Peripheral Mu-opioid Receptors Research Articles

Dermorphin [D-Arg2, Lys4] (1-4) Amide Alleviates Frostbite-Induced Pain by Regulating TRP Channel-Mediated Microglial Activation and Neuroinflammation.

Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1β) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4-L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation.

Peripheral mu-opioid receptor activation by dermorphin [D-Arg2, Lys4] (1–4) amide alleviates behavioral and neurobiological aberrations in rat model of chemotherapy-induced neuropathic pain

Paclitaxel, a frequently utilized chemotherapeutic agent, often gives rise to severe and distressing sensory neuropathy in patients undergoing chemotherapy. Unfortunately, current therapeutics for chemotherapy-induced neuropathic pain (CINP) demonstrate limited effectiveness and are burdened with the potential for central side effects such as sedation, respiratory depression, cognitive impairment, and addiction, posing substantial clinical challenges. In light of these limitations, present study is designed to investigate the therapeutic potential of Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), a preferential peripherally acting mu-opioid receptor agonist, in rat model of CINP. The primary objective was to assess the analgesic properties of DALDA and elucidate the underlying mechanisms governing its therapeutic activity. Our findings revealed that DALDA treatment significantly ameliorated paclitaxel-induced evoked and spontaneous ongoing pain in rats without causing drug addiction and other central side effects. Molecular analyses further unveiled that paclitaxel administration resulted in increased expression of TRP channels, NR2B, voltage-gated sodium channels (VGSCs) and neuroinflammatory markers in both the dorsal root ganglion (DRG) and the spinal cord (L4-L5 region) of rats. DALDA treatment significantly downregulated ion channels (TRPs, VGSCs) and NR2B expressions, concomitant with the inhibition of microglial activation, resulting in the suppression of oxido-nitrosative stress and neuroinflammatory cascade. Findings from the current study suggests that peripheral mu-opioid receptors may offer a potential target for the treatment of patients suffering from CINP, offering new avenues for improved pain relief while minimizing central side effects.

Loperamide, a peripheral Mu-Opioid receptor agonist, attenuates chemotherapy-induced neuropathic pain in rats

Opioids are employed in the management of chemotherapy-induced neuropathic pain (CINP) when other pain management approaches have failed and proven ineffective. However, their use in CINP is generally considered as a second-line or adjunctive therapy owing to their central side effects and development of tolerance with their long-term usage. Targeting peripheral sites may offer several advantages over the conventional CNS-based approaches as peripheral targets modulate pain signals at their source, thereby relieving pain with higher specificity, efficacy and minimizing adverse effects associated with off-site CNS actions. Therefore, present study was designed with an aim to investigate the effect of loperamide, a peripherally acting mu-opioid receptor agonist, on paclitaxel-induced neuropathic pain in rats and elucidate its underlying mechanism. Loperamide treatment significantly attenuated mechanical, and cold hypersensitivity and produced significant place preference behaviour in neuropathic rats indicating its potential to treat both evoked and spontaneous pain. More importantly, loperamide treatment in naïve rats did not produce place preference to drug-paired chamber pointing towards its non-addictive analgesic potential. Further, molecular investigations revealed increased expression of ion channels such as TRPA1, TRPM8; voltage-gated sodium channels (VGSCs) and neuroinflammatory markers in the dorsal root ganglion (DRG) and lumbar (L4-L5) spinal cord of neuropathic rats, which was significantly downregulated upon loperamide treatment. These findings collectively suggest that activation of peripheral mu-opioid receptors contributes to the amelioration of both evoked and spontaneous pain in neuropathic rats by downregulating TRP channels and VGSCs along with suppression of oxido-nitrosative stress and neuroinflammatory cascade.

Abstract PO-089: Opioid-mediated suppression of anti-tumor immunity via peripheral OPRM1 signaling in head and neck squamous cell carcinoma

Abstract Head and Neck squamous cell carcinoma (HNSCC) causes severe pain, beyond what is reported in other cancer types. Opioids are the current backbone of HNSCC pain treatment but may have an immunomodulatory effect in the presence of cancer; T cells express opioid receptors. We recently demonstrated that opioids may affect the efficacy of anti-PD1 monoclonal antibody (mAb) treatment in recurrent/metastastic HNSCC patients; opioid usage was associated with significantly lower progression free survival and overall survival as well as decreased CD8 T cells in the tumor microenvironment. We hypothesized that cancer immunosurveillance is impaired by the immunosuppressive actions of exogenous opioids via peripheral mu-opioid receptor (OPRM1) signaling. A syngeneic mouse oral cancer model was used to determine if analgesic morphine impacted the tumor-associated immune response during tumor progression and in response to anti-PD1 mAb; mouse oral cancer cell line 1 (MOC1) tumor-bearing mice were treated with vehicle or morphine (10mg/kg i.p., 2x daily for 4.5 days) and the tumor-associated immune infiltrate was assessed between groups using flow cytometry. Anti-PD1 mAb (250µg/mouse, 3 × 2 day interval) was initiated directly following morphine treatment. Co-administration of methylnaltrexone (MNTX), a peripheral OPRM1 antagonist used to confirm specificity and site of action of the morphine-induced effects. Finally, any direct effects of morphine on tumor cells were investigated in oral cancer cell lines using quantitative PCR and colorimetric proliferation assays. Morphine induced a 75±5% reduction in CD8+ T cells and a 90±3% reduction in CD19+ B cells in MOC1 compared to sham mice (n=6/group); morphine-induced immunosuppression was completely blocked with co-treatment of MNTX. Studies involving morphine administration prior to anti-PD1 treatment are currently underway but given the substantial suppression in infiltrating lymphocyte populations, efficacy is expected to be lessened. Lastly, Oprm1 expression was not detected at the mRNA level in mouse oral cancer cell lines. In vitro, 10µM morphine did not induce cell proliferation (proliferation relative to vehicle after 48hr; vehicle=100±8.3%, morphine=115.7±9.6%) or improve wound healing (wound closure after 24hr; vehicle=76.2±11.6%, morphine=78.5±11.4%). Taken together, our data suggest that morphine suppresses anti-tumor immunity via peripheral OPRM1 signaling in immune cells but not tumor cells. Further investigation is warranted to determine whether peripheral opioid blockade (i.e. MNTX) can slow tumor progression and improve response to cancer treatments while preserving centrally-mediated analgesia. Citation Format: Lisa A. McIlvried, Mona Yuan, Nicole L. Horan, Megan A. Atherton, Marci L. Nilsen, Dan P. Zandberg, Nicole N. Scheff. Opioid-mediated suppression of anti-tumor immunity via peripheral OPRM1 signaling in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-089.

Opioid-induced bowel dysfunction: a literature review

Opioid therapy plays a crucial role in the management of acute and chronic pain, with opioids being widely prescribed worldwide. However, alongside the analgesic benefits, the use of opioids is associated with a range of adverse effects, including opioid-induced bowel dysfunction. Opioid-induced bowel dysfunction refers to a constellation of gastrointestinal symptoms caused by the effects of opioids on the gastrointestinal tract. These symptoms primarily manifest as constipation, but can also include abdominal pain, bloating, nausea, and vomiting. Opioid-induced bowel dysfunction poses a significant clinical challenge, as it can severely affect patients' quality of life. Non-pharmacological approaches alone are rarely sufficient to counteract the adverse effects of opioid therapy. The primary pharmacological agents used in opioid-induced bowel dysfunction management are laxatives, which should be chosen according to individual patient needs. Patients with poorly controlled symptoms can benefit from new pharmacological approaches, particularly peripheral mu-opioid receptor antagonists. By better understanding the underlying mechanisms, clinical manifestations, diagnostic criteria, and management strategies, healthcare professionals can optimize patient care, minimize complications, and improve patients' overall well-being.

S2744 Loperamide-Induced Ventricular Fibrillation Cardiac Arrest in the Setting of Recently Diagnosed Ulcerative Colitis

Introduction: Loperamide is a peripheral mu opioid receptor agonist that inhibits intestinal peristalsis and decreases fluid and electrolyte loss. While typically used over-the-counter for diarrhea, it may cause cardiotoxicity at higher dosages, leading to arrhythmia and cardiac arrest. Case Description/Methods: A 36 year-old female with a recent diagnosis of ulcerative colitis, presented with unresponsiveness while eating dinner. Cardiopulmonary resuscitation was initiated by family, found to be in ventricular fibrillation by paramedics. Return of spontaneous circulation was achieved after one defibrillation and administration of epinephrine. Upon admission to the intensive care unit, she developed torsades de pointes leading to recurrent ventricular fibrillation cardiac arrest, requiring 12 defibrillations and subsequent esmolol and lidocaine infusions. Computed tomography pulmonary angiogram was unremarkable for pulmonary embolism, and transthoracic ultrasound revealed no structural abnormalities. Cardiac MRI had no evidence of acute myocarditis or infiltrative cardiomyopathy. Cardiac catheterization revealed nonobstructing coronary arteries. For secondary prevention, an implantable cardiac defibrillator was placed. Upon further discussion after unplanned self-extubation, patient disclosed that she had been overutilizing loperamide at about 16 mg daily to help control her frequent episodes of diarrhea. (Figure) Discussion: Loperamide may act similar to antiarrhythmic medications, with dose dependent effects causing ventricular instability. Blockage of sodium channels prolongs the QRS complex causing polymorphic ventricular tachycardia, which may develop into torsades de pointes, ventricular fibrillation and cardiac arrest. Loperamide may be dosed over-the-counter up to 8 mg per day. While the half-life of loperamide is 9 to 14 hours, it may be greater than 40 hours at 16 mg doses, likely due to decreased peristalsis that slows its rate of absorption. Typical management of QTc prolongation arrhythmias due to medications may be refractory in loperamide-induced cardiotoxicity, including sodium bicarbonate, magnesium sulfate, amiodarone and defibrillation. Cardiac stabilization may not be obtained for up to 5 days. While most cases of loperamide-induced cardiotoxicity have been related to alleviating symptoms of opioid withdrawal or causing euphoria, our patient exemplifies an attempt to control symptoms of new onset Ulcerative Colitis.Figure 1.: Telemetry strips showing polymorphic ventricular tachycardia (A) inducing ventricular fibrillation (B).

11C]carfentanil PET imaging for studying the peripheral opioid system in vivo: effect of photoperiod on mu-opioid receptor availability in brown adipose tissue

PurposePhotoperiod determines the metabolic activity of brown adipose tissue (BAT) and affects the food intake and body mass of mammals. Sympathetic innervation of the BAT controls thermogenesis and facilitates physiological adaption to seasonal changes, but the exact mechanism remains elusive. Previous studies have shown that central opioid signaling regulates BAT thermogenesis, and that the expression of the brain mu-opioid receptor (MOR) varies seasonally. Therefore, it is important to know whether MOR expression in BAT shows seasonal variation.MethodsWe determined the effect of photoperiod on BAT MOR availability using [11C]carfentanil positron emission tomography (PET). Adult rats (n = 9) were repeatedly imaged under various photoperiods in order to simulate seasonal changes.ResultsLong photoperiod was associated with low MOR expression in BAT (β = − 0.04, 95% confidence interval: − 0.07, − 0.01), but not in muscles. We confirmed the expression of MOR in BAT and muscle using immunofluorescence staining.ConclusionPhotoperiod affects MOR availability in BAT. Sympathetic innervation of BAT may influence thermogenesis via the peripheral MOR system. The present study supports the utility of [11C]carfentanil PET to study the peripheral MOR system.

GRK2 Dictates a Functional Switch of the Peripheral Mu-Opioid Receptor.

The peripheral mu-opioid receptor (MOR) has been recognized as a potential target to provide safer analgesia with reduced central side effects. Although analgesic incompetence of the peripheral MOR in the absence of inflammation was initially identified more than a decade ago, there has been very limited investigation into the underlying signaling mechanisms. Here we identify that G protein-coupled receptor kinase 2 (GRK2) constitutively interacts with the MOR in peripheral sensory neurons to suppress peripheral MOR activity. Brief exposure to bradykinin (BK) causes uncoupling of GRK2 from the MOR and subsequent restoration of MOR functionality in dorsal root ganglion (DRG) neurons. Interestingly, prolonged BK treatment induces constitutive activation of the MOR through a mechanism that involves protein kinase C (PKC) activation. After silencing Raf kinase inhibitory protein (RKIP) by RNA interference, BK-induced constitutive MOR activation is completely abrogated, which agrees with previous findings that BK activates PKC signaling to initiate GRK2 sequestration by RKIP. Furthermore, we demonstrate that constitutive, peripheral MOR activity requires GRK2 uncoupling and that the FDA-approved SSRI paroxetine promotes this state of uncoupling. Collectively, these results indicate that GRK2 tightly regulates MOR functional states and controls constitutive MOR activity in peripheral sensory neurons, supporting the potential for targeting the kinase to provide safer analgesia.

A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors

The newly designed fentanyl derivative [( ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide] (NFEPP) was recently shown to produce analgesia selectively via peripheral mu-opioid receptors (MOR) at acidic pH in rat inflamed tissues. Here, we examined the pH-dependency of NFEPP binding to brain MOR and its effects on bone cancer-induced pain in mice. The IC50 of NFEPP to displace bound [3H]-DAMGO was significantly higher compared to fentanyl at pH 7.4, but no differences were observed at pH 5.5 or 6.5. Intravenous NFEPP (30–100 nmol/kg) or fentanyl (17–30 nmol/kg) inhibited heat hyperalgesia in mice inoculated with B16-F10 melanoma cells. The peripherally-restricted opioid receptor antagonist naloxone-methiodide reversed the effect of NFEPP (100 nmol/kg), but not of fentanyl (30 nmol/kg). The antihyperalgesic effect of NFEPP was abolished by a selective MOR- (cyprodime), but not delta- (naltrindole) or kappa- (nor-binaltorphimine) receptor antagonists. Ten-fold higher doses of NFEPP than fentanyl induced maximal antinociception in mice without tumors, which was reversed by the non-restricted antagonist naloxone, but not by naloxone-methiodide. NFEPP also reduced heat hyperalgesia produced by fibrosarcoma- (NCTC 2472) or prostate cancer-derived (RM1) cells. These data demonstrate the increased affinity of NFEPP for murine MOR at low pH, and its ability to inhibit bone cancer-induced hyperalgesia through peripheral MOR. In mice, central opioid receptors may be activated by ten-fold higher doses of NFEPP.

Role of peripheral sensory neuron mu-opioid receptors in nociceptive, inflammatory, and neuropathic pain

Background and objectiveThe role of peripheral mu-opioid receptors (MOPs) in chronic pain conditions is not well understood. Here, we used a combination of mouse genetics, behavioral assays, and pharmacologic interventions...

Efficacy and safety of alvimopan use in benign urinary tract reconstruction.

To analyze the use of alvimopan, a peripheral mu-opioid receptor antagonist, in expediting gastrointestinal recovery after benign abdominal urinary tract reconstruction. Alvimopan use has been well defined in the management of radical cystectomy and urinary diversion for oncologic indications. It has not been studied in benign abdominal genitourinary reconstruction. Patients who underwent urinary reconstruction utilizing harvested bowel segments for benign conditions from 12/2014-7/2019 were retrospectively reviewed. From 5/2018-7/2019 our institution approved the use of perioperative alvimopan in the aforementioned patients (N = 11), who were paired 1:2 with patients from a cohort of alvimopan-eligible patients who did not receive the drug (N = 22). Patients were paired by (1) type of reconstruction and (2) presence of neurogenic bowel-bladder (NBB). Of the 70 patients who underwent urinary reconstruction during the study period, 46 patients (66%) were eligible to receive alvimopan. Length of stay was shorter for the alvimopan group compared to the non-alvimopan group (median 5days [IQR 4-5days] vs. 8days [IQR 6-11days]; P = 0.002). Time to first bowel movement was shorter for the alvimopan group (median 4days [IQR 3-4days] vs. 6days [IQR 4-7], P = 0.001). No patient treated with alvimopan required a nasogastric (NG) tube for post-operative ileus compared to 7 (32%) patients in the non-treatment group (P = 0.035). Post-operative complications and 30-day readmissions were similar between the two groups. The use of perioperative alvimopan in benign abdominal urinary tract reconstruction expedited return of bowel function and decreased length of stay compared to a matched cohort of untreated patients.

Naldemedine: A New Option for OIBD.

Opioid-induced bowel dysfunction (OIBD) is a common complication in long-term opioid users and abusers. It is a burdensome condition, which significantly limits quality of life and is associated with increasing health costs. OIBD affects up to 60% of patients with chronic non-cancer pain and over 80% of patients suffering from cancer pain and is one of the conditions of the most common symptoms associated with opioid maintenance. Given the continued use of opioids for chronic pain management in appropriate patients, OIBD is likely to persist in clinical practice in the coming years. We will herein review its underlying pathophysiological mechanisms and the available treatments. In the last years, pharmaceutical research has focused on the opportunity of targeting peripheral mu-opioid receptors without affecting their analgesic activity in the central nervous system, and several peripherally acting mu-opioid receptors antagonists (PAMORAs) drugs have been approved. We will mainly focus on naldemedine, discussing its pharmacological properties, its clinical efficacy and side effects. Head-to-head comparisons between naldemedine and the other PAMORAs are not available yet, but some considerations will be discussed based on the pharmacological and clinical data. As a whole, the available data suggest that naldemedine is a valid treatment option for OIBD, as it is a well-tolerated drug that alleviates constipation without affecting analgesia or causing symptoms of opioid withdrawal.

The role of testosterone in mu-opioid receptor expression in the trigeminal ganglia of opioid-tolerant rats

Although tolerance serves as a major limitation in the long-term clinical use of opioids in patients with chronic severe pain, mechanisms of opioid tolerance are poorly understood. In this study, a morphine tolerance model was established by subcutaneously injecting male rats with morphine (10 mg/kg) twice a day for 10 consecutive days. In addition, a subset of morphine-tolerant rats underwent testosterone replacement therapy. The levels of mu-opioid receptor (MOR) mRNA and protein in the trigeminal ganglia (TGs) of morphine-tolerant versus control rats and of morphine-tolerant rats with vs. without testosterone replacement therapy were measured. We found that testosterone levels were significantly lower in morphine-tolerant rats than in the controls (1.248 ± 0.231 ng/ml vs. 2.223 ± 0.153 ng/ ml, respectively; p = 0.008). Furthermore, chronic morphine exposure led to a downregulation in the levels of MOR mRNA to 79.3%, and of MOR protein to 68.9%. Testosterone replacement therapy restored MOR mRNA and protein levels specifically in rats who had developed a tolerance to morphine, thereby suggesting a potential role of testosterone in the opioid-receptor response to chronic morphine exposure. In summary, our study provides evidence for the involvement of testosterone in the proper regulation of the peripheral MOR system in rats following prolonged morphine exposure. We also suggest that analgesic therapeutic measures should take into account the testosterone levels of patients who have built up a tolerance to morphine.

Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial.

PurposeConstipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation.MethodsThe MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality.ResultsA total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82–2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1–3. However, during days 4–28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4–28 (p = 0.007).ConclusionWe found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded.Electronic supplementary materialThe online version of this article (10.1007/s00134-019-05913-6) contains supplementary material, which is available to authorized users.

The role of opioids in cancer progression.

The role of opioids in cancer progression.

2881 Can Eluxadoline Be Useful in Managing Patients With Functional Diarrhea?

INTRODUCTION: Eluxadoline is an FDA approved medication for use in patients with irritable bowel syndrome with diarrhea (IBS-d). It is a peripheral mu-opioid receptor agonist resulting in a reduction in colonic motility while antagonizing central delta receptors that modify pain and thus targets the two key components of IBS-d. Functional diarrhea (FD) is similar to IBS-d, but there is no pain with FD and there are currently no FDA approved medications for its treatment. This caseseries examines the efficacy of eluxadoline in managing FD. METHODS: Electronic medical records at a private gastroenterology clinic were reviewed from May 2015-present. Patients must have undergone diagnostic evaluation including stool elastase, lactoferrin, breath testing, celiac serology, and both upper and lower endoscopy with biopsies. Detailed clinical histories and medication reconciliation were also performed to exclude other causes for diarrhea. Patients found to have other FGIDs, IBD, bowel obstruction, malabsorption, or cholecystectomy were excluded. Patients must also have failed or demonstrated intolerance to OTC anti-diarrheals, dietary changes and supplemental fiber, and anticholinergics or tricyclics. Eligible patients were treated for 6 months with open label eluxadoline and clinical follow up was required. All patients began 100 mg bid, but were allowed to reduce the dose to 75 mg bid if constipation or abdominal discomfort occurred. There were 2 primary endpoints: Improvement in Bristol Stool Scale (BSS) and decrease in daily stool frequency by 30%. RESULTS: Eleven patients with FD were identified by Rome IV criteria and were included in the series. All completed 6 months of therapy with eluxadoline. Patients had a mean BSS of 6.2 (range 6-7) and mean daily stool frequency of 4.8 (range 3-10) at baseline. Eight patients (73%) satisfied both clinical endpoints with an average reduction in stool frequency to 2.8 (range: every other day to 4 per day). The mean BSS decreased from 6.2 to 4.2, with a range of 2-5. 2 patients developed constipation but responded to the lower dose. The remaining 3 patients (27%) showed moderate clinical improvement but did not meet one or both of the primary endpoints. CONCLUSION: 1. Eluxadoline may be an effective tool in managing FD where conventional therapy has failed. 2. The length of the trial demonstrated durability. 3. This open label case series should stimulate interest into funding a blinded placebo controlled trial.

Comparison of the antinociceptive profiles of morphine and oxycodone in two models of inflammatory and osteoarthritic pain in rat

Oxycodone and morphine are two opioid drugs commonly used for the treatment of moderate to severe pain. However, their use in the management of noncancer pain remains a controversial issue and, in this respect, the evidence on their effectiveness and safety, particularly in osteoarthritis, is being questioned. In order to analyse their analgesic profile, two different pain models in rats were used: the formalin-induced inflammatory pain and the monosodium iodoacetate (MIA)-induced knee osteoarthritic pain. Drugs were administered systemically (i.p.) and their antinociceptive effect and potency were assessed. In the formalin test, both morphine and oxycodone produced a dose-dependent antinociceptive effect, but oxycodone outdid morphine in terms of effectiveness and potency (nearly two times) in the early (acute nociceptive) as in the late phase (inflammatory). In the osteoarthritis model, both drugs reduced movement–evoked pain (knee-bend test), mechanical allodynia (von Frey test) and heat hyperalgesia (Plantar test). Pretreatment with naloxone and naloxone methiodide reduced morphine and oxycodone effects. Peripheral mu-opioid receptors play a crucial role in the antinociceptive effect of both drugs on movement-evoked pain and heat hyperalgesia, but not on tactile allodynia.The main finding of our study is that oxycodone has a better antinociceptive profile in the inflammatory and osteoarthritic pain, being more effective than morphine at 14 days post-MIA injection (phase with neuropathic pain); it overcame the morphine effect by improving the movement-induced pain, tactile allodynia and heat hyperalgesia.Therefore, oxycodone could be an interesting option to treat patients suffering from knee osteoarthritis when opioids are required.

(256) Peripherally-Restricted Dual-Acting Kappa/Delta Opioid Agonist (CA1001) Prevents Formalin-Induced Hyperalgesia

Peripheral mu-opioid receptors (MOR) are responsible for opioid-induced constipation, but in the uninjured state do not participate significantly in the pain pathway. On the other hand, kappa- (KOR) and delta-opioid (DOR) receptors are constitutively present in the periphery. However, the DOR only becomes active following the induction of the inflammatory response. The relative contribution of DOR agonism to KOR agonism was examined in the formalin model. Subcutaneous plantar injection of formalin causes a bi-phasic nocifensive behavioral response in rodents. The early phase (phase 1) lasts for about 5-10 minutes, following which an interphase occurs without any discernible nociceptive reactions, after which the late phase (phase 2) nociceptive reaction ensues continuing from about 20-60 minutes. Phase 2 of the formalin model is a model of continuously present persistent pain. The late phase (phase 2), in particular, is considered as a pharmacodynamic surrogate of central sensitization. A novel dual-acting, peripherally-restricted kappa-delta opioid agonist (CA1001) was compared to a peripherally-restricted kappa agonist (ICI204448) in the formalin model in the mouse. Following IACUC approval, mice were randomly pretreated with inert vehicle, ICI204448 1mg/kg, ICI204448 10mg/kg, CA1001 1mg/kg, or CA1001 10 mg/kg. Spontaneous nocifensive behaviors were blindly assessed (video recording). Neither agent was effective in reducing the acute (0-5 minutes) response to formalin injection (phase 1). CA1001 1 mg/kg was as effective as ICI204448 10 mg/kg in reducing formalin-induced responses at 20-35 minutes; CA1001 10 mg/kg was significantly more effective than ICI204448 10 mg/kg (phase 2; p

Opioid-induced constipation in intensive care – how big is the problem, and can we solve it?

Opioids are commonly used on the intensive care unit (ICU) but are associated with a high incidence of constipation, often resistant to conventional laxative treatment. Recently developed peripheral mu-opioid receptor antagonists (naloxegol, methylnaltrecone, alvimopan) are new in the treatment of

Itch induced by peripheral mu opioid receptors is dependent on TRPV1-expressing neurons and alleviated by channel activation

Opioids remain the gold standard for the treatment of moderate to severe pain. However, their analgesic properties come with important side effects, including pruritus, which occurs frequently after systemic or neuraxial administration. Although part of the opioid-induced itch is mediated centrally, recent evidence shows that the opioid receptor system in the skin also modulates itch. The goal of our study was to identify the peripherally located transducer mechanisms involved in opioid-induced pruritus. Scratching behaviors in response to an intradermal injection of the mu-opioid receptor (MOR) agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) was quantified in mast cell-, PAR2- and TRPV1-deficient mice or following ablation of TRPV1+ sensory neurons. We found that mast cells−/−, PAR-2−/−, or TRPV1−/− mice still exhibit DAMGO-induced itch responses. However, we show that ablation of TRPV1+ neurons or acute TRPV1 activation by capsaicin abolishes DAMGO-induced itch. Overall, our work shows that peripheral DAMGO-induced itch is dependent on the presence of TRPV1-expressing pruriceptors, but not the TRPV1 channel itself. Activation of these fibers by capsaicin prevents the opioid-induced itch.