weight (RMW) analysis. Lignimerin proved to be composed of polyphenols (57.00%), carbohydrates (22.26%) and proteins (7.42%). It also contained metals (6.93%), mainly Ca and, to much lower extent, Mg, Na, Al, Fe, K, Mn, Zn and Cu, bound to the carboxylate and phenate groups. The distribution of lignimerin RMW was assessed to be approximately between 1000 and 8600Da, as well as to consist of lignin and tannin, protein and polysaccharide moieties, strongly aggregated each other. H-lignimerin, its acid derivative, revealed a chemical composition and a RMW distribution very close to that of lignimerin, but a marked metal cations decreasing (1.60%) with respect to lignimerin (6.93%). The humic acid-like nature of both the polymers was assessed. Their potential use as bio-adsorbents of heavy metals is briefly discussed.

Reusing ethyl acetate and aqueous exhausted fractions of dry olive mill residue by saprobe fungi.

Some saprobe fungi (Phlebia radiata, Trametes versicolor, Coriolopsis rigida, Pycnoporus cinnabarinus, Fomes sclerodermus or Pleurotus pulmonarius) were able to bioconvert the ethyl acetate fraction (DEAF) and the corresponding aqueous exhausted fraction (EAF) of dry olive mill residue (DOR), reducing their phytotoxicity on Lepidium sativum seeds. Large amount of hydroxytyrosol together with other eight monomeric phenols were found in the native DEAF fraction, which represents a good source of antioxidants. P. radiata, T. versicolor and F. sclerodermus caused an effective phytotoxicity reduction of EAF in the concentration range of 25-3 gl(-1). In particular, in the range between 12.5 and 3 gl(-1), the EAF samples inoculated with P. radiata and F. sclerodermus surprisingly stimulated the germinability of L. sativum, suggesting their use as a potential biofertilizer. This is the first report which showed the bioconversion of the above fractions in shorter time with respect to the previous findings concerning DOR. The possible implications of laccase in the decrease of DEAF and EAF phytotoxicity was also discussed.

Chemical characterization and effects on Lepidium sativum of the native and bioremediated components of dry olive mill residue.

Dry olive mill residue (DOR) from the olive oil production by two phase centrifugation system was fractionated by a consecutive continuous solid-liquid extraction obtaining the EAF, PF, MF and WF fractions with ethyl acetate, n-propanol, methanol and water, respectively. The chemical, chromatographic and mass spectrometric analyses showed EAF, PF and MF to be mainly composed of simple phenols, phenolic acids, flavonoids and glycosilated phenols (glycosides of phenols, secoiridoids and flavonoids), whereas WF was mainly consisting of polymerin, the metal organic polymeric mixture previously identified in olive oil mill waste waters and composed of carbohydrates, melanin, proteins and metals (K, Na, Ca, Mg and Fe). The identification in DOR of oleoside, 6'-beta-glucopyranosyl-oleoside and 6'-beta-rhamnopyranosyl-oleoside, and of its organic polymeric component, known as polymerin, are reported for the first time in this paper. The inoculation of the previously mentioned fractions with saprobe fungi Coriolopsis rigida, Pycnoporus cynnabarinus or Trametes versicolor indicated these fungi to be able to metabolize both the phenols and glycosilated phenols, but not polymerin. In correspondence, EAF, PF, MF and WF, which proved to be toxic on Lepidium sativum, decreased their toxicity after incubation with the selected fungi, WF showing to be also able to stimulate the growth of the selected seeds. The phytotoxicity appeared mainly correlated to the monomeric phenols and, to a lesser extent, to the glycosilated phenols, whereas polymerin proved to be non toxic. However, the laccase activity was not associated with the decrease of phytotoxicity. The valorization of DOR as a producer of high added value substances of industrial and agricultural interest in native form and after their bioremediation for a final objective of the total DOR recycling is also discussed.

Targeting fatty acid amide hydrolase and transient receptor potential vanilloid-1 simultaneously to modulate colonic motility and visceral sensation in the mouse: A pharmacological intervention with N-arachidonoyl-serotonin (AA-5-HT).

BACKGROUND: Endocannabinoid anandamide (AEA) inhibits intestinal motility and visceral pain, but it may also be proalgesic through transient receptor potential vanilloid-1 (TRPV1). AEA is degraded by fatty acid amide hydrolase (FAAH). This study explored whether dual inhibition of FAAH and TRPV1 reduces diarrhea and abdominal pain. METHODS: Immunostaining was performed on myenteric plexus of the mouse colon. The effects of the dual FAAH/TRPV1 inhibitor AA-5-HT on electrically induced contractility, excitatory junction potential (EJP) and fast (f) and slow (s) inhibitory junction potentials (IJP) in the mouse colon, colonic propulsion and visceromotor response (VMR) to rectal distension were studied. The colonic levels of endocannabinoids and fatty acid amides were measured. KEY RESULTS: CB1-positive neurons exhibited TRPV1; only some TRPV1 positive neurons did not express CB1. CB1 and FAAH did not colocalize. AA-5-HT (100 nM-10 µM) decreased colonic contractility by ~60%; this effect was abolished by TRPV1 antagonist 5'-IRTX, but not by CB1 antagonist, SR141716. AA-5-HT (1 µM-10 µM) inhibited EJP by ~30% and IJPs by ~50%. The effects of AA-5-HT on junction potentials were reversed by SR141716 and 5`-IRTX. AA-5-HT (20 mg/kg; i.p.) inhibited colonic propulsion by ~30%; SR141716 but not 5`-IRTX reversed this effect. AA-5-HT decreased VMR by ~50%-60%; these effects were not blocked by SR141716 or 5`-IRTX. AA-5-HT increased AEA in the colon. CONCLUSIONS AND INFERENCES: The effects of AA-5-HT on visceral sensation and colonic motility are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1 mechanisms, possibly reflecting the distinct neuromodulatory roles of endocannabinoid and endovanilloid FAAH substrates in the mouse intestine.