Peripheral Opioid Agonist Research Articles

Recent Advances in the Treatment of Irritable Bowel Syndrome: Addressing Diarrhea, Constipation, and Abdominal Pain

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder characterized by abdominal pain, bloating, and changes in bowel habits. This paper aim was to provide an overview of recent advancements in the treatment of IBS, focusing on the management of its main symptoms: diarrhea, constipation, and abdominal pain. For individuals with IBS-D, various therapeutic options are available, including rifaximin, peripheral opioid agonists, mixed opioid agonists/antagonists, bile acid sequestrants, and serotonin 5-HT3 receptor antagonists. Rifaximin, a nonabsorbable antibiotic, has demonstrated significant effectiveness in reducing IBS symptoms, such as bloating and loose stools, with good tolerability and safety. Also the repeated use of rifaximin for managing recurrent IBS symptoms. In IBS-C patients, bulking agents, osmotic laxatives, and prokinetic agents like lubiprostone have shown efficacy in improving constipation and overall symptoms. Linaclotide, a drug that increases intestinal chloride secretion, has demonstrated significant improvement in bowel movements and abdominal pain in IBS-C patients. However, it may cause diarrhea in some individuals. IBS-M, characterized by alternating constipation and diarrhea, poses a challenge in terms of specific drug treatments. A comprehensive assessment of potential underlying causes and careful history taking is crucial for effective management. Abdominal pain is a common symptom in IBS, regardless of subtype. Antispasmodic drugs, peppermint oil, and trimebutine have shown effectiveness in reducing pain and improving symptoms. Antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may offer relief by modulating pain pathways and influencing gastrointestinal motility. Benzodiazepines, particularly dextofisopam, have shown potential in improving stool consistency but require further evaluation. In conclusion, recent advancements in the treatment of IBS have provided a range of therapeutic options targeting its main symptoms. However, further research is needed to develop tailored treatments for specific IBS subtypes and to explore the efficacy of potential alternatives, including benzodiazepines. Improved management of IBS symptoms can significantly enhance the quality of life for affected individuals.

Non-pharmacological strategies to treat irritable bowel syndrome: 2022 update.

Irritable bowel syndrome (IBS) is a chronic functional disorder characterized by abdominal pain associated with changes in stool frequency or form, in absence of organic disease. The treatment of IBS is often challenging and should be individually adjusted according to the prevalent symptomatology. Pharmacological treatment for IBS with diarrhea includes peripheral opioid agonists, bile acid sequestrants and antibiotics, while IBS with constipation can be treated with soluble fibers, osmotic agents or prokinetics. In case of abdominal pain, the available pharmacological options are antispasmodics, peripheral opioid agonists or antidepressants. Along with pharmacotherapy, non-pharmacological interventions should be considered as they can play an important role in symptom control. The first-line approach includes lifestyle modifications and dietary advice. Microbiota manipulation through probiotics, prebiotics and symbiotics is a widely used strategy, although the evidence upon the most effective among these in specific IBS subtypes is still unclear. Fecal microbiota transplantation is still in experimental phase for IBS, but it is giving promising results. Psychological therapies may be effective in patients with IBS, despite their application can be limited by long duration, high costs and poor patient's acceptance. Alternative medicine approaches, such as acupuncture, body relaxation techniques, dietary supplements or Chinese herbs, have been proposed; however, the evidence upon their efficacy and safety is still controversial.

AI/ML‐driven simulation of the skin retention of opioid analgesics following topical administration in normal skin and cutaneous lesions

Topical drug administration in the treatment of skin disorders is known to have high efficacy with a favorable safety profile in clinical settings. Disposition of the active pharmaceutical ingredient (API) in the skin layers plays a critical role for the dose regimen calculator required for desired therapy efficiency. Experimental measurements of the API skin concentration are complicated and inaccurate and can be replaced with physiologically based pharmacokinetic modeling predicting local and systemic drug exposure. Opioid analgesics are commonly used in treating severe pain and it is frequently associated with putative adverse effects. Topical applications of opioids were shown to have high efficacy with a favorable safety profile in clinical settings. Clinical investigations of transdermal drug formulations, especially in patients with skin lesions, are often hindered due to the patient intolerance, high cost of the studies, and ethical aspects.BIOiSIM, a hybrid artificial intelligence computational platform integrating machine learning optimization with mechanistic modeling was implemented to accurately simulate in vivo plasma concentration profile and predict partition coefficients and API skin retention for two opioid analgesics in healthy skin and simulated skin lesions. Publicly available drug parameters and physiological data were used for the model building.The platform successfully predicted API systemic exposure and skin concentration following the epicutaneous application of central opioid agonist buprenorphine and peripheral opioid agonist oxycodone in healthy human skin and simulated subjects impaired skin. Experimentally observed plasma concentration for both drugs demonstrated validity of the in‐silico methods. The results indicated that buprenorphine permeates rapidly through the stratum corneum and partitions into the dermis, where its concentration slowly declines as the reservoir in the compound vehicle is depleted. Thus, the impact of lesions is not as significant. In contrast, the hydrophilic oxycodone, where the rate‐limiting stratum corneum layer prevents a significant portion of the compound from permeating deeper in healthy patients. Hence, concentration of oxycodone sharply declines over the first hours of exposure in deeper indicating poorer accumulation capacity in the skin in the presence of lesions.An AI/ML‐driven PBPK model was applied for accurate simulation skin concentrations of two opioid analgesics – buprenorphine and oxycodone. The results have confirmed that both these drugs have good skin retention and can stimulate opioid receptors located in skin. The results suggest that buprenorphine showing substantial skin retention capacity can be applied topically for the treatment of skin disorders in in patients.

Prurit associé à la maladie rénale chronique

Pruritus associated with chronic kidney disease is a frequent and disabling symptom in patients with severe chronic kidney disease treated by dialysis. It is associated with a poor quality of life, an increased risk of comorbidities and even mortality. Nevertheless, its prevalence is underestimated by nephrologists. The pathophysiology of pruritus associated with chronic kidney disease is not well understood, but several mechanisms seem to contribute to its occurrence: accumulation and skin deposition of uremic toxins, peripheral neuropathy causing an activation of the pruritogenic cowhage pathway, chronic microinflammation, opioid imbalance, and kidney disease-related skin xerosis. Optimization of the treatment of chronic kidney disease treatment, of dialysis parameters, and general skin care measures should always be performed prior to the introduction of systemic therapy targeting one or more of these mechanisms. The available therapeutic trials remain mostly at high risk of bias, with small patient numbers. Gabapentinoids are the molecules recommended as first-line therapy. Peripheral opioid agonists could find a place of choice in the treatment of pruritus associated with chronic kidney disease and will soon be available in France. The low level of evidence for the other molecules does not currently allow us to specify a second-line treatment for this condition.

Recent advances in the treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder which presents with abdominal pain and altered bowel habits. It affects about 20% of the general population, mainly women, and has a considerable impact on the quality of life and health care costs. Four different entities of IBS have been identified: IBS with constipation (IBS‑ C), IBS with diarrhea (IBS D), IBS with a mixed pattern of constipation and diarrhea, and unclassified IBS. Although the precise pathogenesis of IBS remains unclear, its multifactorial nature is evident and includes environmental and host factors. Management of patients with this disease is challenging and a personalized approach is required. A strong, reassuring physician‑ patient relationship is crucial, followed by patient education, dietary advice, and stress reduction. For nonresponding patients, the therapeutic approach may include nonpharmacological therapies and / or pharmacotherapy. The choice of pharmacological treatment is based on the predominant symptom and a prespecified time point should be planned for effectiveness evaluation and dose adjustment. In patients with IBS‑ D, the therapeutic options include mainly antibiotics, such as rifaximin, peripheral opioid agonists, mixed opioid agonists / antagonists, bile acid sequestrants, and antagonists of serotonin 5‑ hydroxytryptamine type 3 receptors. Bulking agents and osmotic laxatives represent the first line therapy for IBS‑ C, while lubiprostone and linaclotide should be reserved for difficult to treat patients. The involvement of gastrointestinal microbiota constitutes a fascinating field of exploration as it offers the potential to be modulated by the use of probiotics, prebiotics, synbiotics as well as fecal microbiota transplantation. This review offers an updated overview on the recent advances in the treatment of IBS.

(359) GRK2 constitutively downregulates delta opioid receptor activity in the periphery

Opioids remain the gold standard for prescribed analgesic care, yet opioid treatments systemically produce negative side effects that contraindicate long-term use. Low dose peripheral administration of opioids has been utilized in the clinic and produces sufficient analgesia without debilitating central side effects. However, the analgesic potential of peripheral opioid agonists is significantly limited in the absence of tissue inflammation through an unknown mechanism. Bradykinin, a potent inflammatory mediator, has been demonstrated to increase peripheral opioid efficacy in a protein kinase C (PKC)-dependent manner, thus, “priming” the receptor for agonist activation. Here, we report that G Protein-Coupled Receptor Kinase 2 (GRK2) constitutively associates with delta opioid receptor (DOR) at the plasma membrane in peripheral sensory neurons, which prevents optimal G protein association with the receptor thereby limiting DOR responsiveness. Notably, bradykinin receptor activation induces PKC-dependent phosphorylation of Raf Kinase Inhibitory Protein (RKIP), followed by RKIP self-dimerization and cytosolic sequestration of GRK2. Consequentially, bradykinin-induced scaffolding of GRK2 away from the plasma membrane restores DOR functional competence in peripheral sensory neurons. To determine whether GRK2 governs peripheral DOR analgesic competence, rats were injected intrathecally with antisense oligodeoxynucleotides (AS-ODN) complementary to GRK2 mRNA that nearly ablated GRK2 protein in the dorsal root ganglia. In mismatch control rats, pretreatment with bradykinin was required to elicit peripheral DOR-mediated inhibition of PGE2-induced thermal allodynia. Importantly, GRK2 knockdown eliminated the bradykinin priming requirement for DOR analgesia in the periphery. Collectively, these results characterize a novel role for GRK2 in maintaining DOR analgesically incompetent at the plasma membrane. Furthermore, results provide a more complete mechanism of peripheral opioid priming where bradykinin induces PKC-dependent RKIP phosphorylation, self-dimerization, and scaffolding of GRK2 away from plasma membrane DOR to enhance receptor responsiveness in peripheral sensory neurons. Funding: NINDS/RO1 NS082746 (N.A.J.), NIDCR/T32 DE14318 (A.P.D.), and NIDCR/F31 DE025551 (A.P.D.). Opioids remain the gold standard for prescribed analgesic care, yet opioid treatments systemically produce negative side effects that contraindicate long-term use. Low dose peripheral administration of opioids has been utilized in the clinic and produces sufficient analgesia without debilitating central side effects. However, the analgesic potential of peripheral opioid agonists is significantly limited in the absence of tissue inflammation through an unknown mechanism. Bradykinin, a potent inflammatory mediator, has been demonstrated to increase peripheral opioid efficacy in a protein kinase C (PKC)-dependent manner, thus, “priming” the receptor for agonist activation. Here, we report that G Protein-Coupled Receptor Kinase 2 (GRK2) constitutively associates with delta opioid receptor (DOR) at the plasma membrane in peripheral sensory neurons, which prevents optimal G protein association with the receptor thereby limiting DOR responsiveness. Notably, bradykinin receptor activation induces PKC-dependent phosphorylation of Raf Kinase Inhibitory Protein (RKIP), followed by RKIP self-dimerization and cytosolic sequestration of GRK2. Consequentially, bradykinin-induced scaffolding of GRK2 away from the plasma membrane restores DOR functional competence in peripheral sensory neurons. To determine whether GRK2 governs peripheral DOR analgesic competence, rats were injected intrathecally with antisense oligodeoxynucleotides (AS-ODN) complementary to GRK2 mRNA that nearly ablated GRK2 protein in the dorsal root ganglia. In mismatch control rats, pretreatment with bradykinin was required to elicit peripheral DOR-mediated inhibition of PGE2-induced thermal allodynia. Importantly, GRK2 knockdown eliminated the bradykinin priming requirement for DOR analgesia in the periphery. Collectively, these results characterize a novel role for GRK2 in maintaining DOR analgesically incompetent at the plasma membrane. Furthermore, results provide a more complete mechanism of peripheral opioid priming where bradykinin induces PKC-dependent RKIP phosphorylation, self-dimerization, and scaffolding of GRK2 away from plasma membrane DOR to enhance receptor responsiveness in peripheral sensory neurons. Funding: NINDS/RO1 NS082746 (N.A.J.), NIDCR/T32 DE14318 (A.P.D.), and NIDCR/F31 DE025551 (A.P.D.).

Peripheral G protein‐coupled inwardly rectifying potassium channels are involved in δ‐opioid receptor‐mediated anti‐hyperalgesia in rat masseter muscle

Although the efficacy of peripherally administered opioid has been demonstrated in preclinical and clinical studies, the underlying mechanisms of its anti-hyperalgesic effects are poorly understood. G protein-coupled inwardly rectifying potassium (GIRK) channels are linked to opioid receptors in the brain. However, the role of peripheral GIRK channels in analgesia induced by peripherally administered opioid, especially in trigeminal system, is not clear. Expression of GIRK subunits in rat trigeminal ganglia (TG) was examined with reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. Chemical profiles of GIRK-expressing neurons in TG were further characterized. Behavioural and Fos experiments were performed to examine the functional involvement of GIRK channels in δ-opioid receptor (DOR)-mediated anti-hyperalgesia under an acute myositis condition. TG expressed mRNA and proteins for GIRK1 and GIRK2 subunits. Majority of GIRK1- and GIRK2-expressing neurons were non-peptidergic afferents. Inhibition of peripheral GIRK using Tertiapin-Q (TPQ) attenuated antinociceptive effects of peripherally administered DOR agonist, [D-Pen(2), D-Pen(6) ]-enkephalin (DPDPE), on mechanical hypersensitivity in masseter muscle. Furthermore, TPQ attenuated the suppressive effects of peripheral DPDPE on neuronal activation in the subnucleus caudalis of the trigeminal nucleus (Vc) following masseteric injection of capsaicin. Our data indicate that peripheral DOR agonist-induced suppression of mechanical hypersensitivity in the masseter muscle involves the activity of peripheral GIRK channels. These results could provide a rationale for developing a novel therapeutic approach using peripheral GIRK channel openers to mimic or supplement the effects of peripheral opioid agonist.

Peripheral Opioid Agonists for Analgesia

Peripheral Opioid Agonists for Analgesia

Peripheral opioid agonists for pain management?

Peripheral opioid agonists for pain management?

Peripheral opioid analgesia.

Opioids have long been thought to act exclusively within the central nervous system. An increasing number of studies recently reported the existence of opioid receptors outside the central nervous system and therefore suggested that opioids are also able to produce analgesic effects in the periphery. Such effects are particularly prominent under painful inflammatory conditions, both in animals and in humans. During inflammatory processes, opioid receptors are transported from dorsal root ganglia towards the peripheral sensory nerve endings. At the same time, immune cells containing endogenous opioid peptides accumulate within the inflamed tissue. Environmental stimuli (e.g. stress) as well as releasing agents (e.g. corticotropin releasing factor, cytokines) can liberate these opioid peptides to interact with the neuronal opioid receptors and elicit local analgesia. The inflammation-induced activation of opioid production and the release of endogenous opioids from immune cells may lead to novel approaches for the development of peripherally acting analgesics. Clinical investigation now focuses on the development of new peripheral opioid agonists as well as on ways to stimulate the endogenous analgesic system in order to induce effective peripheral analgesia with reduced central side effects typically associated with opioids.

Effect of Loperamide on Gastro-oesophageal Reflux

We have recently shown that morphine reduces gastro-oesophageal reflux (GOR) by stimulating opioid receptors. Our aim was therefore to investigate the effect of loperamide, a peripheral opioid agonist, on GOR. Nine patients with GOR disease underwent two ambulatory 24-h intra-oesophageal pH monitoring sessions separated by a period of at least 7 days under double-blind randomized conditions during the administration of placebo or loperamide solution p.o. (8 mg + 4 mg + 4 mg, 12 h and 2 h before, and 7 h after the start of the recording). Twenty-four-hour oesophageal acid exposure and the number of reflux episodes/hour were similar under the two experimental conditions: a median (IQ range) of 6.2% (3.3%-11.0%) of the time at pH < 4 and 2.6 (1.6-3.5)/h during placebo versus 8.8% (3.7%-14.8%) and 2.8 (2.3-4.9)/h during loperamide (P = ns). Acid clearance time was also similar: 1.8 +/- 0.3 min versus 1.6 +/- 0.2 min (P = ns). Loperamide did not decrease GOR, thus suggesting that an opioid agonist may not be useful in the treatment of GOR disease.

Lack of opioid or dopaminergic effects on unconditioned sexual incentive motivation in male rats.

The effects of dopaminergic and opioidergic drugs on sexual incentive motivation were evaluated in sexually inexperienced male rats subjected to a choice procedure. Various parameters of ambulatory activity were recorded as well. Two drugs stimulating dopaminergic neurotransmission, amphetamine and apomorphine, failed to affect sexual incentive motivation, although ambulatory activity was enhanced by amphetamine. The dopamine antagonist cis(Z)-flupenthixol reduced sexual incentive motivation, but only at a dose that severely disrupted motor function. Morphine had marginal effects on sexual motivation but reduced ambulatory activity. These effects were not reduced by a peripheral opioid antagonist, methylnaloxone. Loperamide, a peripheral opioid agonist, reduced sexual motivation through an opioid-independent action. Naloxone was ineffective. Neither dopamine nor opioids seem to be important for sexual incentive motivation.

Effect of Loperamide on Gastro-oesophageal Reflux

Background: We have recently shown that morphine reduces gastro-oesophageal reflux (GOR) by stimulating opioid receptors. Our aim was therefore to investigate the effect of loperamide, a peripheral opioid agonist, on GOR. Methods: Nine patients with GOR disease underwent two ambulatory 24-h intra-oesophageal pH monitoring sessions separated by a period of at least 7 days under double-blind randomized conditions during the administration of placebo or loperamide solution p.o. (8 mg + 4 mg + 4mg, 12h and 2 h before, and 7 h after the start of the recording). Results: Twenty-four-hour oesophageal acid exposure and the number of reflux episodes/hour were similar under the two experimental conditions: a median (IQ range) of 6.2% (3.3%-11.0%) of the time at pH <4 and 2.6 (1.6-3.5)/h during placebo versus 8.8% (3.7%-14.8%) and 2.8 (2.3-4.9)/h during loperamide (P = ns). Acid clearance time was also similar: 1.8 ± 0.3 min versus 1.6 ± 0.2 min (P = ns). Conclusions: Loperamide did not decrease GOR, thus suggesting that an opioid agonist may not be useful in the treatment of GOR disease.

Fedotozine reverses ileus induced by surgery or peritonitis: Action at peripheral Κ-Opioid receptors

Background: Fedotozine is a peripheral opioid agonist. Its effects were assessed in experimental ileus in rats. Methods: Ileus was induced by abdominal surgery (laparotomy and cecum palpation) or peritonitis (acetic acid, intraperitoneally). Digestive motility was recorded by electromyography and gastrointestinal transit estimated using a 51Cr-labeled test meal. Results: Surgery or peritonitis inhibited motility and migrating myoelectrical complexes for 2–3 hours. In both models, fedotozine (3 mg/kg, intravenously; 10 mg/kg, subcutaneously) restored a normal motility pattern. This action was reproduced by the Κ-agonist, U-50, and 488H and was blocked by subcutaneous naloxone, naloxone-methiodide, or nor-binaltorphimine, a selective Κ-antagonist. Peritonitis induced a 57% inhibition of gastric emptying and intestinal transit that was reversed by fedotozine (1–10 mg/kg, subcutaneously) or Κ-agonists (U-50, 488H, bremazocine) but not δ-agonists (DPDPE, [d-Ala2]-deltorphin-II), whereas μ-agonists (morphine, fentanyl) potentiated ileus. Fedotozine restoration of transit was blocked by subcutaneous naloxone, naloxone-methiodide, or nor-binaltorphimine but not by intracerebroventricular naloxone. Fedotozine was inactive up to 300 μg/rat when given intracerebroventrically or intrathecally. Conclusion: Fedotozine reverses experimental ileus via an action at peripheral Κ-opioid receptors.