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Byron C. Yoburn - One of the best experts on this subject based on the ideXlab platform.
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The relative potency of inverse Opioid agonists and a neutral Opioid Antagonist in precipitated withdrawal and antagonism of analgesia and toxicity.
The Journal of pharmacology and experimental therapeutics, 2009Co-Authors: Sunil Sirohi, Shveta V. Dighe, Priyanka A. Madia, Byron C. YoburnAbstract:Opioid Antagonists can be classified as inverse agonists and neutral Antagonists. In the Opioid-dependent state, neutral Antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral Opioid Antagonists may offer advantages over inverse agonists in the management of Opioid overdose. In this study, the relative potency of three Opioid Antagonists to block Opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two Opioid inverse agonists (naltrexone and naloxone) and a neutral Antagonist (6β-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone > naloxone > 6β-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the Antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone > naloxone 6β-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral Antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6β-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6β-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6β-naltrexol is a neutral Antagonist. These data demonstrate that inverse agonists and neutral Antagonists have generally comparable potencies to block Opioid analgesia and lethality, whereas the neutral Opioid Antagonist is substantially less potent in precipitating Opioid withdrawal. These results support suggestions that neutral Antagonists may have advantages over inverse agonists in the management of Opioid overdose.
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μ Opioid receptor up regulation and functional supersensitivity are independent of Antagonist efficacy
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Sunil Sirohi, Priyank Kumar, Byron C. YoburnAbstract:Chronic Opioid Antagonist treatment up-regulates Opioid receptors and produces functional supersensitivity. Although Opioid Antagonists vary from neutral to inverse, the role of Antagonist efficacy in mediating the chronic effects of Opioid Antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral Antagonist (6β-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6β-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6β-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1–10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6β-naltrexol (0.2–20 mg/kg/day), and spinal μ-Opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All Antagonists up-regulated μ-Opioid receptors (60–122%) and induced supersensitivity (1.8–2.0-fold increase in morphine potency). There were no differences in Antagonist potency to produce up-regulation or supersensitivity. These data suggest that Opioid Antagonist-induced μ-Opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that Antagonist efficacy is not critical. Finally, the ED50 to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6β-naltrexol produced withdrawal jumping, although potencies relative to 6β-naltrexol were 211, 96, and 1, respectively. Thus, Antagonist potency to precipitate Opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the Opioid Antagonists was a function of the outcome measured, and inverse agonist activity was not required for μ-Opioid receptor up-regulation and supersensitivity.
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Opioid Antagonist-induced receptor upregulation: Effects of concurrent agonist administration
Brain Research Bulletin, 1994Co-Authors: Byron C. Yoburn, Alokesh Duttaroy, Sukrut Shah, Trong DavisAbstract:Abstract The present study examined whether Opioid Antagonist-induced receptor upregulation could be antagonized by simultaneous treatment with Opioid agonists. Mice were treated concurrently with Opioid agonists (morphine, fentanyl, etorphine) and Antagonists (naloxone, naltrexone) over a period of 7–8 days. Concurrent morphine (1 or 4, 75mg SC implanted pellets), fentanyl (5.0mgkg/day, infusion) or etorphine (0.25mg/kg/day, infusion) administration were unable to inhibit upregulation of μ Opioid (DAMGO) receptors by either naloxone (1mg/kg/day, infusion) or naltrexone (15mg or 2mg SC implanted pellet). Only a very high infusion dose of etorphine (10mg/kg/day) inhibited upregulation by naltrexone (2mg SC implanted pellet). These results indicate that Antagonist-induced upregulation is a robust, receptor-mediated phenomenon.
Ian S. Zagon - One of the best experts on this subject based on the ideXlab platform.
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low dose naltrexone targets the Opioid growth factor Opioid growth factor receptor pathway to inhibit cell proliferation mechanistic evidence from a tissue culture model
Experimental Biology and Medicine, 2011Co-Authors: Renee N Donahue, Patricia J. Mclaughlin, Ian S. ZagonAbstract:Naltrexone (NTX) is an Opioid Antagonist that inhibits or accelerates cell proliferation in vivo when utilized in a low (LDN) or high (HDN) dose, respectively. The mechanism of Opioid Antagonist action on growth is not well understood. We established a tissue culture model of LDN and HDN using short-term and continuous Opioid receptor blockade, respectively, in human ovarian cancer cells, and found that the duration of Opioid receptor blockade determines cell proliferative response. The alteration of growth by NTX also was detected in cells representative of pancreatic, colorectal and squamous cell carcinomas. The Opioid growth factor (OGF; [Met(5)]-enkephalin) and its receptor (OGFr) were responsible for mediating the action of NTX on cell proliferation. NTX upregulated OGF and OGFr at the translational but not at the transcriptional level. The mechanism of inhibition by short-term NTX required p16 and/or p21 cyclin-dependent inhibitory kinases, but was not dependent on cell survival (necrosis, apoptosis). Sequential administration of short-term NTX and OGF had a greater inhibitory effect on cell proliferation than either agent alone. Given the parallels between short-term NTX in vitro and LDN in vivo, we now demonstrate at the molecular level that the OGF-OGFr axis is a common pathway that is essential for the regulation of cell proliferation by NTX.
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therapy with the Opioid Antagonist naltrexone promotes mucosal healing in active crohn s disease a randomized placebo controlled trial
Digestive Diseases and Sciences, 2011Co-Authors: Jill P Smith, Sandra I Bingaman, Francesca Ruggiero, David T Mauger, Aparna Mukherjee, Christopher O Mcgovern, Ian S. ZagonAbstract:Background Endogenous Opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous Opioid system is involved in inflammatory bowel disease, and antagonism of the Opioid‐Opioid receptor will lead to reversal of inflammation. Aims A randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an Opioid Antagonist for 12 weeks in adults with active Crohn’s disease. Methods Forty subjects with active Crohn’s disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn’s Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology. Results Eighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn’s disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score \6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo. Conclusions Naltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn’s disease compared to placebo-treated controls. Strategies to alter the endogenous Opioid system provide promise for the treatment of Crohn’s disease.
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Adaptation of homeostatic ocular surface epithelium to chronic treatment with the Opioid Antagonist naltrexone.
Cornea, 2006Co-Authors: Ian S. Zagon, Joseph W. Sassani, Patricia J. MclaughlinAbstract:Purpose:To determine how ocular surface epithelium adjusts to an increase in cell replication after treatment with the Opioid Antagonist naltrexone (NTX).Methods:Adult male rats were given twice daily injections of 30 mg/kg NTX or vehicle for 7 days. Outcomes of NTX administration included DNA synth
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naltrexone an Opioid Antagonist facilitates reepithelialization of the cornea in diabetic rat
Diabetes, 2002Co-Authors: Ian S. Zagon, Joseph W. Sassani, Joe B Jenkins, James D Wylie, Torre B Ruth, Jamie L Fry, Max C Lang, Patricia J. MclaughlinAbstract:Ulcers and erosions of the corneal epithelium, as well as delays in resurfacing of the cornea after wounding, are major causes of ocular morbidity and visual loss in diabetes. To study whether intervention by the Opioid Antagonist naltrexone (NTX; 30 mg/kg, twice daily) can restore reepithelialization in diabetic cornea, we induced diabetes in rats by intravenous injection of 65 mg/kg streptozotocin. After confirmation of diabetes, 5-mm-diameter epithelial defects that did not include the limbus were created by mechanical scraping of the cornea. At 4 and 8 weeks, corneal reepithelialization was markedly subnormal, with delays ranging from 11% to 17-fold in the diabetic animals compared with control counterparts. Rats that were diabetic for 8 weeks also had a significant decrease in the incidence of complete wound closure. At 4 and 8 weeks, diabetic animals that were receiving NTX had an acceleration in reepithelialization compared with diabetic animals that were receiving vehicle and even surpassed controls. DNA synthesis in the corneal epithelium of diabetic rats was decreased up to 90% of control levels, and NTX exposure of diabetic subjects elevated the labeling index by up to eightfold from diabetic animals that were receiving vehicle. Opioid growth factor and Opioid growth factor receptor distribution were comparable in diabetic and control animals. These results indicate a delay in reepithelialization that is dependent on the duration of diabetes and that intervention of endogenous Opioid-receptor interfacing with an Opioid Antagonist can facilitate the process of wound healing.
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TRANSPLACENTAL TRANSFER OF NALTREXONE IN RATS
Life sciences, 1997Co-Authors: Ian S. Zagon, W.jeffrey Hurst, Patricia J. MclaughlinAbstract:Extracts of fetal (20 days gestation) brain, heart, and liver were evaluated for naltrexone in rats 1 hour following maternal injection of 50 mg/kg Opioid Antagonist; adult plasma from the pregnant rats was analyzed. Samples were prepared by ultrafiltration, lyophilized, reconstituted in mobile phase, and separated by reversed phase high-performance liquid chromatography with ultraviolet detection. This qualitative analysis revealed the presence of naltrexone in all fetal tissues, as well as in adult plasma. These results indicate naltrexone, maternally administered, passes through the placenta and enters the fetus. The data would suggest that reports concerning somatic and neurobiological acceleration in offspring exposed to naltrexone during gestation may be the result of a direct Opioid Antagonist action in the fetus.
Antero Kallio - One of the best experts on this subject based on the ideXlab platform.
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multicenter investigation of the Opioid Antagonist nalmefene in the treatment of pathological gambling
American Journal of Psychiatry, 2006Co-Authors: Jon E Grant, Marc N Potenza, Eric Hollander, Renee M Cunninghamwilliams, Tommi Nurminen, Gerard Smits, Antero KallioAbstract:Objective: Pathological gambling is a disabling disorder experienced by approximately 1%–2% of adults and for which there are few empirically validated treatments. The authors examined the efficacy and tolerability of the Opioid Antagonist nalmefene in the treatment of adults with pathological gambling. Method: A 16-week, randomized, doseranging, double-blind, placebo-controlled trial was conducted at 15 outpatient treatment centers across the United States between March 2002 and April 2003. Two hundred seven persons with DSM-IV pathological gambling were randomly assigned to receive nalmefene (25 mg/day, 50 mg/day, or 100 mg/day) or placebo. Scores on the primary outcome measure (Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling) were analyzed by using a linear mixed-effects model. Results: Estimated regression coefficients showed that the 25 mg/day and 50 mg/day nalmefene groups had significantly different scores on the Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling, compared to the placebo group. A total of 59.2% of the subjects who received 25 mg/day of nalmefene were rated as “much improved” or “very much improved” at the last evaluation, compared to 34.0% of those who received placebo. Adverse experiences included nausea, dizziness, and insomnia. Conclusions: Subjects who received nalmefene had a statistically significant reduction in severity of pathological gambling. Low-dose nalmefene (25 mg/day) appeared efficacious and was associated with few adverse events. Higher doses (50 mg/day and 100 mg/day) resulted in intolerable side effects.
Trong Davis - One of the best experts on this subject based on the ideXlab platform.
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Opioid Antagonist-induced receptor upregulation: Effects of concurrent agonist administration
Brain Research Bulletin, 1994Co-Authors: Byron C. Yoburn, Alokesh Duttaroy, Sukrut Shah, Trong DavisAbstract:Abstract The present study examined whether Opioid Antagonist-induced receptor upregulation could be antagonized by simultaneous treatment with Opioid agonists. Mice were treated concurrently with Opioid agonists (morphine, fentanyl, etorphine) and Antagonists (naloxone, naltrexone) over a period of 7–8 days. Concurrent morphine (1 or 4, 75mg SC implanted pellets), fentanyl (5.0mgkg/day, infusion) or etorphine (0.25mg/kg/day, infusion) administration were unable to inhibit upregulation of μ Opioid (DAMGO) receptors by either naloxone (1mg/kg/day, infusion) or naltrexone (15mg or 2mg SC implanted pellet). Only a very high infusion dose of etorphine (10mg/kg/day) inhibited upregulation by naltrexone (2mg SC implanted pellet). These results indicate that Antagonist-induced upregulation is a robust, receptor-mediated phenomenon.
G L Robertson - One of the best experts on this subject based on the ideXlab platform.
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The effect of the nonselective Opioid Antagonist diprenorphine on vasopressin secretion in the rat.
Endocrinology, 1994Co-Authors: Yasumasa Iwasaki, M B Gaskill, C A Boss, G L RobertsonAbstract:Although endogenous Opioids are thought to be involved in the regulation of vasopressin secretion, their precise role is unclear. We studied the effect of the potent nonselective Opioid Antagonist diprenorphine on the vasopressin response to osmotic (hypertonic saline, ip), hypovolemic (polyethylene glycol, ip), and hypotensive (sodium nitroprusside, sc) stimuli in male rats. We found that diprenorphine sc produced a time- and dose-dependent inhibition of the plasma vasopressin response to the hypovolemic stimulus. This inhibition was greatest 30 min after injection of the drug, but lasted for at least 4 h, was evident at doses as low as 0.0022 mumol/kg, and reached a maximum of about 85% of the stimulated control at a dose of 2.2 mumol/kg. Diprenorphine also inhibited the vasopressin response to an osmotic or a hypotensive stimulus, but the effect was less complete (approximately 50%), required 100-fold higher doses of the drug, and appeared to be bimodal. The potent kappa 1-selective Opioid agonist U-50...
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Opioid Antagonist diprenorphine microinjected into parabrachial nucleus selectively inhibits vasopressin response to hypovolemic stimuli in the rat.
The Journal of clinical investigation, 1993Co-Authors: Yasumasa Iwasaki, M B Gaskill, Clifford B. Saper, G L RobertsonAbstract:Subcutaneous injection of the potent, nonselective Opioid Antagonist diprenorphine inhibits the vasopressin response to acute hypovolemia. To determine if this inhibition is due to antagonism of Opioid receptors in brain pathways that mediate volume control, we determined the vasopressin response to different stimuli when diprenorphine or other opiates were injected into the cerebral ventricles, the nucleus tractus solitarius (NTS), or the lateral parabrachial nucleus (PBN) of rats. We found that the vasopressin response to hypovolemia was inhibited by injection of diprenorphine into the cerebral ventricles at a dose too low to be effective when given subcutaneously. This response also was inhibited when a 20-fold lower dose of diprenorphine was injected into the PBN but not when it was injected into the NTS. The inhibitory effect of diprenorphine in the PBN was not attributable to a decrease in osmotic or hypovolemic stimulation and did not occur with osmotic or hypotensive stimuli. Injecting the PBN with equimolar doses of the mu Antagonist naloxone, the delta Antagonist ICI-154,129 or the kappa-1 agonist U-50,488H had no effect on basal or volume-stimulated vasopressin. We conclude that the inhibition of vasopressin by diprenorphine is due partially to action at a novel class of Opioid receptors that transmit volume stimuli through the PBN.