PKD2, or polycystin 2, the product of gene mutated in type 2 autosomal dominant polycystic kidney disease, belongs to transient receptor potential channel superfamily and has been shown function as a nonselective cation plasma membrane. However, mechanism PKD2 activation remains elusive. We show that overexpression increases epidermal growth factor (EGF)-induced inward currents LLC-PK(1) epithelial cells, while knockdown endogenous by RNA interference expression pathogenic missense variant,...

Opioid use is epidemic in cirrhosis, which could precipitate hepatic encephalopathy (HE) potentially through gut dysbiosis and inflammation.To define the effect of opioids on readmissions microbiota composition functionality.Cohort 1 had 200 cirrhotic in-patients (with/without opioid use) followed prospectively index hospitalisation 6 months post discharge. Readmissions (HE-related/unrelated) were compared between patients discharged to rest, including using a multi-variable analysis. Cohort...

Rationale: TRV130 (oliceridine; N-[(3-methoxythiophen-2-yl)methyl]-2-[(9 R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine) is a novel mu opioid receptor (MOR) agonist that preferentially activates G-protein versus β-arrestin signaling pathways coupled to MORs. Prevailing evidence suggests and other G-protein-biased MOR agonists may produce therapeutic analgesic effects with reduced adverse compared existing agonists. Objectives: This study the of acute repeated administration on...

There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine other narcotics are most widely prescribed therapy moderate to severe pain clinically, they have been noted alter microbial composition promote bacterial translocation tissues. Here we examined pharmacodynamic properties chronic mice following depletion with oral gavage an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria...

Δ⁹-Tetrahydrocannbinol (THC), the primary active constituent of <i>Cannabis sativa</i>, has long been known to reduce opioid withdrawal symptoms. Although THC produces most its pharmacological actions through activation CB₁ and CB₂ cannabinoid receptors, role these receptors play in reducing variety symptoms remains unknown. The endogenous cannabinoids, <i>N</i>-arachidonoylethanolamine (anandamide; AEA) 2-arachidonylglycerol (2-AG), activate both but are...

The α 2A -adrenergic receptor (adrenoceptor) was stably expressed in AtT20 mouse pituitary tumor cells; adrenoceptor agonists inhibited adenylyl cyclase, voltage-dependent calcium currents, and increased inwardly rectifying potassium currents. An aspartic acid residue (Asp 79 ) highly conserved among guanine nucleotide-binding protein (G protein)-coupled receptors mutated to asparagine; cells transfected with the mutant 2 -receptor, cyclase currents but did not increase Because distinct G...

Abstract Clinical studies reveal concomitant occurrence of several gastrointestinal and urologic disorders, including irritable bowel syndrome interstitial cystitis. The purpose this study was to determine the mechanisms underlying cross‐organ sensitization at level dorsal root ganglion (DRG) after acute subsided inflammation. DiI (1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate) Fast Blue were injected into distal colon urinary bladder male rats, respectively. Convergent...

The capsaicin receptor TRPV1 is a nonselective cation channel that expressed in sensory neurons. In this study, we examined the role of nonreceptor cellular tyrosine kinase c-Src modulation rat TRPV1. Capsaicin-induced currents identified colonic dorsal root ganglion neurons were blocked by inhibitor PP2 and enhanced phosphatase sodium orthovandate. also abolished human embryonic kidney-293 cells transfected with TRPV1, whereas cotransfection v-Src resulted fivefold increase...

Synaptodendritic injury is thought to underlie HIV-associated neurocognitive disorders and contributes exaggerated inflammation cognitive impairment seen in opioid abusers with HIV-1. To examine events triggering combined transactivator of transcription (Tat)- morphine-induced synaptodendritic systematically, striatal neuron imaging studies were conducted <i>in vitro</i>. These demonstrated nearly identical pathologic increases dendritic varicosities as Tat transgenic mice vivo</i>. caused...

Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is combine opioids other antinociceptive agents. The combination primary active constituent cannabis (Δ⁹-tetrahydrocannabinol) produces enhanced actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether...

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes dysbiosis. Depleting gut bacteria can preclude development of tolerance opioid-induced antinociception, suggesting an important role gut-brain axis in mediating effects. The mechanism underlying dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for integrity barrier they prevent pathogenesis enteric microbiota....

Repeated administration of morphine is associated with tolerance to its antinociceptive properties. However, constipation remains the major side effect chronic exposure morphine. In contrast, previous studies suggest that opioids develops in ileum several species. this study, we provide evidence may arise due a lack development colon. Mice received implants either placebo or 75 mg pellets, and they were examined for antinociception, defecation, intestinal colonic transit after 72 h. Tissues...

The enteric nervous system is a vast network of neurons and glia running the length gastrointestinal tract that functionally controls motility. A procedure for isolation culture mixed population from myenteric plexus described. primary cultures can be maintained over 7 days, with connections developing among glia. longitudinal muscle strip attached stripped underlying circular mouse ileum or colon subjected to enzymatic digestion. In sterile conditions, isolated neuronal are preserved within...

β-Arrestin2 has been reported to play an essential role in analgesic tolerance. Analgesic tolerance without concomitant constipation is a limiting side effect of chronic morphine treatment. Because develops the mouse ileum but not colon, we therefore examined whether β-arrestin2 mechanism differs and colon. In both guinea pig mouse, vitro exposure (2 h, 10 μM) resulted development isolated The IC₅₀ values for morphine-induced inhibition electrical field stimulation contraction...

The ATP-sensitive potassium channel (K(ATP)) in mouse colonic smooth muscle cell is a complex containing pore-forming subunit (Kir6.1) and sulfonylurea receptor (SUR2B). These channels contribute to the cellular excitability of cells hence regulate motility patterns colon. Whole-cell voltage-clamp techniques were used study alterations K(ATP) experimental colitis. Colonic inflammation was induced BALB/C mice after intracolonic administration trinitrobenzene sulfonic acid. currents measured...

Abstract Background In humans, inflammation of either the urinary bladder or distal colon often results in sensory cross-sensitization between these organs. Limited information is known about mechanisms underlying this clinical syndrome. Studies with animal models have demonstrated that activation primary afferent pathways may a role mediating viscero-visceral cross-organ sensitization. Methods Colonic was induced by single dose tri-nitrobenzene sulfonic acid (TNBS) instilled...

Gastrointestinal peristalsis is significantly dependent on the enteric nervous system. Constipation due to reduced a major side-effect of morphine, which limits chronic usefulness this excellent pain reliever in man. The ionic basis for inhibition neuron excitability by morphine not well characterized as previous studies have mainly utilized microelectrode recordings from whole mount myenteric plexus preparations guinea pigs. Here we developed Swiss-Webster mouse culture and examined their...

Hydrogen sulfide (H 2 S) is an endogenous gaseous mediator affecting many physiological and pathophysiological conditions. Enhanced expression of H S reactive nitrogen/oxygen species (RNS/ROS) during inflammation alters cellular excitability via modulation ion channel function. Sulfhydration cysteine residues tyrosine nitration are the posttranslational modifications induced by RNS, respectively. The objective this study was to define interaction between sulfhydration within ATP-sensitive K...