methylnaltrexone and Disease-Models--Animal

In this study, we investigated the effects of recurrent hypoglycaemia on the adrenal catecholamine synthetic enzymes in a rat model of hypoglycaemia-associated autonomic failure (HAAF). We found that plasma adrenaline was significantly reduced by about 50% in response to recurrent hypoglycaemia versus single hypoglycaemia. However, tyrosine hydroxylase (TH) protein and phosphorylation at Ser31 and Ser40 were increased in HAAF; similarly, aromatic aminoacid decarboxylase protein was also increased indicating a likely increase in catecholamine synthesis in the adrenal gland. Opioid antagonists, naloxone and methylnaltrexone did not restore plasma adrenaline in HAAF; however, naloxone increased TH phosphorylation at Ser31 and Ser40.

Topics: Animals; Blood Glucose; Disease Models, Animal; Epinephrine; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pure Autonomic Failure; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Serine; Tyrosine 3-Monooxygenase

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter in itch and impaired serotonin signaling has been linked to a variety of itch conditions. Intradermal injection of 5-HT induces scratching behavior in mice through stimulation of 5-HT receptors. Previous studies have demonstrated that selective 5-HT1B/1D receptors agonists, including sumatriptan, inhibits neurotransmission. We have also reported that sumatriptan suppresses chloroquine-induced itch. Therefore, we investigated if sumatriptan has inhibitory effects on serotonin-induced itch in mice. Here, we show that intradermal and intraperitoneal administration of sumatriptan significantly reduce 5-HT-induced scratching behavior in mice. While intradermal injection of GR-127935, a selective 5-HT1B/1D receptors antagonist, reverses the anti-pruritic effects of sumatriptan. In addition, we show that intradermal and intraperitoneal naltrexone (NTX), a non-specific opioid receptor antagonist, and methylnaltrexone (MNTX), a peripherally acting opioid receptor antagonist, significantly decrease the 5-HT-induced scratching behavior. Additionally, combined treatment with sub-effective doses of sumatriptan and an opioid receptor antagonist, naltrexone, decreases 5-HT-evoked scratching responses. We conclude that sumatriptan inhibits 5-HT-induced itch by activating the peripheral 5-HT1B/1D receptors. Moreover, peripheral opioid receptors have a role in serotonin-induced itch, and anti-pruritic effects of sumatriptan seem to involve the opioid system. These data suggest that 5-HT1B/1D receptors agonists maybe useful to treat a variety of pathologic itch conditions with impaired serotonergic system.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Humans; Injections, Intradermal; Male; Mice; Naltrexone; Narcotic Antagonists; Opioid Peptides; Oxadiazoles; Piperazines; Pruritus; Quaternary Ammonium Compounds; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Sumatriptan

Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.

Topics: Analgesia; Analgesics, Opioid; Animals; Chronic Pain; Disease Models, Animal; Drug Tolerance; Gene Deletion; Hyperalgesia; Long-Term Potentiation; Mice; Mice, Knockout; Microglia; Morphine; Naltrexone; Nociception; Nociceptors; Pain, Postoperative; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Signal Transduction; Spinal Cord

Postoperative ileus (POI) is often exacerbated by opioid analgesic use during and following surgery, since mu opioid receptor activation results in a further delay of gastrointestinal (GI) transit. The effects of alvimopan, a novel, selective, and peripherally acting mu opioid receptor antagonist, and the reference compound methylnaltrexone, upon POI were investigated in rats. Under isoflurane anesthesia, POI was induced by laparotomy with intestinal manipulation. Immediately after the surgery, the rats received (51)Cr by gavage. Three hours after the surgery, the rats were sacrificed and GI transit was estimated using the geometric center (GC) of (51)Cr. Alvimopan (0.1-3 mg/kg) or methylnaltrexone (100 mg/kg) were administered by gavage either before or after the surgery, with or without morphine administration (1 mg/kg). GI transit was delayed by intestinal manipulation (GC = 2.92 +/- 0.17). Alvimopan (1 and 3 mg/kg) significantly reversed this delayed GI transit when administered 45 min prior to surgery. However, the effects of alvimopan were less pronounced when administered following surgery. Morphine administration further delayed GI transit induced by intestinal manipulation (GC = 1.97 +/- 0.11). Under these conditions, alvimopan (1 and 3 mg/kg) also significantly improved delayed GI transit when administered before surgery. Methylnaltrexone was inactive under all experimental conditions. These data suggest that mu opioid receptors play a role in the pathogenesis of POI, and that the clinical benefit reported to be afforded by alvimopan may be in part mediated via inhibition of an endogenous opioid release as well as blockade of the unwanted GI actions of analgesic agents.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Transit; Ileus; Laparotomy; Male; Naltrexone; Narcotic Antagonists; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley

Opioids are frequently used analgesics, and emesis is a common opioid-induced adverse effect. Methylnaltrexone, a peripheral opioid antagonist, has the potential to block the undesired effects of opioids that are mediated by peripheral receptors while sparing the analgesic effect. We used a rat model of simulated emesis or pica to study if methylnaltrexone decreases morphine induced-kaolin consumption. We observed that after morphine administration, kaolin intake increased significantly compared to intake in the vehicle group, and the increase could be attenuated by ondansetron administration. Methylnaltrexone dose-dependently reduced kaolin ingestion induced by morphine. Morphine and methylnaltrexone did not significantly affect food intake and body weight in the experimental animals. Our data suggest that methylnaltrexone has therapeutic value in treating opioid-induced nausea and vomiting.

Topics: Animals; Antiemetics; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Injections, Intraperitoneal; Kaolin; Male; Morphine; Naltrexone; Narcotic Antagonists; Ondansetron; Pica; Quaternary Ammonium Compounds; Rats; Rats, Wistar

Morphine administration prior to challenge with the antigen 2,4-dinitro-fluorobenzene increases the contact hypersensitivity (CHS) response in rats. The present study extended these findings by showing that central, but not systemic, administration of N-methylnaltrexone antagonized the morphine-induced enhancement of the CHS response. The importance of the neuroimmune mediator substance P was shown via the attenuation of the morphine-induced enhancement following both systemic and topical administration of the NK-1 antagonist WIN51,708. Taken together, the findings of the present study provide new data showing that central opioid receptors and peripheral substance P are involved in the morphine-induced enhancement of the CHS response.

Topics: Androstanes; Animals; Benzimidazoles; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Drug Administration Routes; Male; Morphine; Naltrexone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Inbred Lew; Receptors, Opioid; Specific Pathogen-Free Organisms; Substance P