scholarly journals Critical interactions between opioid and cannabinoid receptors during tolerance and physical dependence development to opioids in the murine gastrointestinal tract: proof of concept

2021 ◽  
Author(s):  
Agata Szymaszkiewicz ◽  
Mikołaj Świerczyński ◽  
Marcin Talar ◽  
Prabhakar Reddy Polepally ◽  
Jordan K. Zjawiony ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Physical Dependence ◽  
Smooth Muscles ◽  
Inhibitory Effect ◽  
Opioid Therapy ◽  
Gi Tract ◽  
Promising Alternative ◽  
Co Activation ◽  
Cb1 Antagonist ◽  
Withdrawal Response

Abstract Introduction Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract. Methods TOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The OR/CB interactions were evaluated using mixed agonist (PR-38) and AM-251 (CB1 antagonist). Results The inhibitory effect of morphine on ileal contractions was weaker in tissue incubated with this opioid than in tissue incubated without opioid. The opposite was noted for PR-38. In tissues exposed to morphine, but not to PR-38, naloxone induced a WR. The blockage of CB1 receptors with AM-251 before the addition of PR-38 resulted in a naloxone-induced WR. Conclusion The co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs.

Solitary Peutz-Jeghers Type Polyp of Jejunum with Gastric Fundic and Antral Gland Lining Mucosa: A Case Report and Review of Literature

2021 ◽  
pp. 106689692110677
Author(s):  
Bella Lingjia Liu ◽  
Huifang Zhou ◽  
Martina Risech ◽  
Alex Ky ◽  
Jane Houldsworth ◽  
...  
Keyword(s):  
Family History ◽  
Small Bowel ◽  
Smooth Muscles ◽  
Fundic Gland ◽  
Muscularis Mucosa ◽  
Hamartomatous Polyp ◽  
Gi Tract ◽  
First Case ◽  
Mucocutaneous Pigmentation ◽  
Peutz Jeghers Syndrome

Solitary Peutz-Jeghers type polyps are characterized by a hamartomatous polyp of the gastrointestinal (GI) tract in a patient without mucocutaneous pigmentation, family history of Peutz-Jeghers syndrome, or STK11/LKB1 mutations. Histologically identical to the polyps in Peutz-Jeghers syndrome, these sporadic polyps can arise anywhere along the GI tract, with typical arborizing smooth muscles extending from the muscularis mucosa. While the lining mucosa is generally the same as the organ in which it arises, gastric pyloric and osseous metaplasia have been reported in intestinal polyps in Peutz-Jeghers syndrome. Herein, the authors report the first case of a small intestinal solitary Peutz-Jeghers type polyp with gastric antral and fundic gland lining mucosa. A 43-year-old male was admitted for small bowel obstruction. Diagnostic laparoscopy revealed jejuno-jejunal intussusception with an associated polyp measuring 7.2 cm. Histological examination showed a hamartomatous polyp with arborizing smooth muscle bundles extending from the muscularis mucosae. The polyp was lined by non-dysplastic gastric antral and fundic gland mucosa, and was sharply demarcated from the adjacent non-polypoid intestinal mucosa. Colonoscopy, esophagogastroduodenoscopy and small bowel enteroscopy revealed no additional polyps or masses. Thorough investigation of the patient's family history was negative for Peutz-Jeghers syndrome or mucocutaneous pigmentation. Molecular analysis of the lesion was negative for STK11/LKB1 mutations. A diagnosis of solitary Peutz-Jeghers type polyp of the small bowel with gastric antral and fundic gland mucosal lining was rendered.

Zinc deficiency: A cause of opioid-induced physical dependence and addiction in post-operative total hip arthroplasty patients

2021 ◽  
Vol 17 (2) ◽  
pp. 145-154
Author(s):  
Tyler J. Tantillo, DO ◽  
Manoj R. Jagtiani, DO ◽  
Eric R. Silverman, MD ◽  
Adam D. Bitterman, DO ◽  
Giles R. Scuderi, MD
Keyword(s):  
Total Hip Arthroplasty ◽  
Linear Regression ◽  
Multiple Linear Regression ◽  
Zinc Deficiency ◽  
Hip Arthroplasty ◽  
Physical Dependence ◽  
Univariate Analysis ◽  
Opioid Therapy ◽  
Opioid Use ◽  
Total Hip

Objectives: Recently, opioid abuse and related overdoses have increased warranting the need for research directed against the opioid epidemic. Previous studies identified that patients on opioid therapy may become zinc deficient and that zinc, in a murine model, may antagonistically affect the opioid receptor.13 Further understanding the relationship between opioid use and zinc deficiency may mitigate the opioid epidemic.Methods: A retrospective study was conducted to identify zinc (Zn2+) deficiencies among post-operative total hip arthroplasty (THA) patients. On post-operative day one, patients had routine blood tests, including Zn2+ plasma levels. Patients were considered Zn2+-deficient if their Zn2+ plasma was 56 μg/dL (Reference: 56-134 μg/dL). Upon discharge from the hospital, the patients’ inpatient opioid medication consumption per day was determined by dividing total morphine milligram equivalents (MMEs) by length of stay. A Student's t-test was performed to compare the total MMEs for Zn2+-deficient patients versus Zn2+-normal patients. A univariate analysis followed by multiple linear regression was performed to identify demographic or surgical predictors of MMEs/day. Results: For Zn2+-deficient patients, the total MMEs/day was 33.62 ( ± 27.06), as compared to Zn2+-normal patients who consumed 16.22 ( ±16.01) MMEs/day (p = 0.031). The univariate analysis and multiple linear regression showed that patients’ Zn2+ status had a significant contribution toward predicting MMEs/day, with p = 0.022 and p = 0.04, respectively.Conclusion: The results of this study suggest that Zn2+ deficiency may potentiate opioid consumption. Thus, Zn2+ supplementation may be a simple approach to reducing opioid addiction and dependence.

scholarly journals A dynamic role for dopamine receptors in the control of mammalian spinal networks

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Simon A. Sharples ◽  
Nicole E. Burma ◽  
Joanna Borowska-Fielding ◽  
Charlie H. T. Kwok ◽  
Shane E. A. Eaton ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Inhibitory Effect ◽  
Endogenous Dopamine ◽  
Co Activation ◽  
Dopaminergic Pathway ◽  
Network Output ◽  
Spinal Network ◽  
Specific Receptors ◽  
Differential Control ◽  
Parallel Activation

Abstract Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors; however, how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.

Molecular diversity of KVα- and β-subunit expression in canine gastrointestinal smooth muscles

1999 ◽  
Vol 277 (1) ◽  
pp. G127-G136 ◽  
Author(s):  
Anne Epperson ◽  
Helena P. Bonner ◽  
Sean M. Ward ◽  
William J. Hatton ◽  
Karri K. Bradley ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscles ◽  
Muscle Cells ◽  
Pcr Analysis ◽  
Transcriptional Level ◽  
Gi Tract ◽  
Excitable Cells ◽  
Subunit Expression ◽  
Molecular Components

Voltage-activated K+(KV) channels play an important role in regulating the membrane potential in excitable cells. In gastrointestinal (GI) smooth muscles, these channels are particularly important in modulating spontaneous electrical activities. The purpose of this study was to identify the molecular components that may be responsible for the KV currents found in the canine GI tract. In this report, we have examined the qualitative expression of eighteen different KV channel genes in canine GI smooth muscle cells at the transcriptional level using RT-PCR analysis. Our results demonstrate the expression of KV1.4, KV1.5, KV1.6, KV2.2, and KV4.3 transcripts in all regions of the GI tract examined. Transcripts encoding KV1.2, KVβ1.1, and KVβ1.2 subunits were differentially expressed. KV1.1, KV1.3, KV2.1, KV3.1, KV3.2, KV3.4, KV4.1, KV4.2, and KVβ2.1 transcripts were not detected in any GI smooth muscle cells. We have also determined the protein expression for a subset of these KV channel subunits using specific antibodies by immunoblotting and immunohistochemistry. Immunoblotting and immunohistochemistry demonstrated that KV1.2, KV1.4, KV1.5, and KV2.2 are expressed at the protein level in GI tissues and smooth muscle cells. KV2.1 was not detected in any regions of the GI tract examined. These results suggest that the wide array of electrical activity found in different regions of the canine GI tract may be due in part to the differential expression of KV channel subunits.

scholarly journals Inhibitory effect of X 537A on vascular and intestinal smooth muscles

1983 ◽  
Vol 33 ◽  
pp. 141
Author(s):  
Kazuyasu Murakami ◽  
Hideaki Karaki ◽  
Norimoto Urakawa
Keyword(s):  
Smooth Muscles ◽  
Inhibitory Effect ◽  
Intestinal Smooth Muscles

Isoproterenol attenuates myosin phosphorylation and contraction of tracheal muscle

1989 ◽  
Vol 66 (5) ◽  
pp. 2017-2022 ◽  
Author(s):  
K. Obara ◽  
P. de Lanerolle
Keyword(s):  
Light Chain ◽  
Myosin Light Chain ◽  
Isometric Force ◽  
Smooth Muscles ◽  
Inhibitory Effect ◽  
Isometric Tension ◽  
Myosin Light Chain Phosphorylation ◽  
Response Curves ◽  
Shortening Velocity ◽  
Myosin Phosphorylation

The effects of isoproterenol on isometric force, unloaded shortening velocity, and myosin phosphorylation were examined in thin muscle bundles (0.1–0.2 mm diam) dissected from lamb tracheal smooth muscle. Methacholine (10(-6) M) induced rapid increases in isometric force and in phosphorylation of the 20,000-Da myosin light chain. Myosin phosphorylation remained elevated during steady-state maintenance of isometric force. The shortening velocity peaked at 15 s after stimulation with methacholine and then declined to approximately 45% of the maximal value by 3 min. Isoproterenol pretreatment inhibited methacholine-stimulated myosin light chain phosphorylation, shortening velocity, and force during the early stages of force generation. However, the inhibitory effect of isoproterenol on force and myosin phosphorylation is proportionally greater than that on shortening velocity. Isoproterenol pretreatment also caused a rightward non-parallel shift in the methacholine dose-response curves for both isometric tension and myosin light chain phosphorylation. These data demonstrate that isoproterenol attenuates the contractile properties of airway smooth muscles by affecting the rate and extent of myosin light chain phosphorylation, perhaps through a mechanism that involves the synergistic interaction of myosin light chain kinase phosphorylation and Ca2+ metabolism.

Effect of 1,1-dimethylphenyl 1,4-piperazinium on mouse tracheal smooth muscle responsiveness

2005 ◽  
Vol 288 (6) ◽  
pp. L1139-L1145 ◽  
Author(s):  
G. Dorion ◽  
E. Israël-Assayag ◽  
M. J. Beaulieu ◽  
Y. Cormier
Keyword(s):  
Smooth Muscle ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Bronchial Hyperresponsiveness ◽  
Smooth Muscles ◽  
Inhibitory Effect ◽  
Tracheal Smooth Muscle ◽  
In Vivo Model ◽  
Airway Response

Bronchial hyperresponsiveness is one of the main features of asthma. A nicotinic receptor agonist, 1,1-dimethylphenyl 1,4-piperazinium (DMPP), has been shown to have an inhibitory effect on airway response to methacholine in an in vivo model of asthma. The aims of this study were to 1) verify whether nicotinic acetylcholine receptors (nAChR) were present on mouse tracheal smooth muscle, 2) verify whether bronchoprotection observed in mice was due to a direct effect on airway smooth muscle, and 3) compare the effects of nicotinic agonists to that of salbutamol. α3-, α4-, and α7-nAChR subunits were detected by immunofluorescence on tracheal tissues from normal BALB/c mice. The effect of DMPP on tracheal responsiveness was verified by an isometric method. Tracheas were isolated from normal mice, placed in organ baths, and contracted with a single dose of methacholine. Cumulative doses of DMPP or salbutamol were added to the baths. Results show that mouse tracheal smooth muscle is positive for α4- and α7-nAChR subunits and that the epithelium is positive for α3-, α4-, and α7-subunits. DMPP induced a greater dose-dependent relaxation of tracheal smooth muscles precontracted with methacholine than with salbutamol. These results suggest that the smooth muscle-relaxing effect of DMPP could have some interest in the treatment of obstructive pulmonary diseases.

Discharge prescribing of enteral opioids after initiation as a weaning strategy from continuous opioid infusions in the Intensive Care Unit

2018 ◽  
Vol 14 (1) ◽  
pp. 35 ◽  
Author(s):  
Bridgette Kram, PharmD, BCPS, BCCCP ◽  
Kylie M. Weigel, PharmD, BCPS ◽  
Michelle Kuhrt, PharmD ◽  
Daniel L. Gilstrap, MD
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Hospital Discharge ◽  
Physical Dependence ◽  
Total Duration ◽  
Opioid Therapy ◽  
Hospital Length ◽  
Patients At Risk ◽  
Long Acting ◽  
Discharge Prescription

Objective: To evaluate the proportion of patients receiving a hospital discharge prescription for a scheduled enteral opioid following initiation as a weaning strategy from a continuous opioid infusion in the Intensive Care Unit (ICU).Design: Retrospective, observational study.Setting: Five adult ICUs at a large, quaternary care academic medical center.Patients: Endotracheally intubated, opioid-naive adults receiving a continuous opioid infusion with a concomitant scheduled enteral opioid initiated. Exclusion criteria were receipt of fewer than two enteral opioid doses, documentation of a long-acting opioid as a home medication, the indication for the enteral opioid was not a weaning strategy, death during hospital admission or discharge to hospice. Interventions: None.Main outcome measures: The proportion of ICU and hospital survivors who received a discharge prescription for a scheduled enteral opioid, total duration of continuous opioid infusion, duration of continuous opioid infusion after initiation of an enteral opioid therapy, total duration of enteral therapy, ICU and hospital length of stay.Results: Of 62 included patients, 19 patients (30.6 percent) received a new prescription for a scheduled enteral opioid at hospital discharge. The median duration of enteral opioid therapy was longer for patients who received a discharge prescription compared to those who did not (20.09 vs 8.89 days, p = 0.02), though the remaining endpoints were not different.Conclusions: Utilizing scheduled enteral opioids as a weaning strategy from continuous opioid infusions may place patients at risk of ICU-acquired physical dependence on opioids.

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