Insights into the Current and Possible Future Use of Opioid Antagonists in Relation to Opioid-Induced Constipation and Dysbiosis.

Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.

Pregabalin-Tolperisone Combination to Treat Neuropathic Pain: Improved Analgesia and Reduced Side Effects in Rats.

The current treatment of neuropathic pain (NP) is unsatisfactory; therefore, effective novel agents or combination-based analgesic therapies are needed. Herein, oral tolperisone, pregabalin, and duloxetine were tested for their antinociceptive effect against rat partial sciatic nerve ligation (pSNL)-induced tactile allodynia described by a decrease in the paw withdrawal threshold (PWT) measured by a dynamic plantar aesthesiometer. On day 7 after the operation, PWTs were assessed at 60, 120, and 180 min post-treatment. Chronic treatment was continued for 2 weeks, and again, PWTs were measured on day 14 and 21. None of the test compounds produced an acute antiallodynic effect. In contrast, after chronic treatment, tolperisone and pregabalin alleviated allodynia. In other experiments, on day 14, the acute antiallodynic effect of the tolperisone/pregabalin or duloxetine combination was measured. As a novel finding, a single dose of the tolperisone/pregabalin combination could remarkably alleviate allodynia acutely. It also restored the neuropathy-induced elevated CSF glutamate content. Furthermore, the combination is devoid of adverse effects related to motor and gastrointestinal transit functions. Tolperisone and pregabalin target voltage-gated sodium and calcium channels, respectively. The dual blockade effect of the combination might explain its advantageous acute analgesic effect in the present work.

The Acute Antiallodynic Effect of Tolperisone in Rat Neuropathic Pain and Evaluation of Its Mechanism of Action.

Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain.

Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model.

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30-60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.

[Increased Ventricular Pacing Threshold Caused by Intake of Dronedaron]. / Erhöhung der ventrikulären Reizschwelle durch Dronedaron-Einnahme.

HISTORY: The 75 year old patient was hospitalized because of vertigo, exertional dyspnea and clamminess. Based on ischemic heart disease with sick sinus syndrome a pacemaker was implanted 5.5 years ago. In consequence of non-permanent atrial fibrillation Dronedaron was added to medication 8 months ago. FINDINGS AND DIAGNOSIS: The patient presented unstable. The ECG showed a second-degree atrioventricular block with wenckebach periodic and a frequency of 29 bpm. The pacemaker survey showed primary a proper atrial function but ineffective ventricular stimulation. THERAPY AND COURSE: After initial external pacing the pacemaker was reprogrammed and in this way the ventricle stimulated effectively. Dronedaron was ceased after checking trigger factors and the patient left hospital after 3 days free of complaints. The pacemaker survey 18 days later showed a proper function with stabilized pacing threshold close to the old level. CONCLUSIONS: In patients with dysfunction of a permanent pacemaker an increased pacing threshold should be excluded and if any the current medication needs to be controlled. Caution should be exercised to Dronedaron here.

Similarity and dissimilarity in antinociceptive effects of dipeptidyl-peptidase 4 inhibitors, Diprotin A and vildagliptin in rat inflammatory pain models following spinal administration.

Dipeptidyl-peptidase 4 (DPP4) enzyme is involved in the degradation of many biologically active peptides including opioids. Its role in pain transmission is poorly elucidated. Recently we reported on the spinal antihyperalgesic effects of DPP4 inhibitors, Ile-Pro-Ile (Diprotin A) and vildagliptin in carrageenan-evoked acute inflammatory pain in rats. The present study investigated the effects of intrathecal (it.) diprotin A and vildagliptin in Complete Freund's Adjuvant- (CFA) and formalin induced pain in rats. The former assay can model the subchronic inflammatory pain condition and the later one reflects both acute tonic and inflammatory pain conditions. The involvement of opioid receptor (OR) subtypes, Y1-, and GLP1 receptors were also investigated. In CFA pain model it. diprotin A or vildagliptin dose-dependently inhibits hyperalgesia in ipsilateral while has no effect in contralateral paws. The peak effect was achieved 30 min following drug administration which was used for further analysis. Both compounds showed naltrexone reversible antihyperalgesia. Co-administration of OR-subtype-selective antagonists with diprotin A and vildagliptin revealed involvement of µ and δ > µ opioid receptors, respectively. Co-administered Y1 but not GLP1 receptor antagonists reversed the antihyperalgesic action of both DPP4 inhibitors. In touch-hypersensitivity both compounds were ineffective. In formalin test only diprotin A showed µ and δ OR-mediated antinociception and only in the 2nd phase. This effect was Y1 or GLP-1 receptor antagonist insensitive. In conclusion, diprotin A and vildagliptin display antinociception of different mechanisms of action in subchronic inflammatory pain. Furthermore, the spinal pain relay points of inflammatory pain of acute or subchronic conditions were more effectively affected by diprotin A than vildagliptin which needs future elucidation.

Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies.

OBJECTIVES: Cell therapy may offer novel therapeutic options for chronic ischemic heart disease. In a clinical trial, we first assessed the feasibility and safety of intramyocardial CD133+ bone marrow cell injection together with coronary artery bypass grafting (CABG). We then tested the hypothesis that CABG plus CD133+ cell injection would result in better contractile function than CABG alone. METHODS: Fifteen patients took part in the safety study, followed by 40 patients who underwent either CABG with cell therapy or CABG alone. Bone marrow was harvested from the iliac crest one day before surgery, and purified CD133+ progenitor cells were injected in the infarct border zone during the CABG operation. LV function was measured by echocardiography and myocardial perfusion by SPECT. RESULTS: In the safety study, no procedure-related complications were observed for up to 3 years. LV injection fraction (LVEF) increased from 39.0% +/- 8.7% preoperatively to 50.2% +/- 8.5% at 6 months and 47.9% +/- 6.0% at 18 months (F = 6.03, P = .012). In the efficacy study, LCEF rose form 37.4% +/- 8.4% to 47.1% +/- 8.3% at 6 months in the group with CABG and cell therapy (F = 24.16, P < .0001) but only from 37.9% +/- 10.3% to 41.3% +/- 9.1% in the CABG-only group (F = 7.72, P = .012). LVEF was significantly higher at 6 months in the group with CABG and cell therapy than in the CABG-only group (P = .03). Similarly, perfusion of the infarcted myocardium improved more in patients treated with CABG and cell therapy than in those treated with CABG alone. CONCLUSION: Intramyocardial delivery of purified bone marrow stem cells together with CABG surgery is safe and provides beneficial effects, though it remains to be seen whether thewe effects produce a lasting clinical advantage.

Intramyocardial delivery of human CD133+ cells in a SCID mouse cryoinjury model: Bone marrow vs. cord blood-derived cells.

OBJECTIVE: The regenerative potential of endothelial and hematopoietic progenitor cells in the heart may vary according to their origin. This study was designed to compare the functional effects of CD133+ cells from human cord blood and bone marrow in a mouse model of myocardial injury. METHODS: 5 x 10(5) CD133+ cells from bone marrow (BM(CD133)) or cord blood (UCB(CD133)) were injected in the necrosis border zone of NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice with left ventricular cryoinjury (CI+). Transplanted cells were tracked by immunostaining for hNuclear antigen and by PCR for hDNA. Echocardiography was used to measure contractility. Scar size, capillary density, and cardiomyocyte apoptosis were evaluated by histology. In addition, the myogenic and endothelial differentiation capacity of BM(CD133) and UCB(CD133) was compared in vitro. RESULTS: DNA was detected 4 weeks after cell injection by PCR, but hNuc+ cells were found by immunostaining only after 48 h. Capillary density in both BM(CD133) and UCB(CD133) cell-treated CI+ mice was higher than in control CI+ mice, but not different between BM(CD133) and UCB(CD133) cell-treated hearts. There were no differences in scar size and myocardial mass among BM(CD133), UCB(CD133) and control CI+ mice, but cardiomyocyte apoptosis was reduced by both BM(CD133) and UCB(CD133) cells. The post-injury deterioration of shortening fraction (46.2+/-1% in sham-operated mice and 41.3+/-0.8% in control CI+ mice) was prevented by BM(CD133) cells (45.4+/-0.9%), but not by UCB(CD133) cells (40.8+/-0.7%). On the other hand, both BM(CD133) and UCB(CD133) cells abolished post-injury mortality. In vitro, neither cultivated BM(CD133) or UCB(CD133) cells developed into myocytes, but both readily differentiated towards an endothelial cell phenotype. CONCLUSIONS: While both cord blood and marrow CD133+ cells have some beneficial effects on post-injury angiogenesis and survival, only marrow cells appear to improve myocardial contractility.