A new opioid designed multiple ligand derived from the μ opioid agonist endomorphin-2 and the δ opioid antagonist pharmacophore Dmt-Tic

Background: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at μ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a μ-opioid antagonist and κ-opioid agonist. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. Results: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. Conclusions: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

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The importance of oxytocin mechanisms in the control of mouse parturition

Reproduction ◽

10.1530/rep.0.1230543 ◽

2002 ◽

pp. 543-552 ◽

Cited By ~ 37

Author(s):

AJ Douglas ◽

G Leng ◽

JA Russell

Keyword(s):

Red Light ◽

Endogenous Opioids ◽

Beta Agonist ◽

Early Gene ◽

Opioid Antagonist ◽

Dependent Manner ◽

Birth Process ◽

Opioid Agonist ◽

Adrenergic Antagonist ◽

Oxytocin Neurones

The role of oxytocin in parturition in mice was investigated. Pup birth profiles, blood samples and brains were collected from parturient mice observed under red light conditions in a reversed light:dark photoperiod. Peripheral administration of an oxytocin antagonist in a dose-dependent manner delayed the birth of subsequent pups, indicating that oxytocin is required for a normal pup birth profile. Oxytocin neurones were activated during birth as shown by both increased immediate early gene ( Fos) expression in oxytocin neurones in the supraoptic nucleus and increased plasma oxytocin concentrations during birth. In addition, the nucleus of the tractus solitarius and the olfactory bulbs, sites that process inputs to oxytocin neurones, become activated during parturition. Exposure to stress during parturition halted subsequent deliveries; at this stage plasma oxytocin concentrations were not higher than those of virgin mice, and birth was restored by administration of oxytocin. Administration of beta-adrenergic antagonist (propranolol) also restored stress-delayed birth, whereas administration of ritrodrine (beta-agonist) delayed birth in non-stressed mice, indicating that adrenergic mechanisms contribute to stress-delayed births in mice. Administration of morphine (mu-opioid agonist) delayed births transiently, but naloxone (opioid antagonist) did not prevent stress-delayed birth, indicating that endogenous opioids do not appear to contribute to neuroendocrine or uterine mechanisms that promote birth in mice. Therefore, despite evidence in oxytocin knockout mice that oxytocin is not essential for parturition in this species, the results of the present study indicate that oxytocin neurone activity and secretion contribute to the birth process in normal mice.

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Development of Potent Bifunctional Endomorphin-2 Analogues with Mixed μ-/δ-Opioid Agonist and δ-Opioid Antagonist Properties

Journal of Medicinal Chemistry ◽

10.1021/jm030649p ◽

2004 ◽

Vol 47 (14) ◽

pp. 3591-3599 ◽

Cited By ~ 39

Author(s):

Yoshio Fujita ◽

Yuko Tsuda ◽

Tingyou Li ◽

Takashi Motoyama ◽

Motohiro Takahashi ◽

...

Keyword(s):

Opioid Antagonist ◽

Opioid Agonist

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kappa-Opioid agonist inhibition of osmotically induced AVP release: preferential action at hypothalamic sites

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.2.e367 ◽

1996 ◽

Vol 270 (2) ◽

pp. E367-E372 ◽

Cited By ~ 2

Author(s):

N. F. Rossi ◽

D. P. Brooks

Keyword(s):

Potent Inhibitor ◽

Opiate Receptors ◽

Opioid Antagonist ◽

Posterior Pituitary ◽

Opioid Agonist ◽

Kappa Opioid ◽

Water Diuresis ◽

Kappa Agonist ◽

Opioid Agonists ◽

Kappa Opioid Agonist

Although several studies indicate that kappa-opioid agonists induce a water diuresis by inhibiting vasopressin (AVP) secretion, the locus of the kappa-receptors (neurohypophysial vs. hypothalamic) responsible for this effect remains unclear. We have ascertained the effect of the selective kappa-agonist BRL-52656 (BRL) on AVP secretion by using compartmentalized rat hypothalamoneurohypophysial explants in culture. When applied to the hypothalamus, nanomolar concentrations of BRL inhibited osmotically stimulated AVP secretion. This response was blocked by the highly selective kappa-opioid antagonist nor-binaltorphimine (BNI). However, osmotically stimulated AVP release was suppressed at the neurohypophysial site only by 100 nM BRL and was not reversed by BNI but only by naloxone. This dose of BRL, administered to the posterior pituitary compartment, did not appear to act by the agonist gaining access to hypothalamic kappa-opiate receptors, because BNI added to the hypothalamus failed to prevent the inhibition of AVP secretion. The data demonstrate that BRL is a potent inhibitor of osmotically stimulated AVP secretion via activation of kappa-opiate receptors within the hypothalamus, but that higher concentrations of the drug may also stimulate non-kappa-neurohypophysial opiate receptors that suppress AVP release.

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Opioids and nitric oxide contribute to hypoxia-induced pial arterial vasodilation in newborn pigs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.1.h226 ◽

1995 ◽

Vol 268 (1) ◽

pp. H226-H232 ◽

Cited By ~ 11

Author(s):

W. M. Armstead

Keyword(s):

Nitric Oxide ◽

Direct Action ◽

Opioid Antagonist ◽

Opioid Agonist ◽

Methionine Enkephalin ◽

Mu Opioid ◽

Cranial Window ◽

Newborn Pigs ◽

Synthase Inhibitor ◽

Arteriolar Diameter

The present study was designed to investigate the contribution of opioids and nitric oxide (NO) to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial arteriolar diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and guanosine 3',5'-cyclic monophosphate (cGMP). Hypoxia-induced pial dilation was potentiated by norbinaltorphimine, 10(-6) M, a kappa-opioid antagonist (25 +/- 2 vs. 33 +/- 3%, n = 5), but was blunted by beta-funaltrexamine, 10(-8) M, a mu-opioid antagonist (28 +/- 2 vs. 19 +/- 1%, n = 5). Hypoxia-induced vasodilation was associated with increased CSF methionine enkephalin, a mu-opioid agonist (884 +/- 29 vs. 2,638 +/- 387 pg/ml, n = 5). N omega-nitro-L-arginine (L-NNA), an NO synthase inhibitor (10(-6) M), also blunted hypoxia-induced vasodilation that was further diminished by coadministration of L-NNA and beta-funaltrexamine (26 +/- 2, 14 +/- 1, and 9 +/- 1%, respectively, n = 5). Reversal of the above order of antagonist administration resulted in similar inhibition of hypoxia-induced pial dilation. Hypoxia-induced vasodilation was also associated with an increase in CSF cGMP that was attenuated by L-NNA (2.1 +/- 0.1- vs. 1.1 +/- 0.2-fold change in CSF cGMP, n = 5). Sodium nitroprusside (10(-6) M) increased CSF cGMP and methionine enkephalin concentration similar to hypoxia. These data suggest that hypoxia-induced pial arterial vasodilation, in part, is due to NO and/or cGMP-induced methionine enkephalin release as well as the direct action of NO.

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Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Molecules ◽

10.3390/molecules25184163 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4163 ◽

Cited By ~ 2

Author(s):

Wolfgang Sadee ◽

John Oberdick ◽

Zaijie Wang

Keyword(s):

Opioid Dependence ◽

Pain Therapy ◽

Active Form ◽

Opioid Analgesics ◽

Opioid Antagonist ◽

Opioid Antagonists ◽

Opioid Use ◽

Opioid Agonist ◽

Opposing Effects

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

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Inflammation-reactive astrocytes can be restored with a three drug combination

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2014.05.016 ◽

2014 ◽

Vol 5 (3) ◽

pp. 209-209

Author(s):

E. Hansson ◽

L. Block ◽

U. Björklund ◽

B. Biber

Keyword(s):

Opioid Receptor ◽

Primary Cultures ◽

Reactive Astrocytes ◽

Opioid Antagonist ◽

Opioid Agonist ◽

Cell Parameters ◽

Ultralow Concentrations ◽

Inflammatory State ◽

Μ Opioid Receptor

Abstract Aims In inflammation-reactive astrocytes the cell parameters, Ca2+ signalling, Na+ transporters, cytoskeleton, and release of proinflammatory cytokines are affected. We want to re-establish these parameters with agents, which might have a potential to restore the cells back to a normal non-inflammatory level. Methods Astrocytes in primary cultures were incubated with lipopolysaccharide (LPS) (10 ng/ml) for 24 h to become inflammation-reactive. Different parameters were analysed to verify this inflammation: Ca2+ signalling, Na+/K+-ATPase expression, actin filament organization, and interleukin-1beta release (IL-1β). Results We have used an opioid agonist, endomorphin-1, that stimulates the Gi/o protein of the μ-opioid receptor, an opioid antagonist, naloxone, that inhibits the Gs protein of the μ-opioid receptor in ultralow concentrations, and an anti-epileptic agent, levetiracetam, that counteracts the release of IL-1β. The combination of these three agents managed to activate the Gi/o protein and Na+/K+-ATPase activity, inhibit the Gs protein, and decrease the release of IL-1β. The disorganized actin filaments were restored. Conclusions The findings that the important cell parameters in astrocytes were restored back to their normal non-inflammatory state after the cells were treated with the inflammatory agent LPS could be of clinical significance. It may be useful for the treatment of neuroinflammation and also maybe of long-term pain. The astrocyte networks play a significant role and therefore a well-working intercellular Ca2+ signalling is of utmost importance. Significance These findings put new potential drug regimens towards treatment of neuroinflammation and long-term pain into focus.

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Clinically Relevant Infusion Rates of μ-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Bötzinger Complex Region

Journal of Neurophysiology ◽

10.1152/jn.00188.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 409-418 ◽

Cited By ~ 36

Author(s):

Sanda Mustapic ◽

Tomislav Radocaj ◽

Antonio Sanchez ◽

Zoran Dogas ◽

Astrid G. Stucke ◽

...

Keyword(s):

Opioid Analgesic ◽

Plasma Concentrations ◽

Respiratory Neurons ◽

Opioid Antagonist ◽

Direct Effects ◽

Opioid Agonist ◽

Homocysteic Acid ◽

Respiratory Rhythmogenesis ◽

Bötzinger Complex

Systemic administration of μ-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MORs) on pre-Bötzinger Complex (pre-BötC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pre-BötC MORs to the bradypnea produced in vivo by intravenous administration of clinically relevant infusion rates of remifentanil (remi), a short-acting, potent μ-opioid analgesic. In decerebrate dogs, multibarrel micropipettes were used to record pre-BötC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist d-homocysteic acid (DLH, 20 mM), or the MOR agonist [d-Ala2, N-Me-Phe4, gly-ol5]-enkephalin (DAMGO, 100 μM). Inspiratory and expiratory durations ( TI and TE) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The pre-BötC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (∼60% decrease in central breathing frequency, fB), bilateral injections of NAL in the pre-BötC did not change TI, TE, fB, and PPA. Also, NAL picoejected onto single pre-BötC neurons depressed by intravenous remi had no effect on their discharge. In contrast, ∼60 μg/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the pre-BötC increased fB by 44%, while subsequent intravenous remi infusion more than offset this DAMGO induced tachypnea. These results indicate that μ-opioids at plasma concentrations that cause profound analgesia produce their bradypneic effect via MORs located outside the pre-BötC region.

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