Opiate Receptor Antagonist Research Articles

Conversation with Charles P. O'Brien

Conversation with <scp>C</scp>harles <scp>P</scp>. <scp>O</scp>'<scp>B</scp>rien

Methadone-induced bilateral severe sensorineural hearing loss

Methadone, a long-acting opiate agonist, and naltrexone, an opiate receptor antagonist, are both commonly used to treat patients with morphine and heroin addiction. We present a rare case of methadone-induced persistent bilateral sensorineural hearing loss (SNHL) after chronic naltrexone use and review opioid-induced hearing loss in the literature. Methadone-induced hearing loss has been described previously described in the literature with all reported cases recovering functional hearing. This is the first description of persistent bilateral severe SNHL following methadone ingestion. We propose opiate receptor sensitization from prolonged naltrexone use as a predisposing factor for methadone-induced irreversible cochlear injury.

Effects of naltrexone on adolescent alcohol cue reactivity and sensitivity: an initial randomized trial

Adolescent alcohol use is associated with myriad adverse consequences and contributes to the leading causes of mortality among youth. Despite the magnitude of this public health problem, evidenced-based treatment initiatives for alcohol use disorders in youth remain inadequate. Identifying promising pharmacological approaches may improve treatment options. Naltrexone is an opiate receptor antagonist that is efficacious for reducing drinking in adults by attenuating craving and the rewarding effects of alcohol. Implications of these findings for adolescents are unclear; however, given that randomized trials of naltrexone with youth are non-existent. We conducted a randomized, double-blinded, placebo-controlled cross-over study, comparing naltrexone (50 mg/daily) and placebo in 22 adolescent problem drinkers aged 15-19 years (M = 18.36, standard deviation = 0.95; 12 women). The primary outcome measures were alcohol use, subjective responses to alcohol consumption, and alcohol-cue-elicited craving assessed in the natural environment using ecological momentary assessment methods, and craving and physiological reactivity assessed using standard alcohol cue reactivity procedures. Results showed that naltrexone reduced the likelihood of drinking and heavy drinking (P's ≤ 0.03), blunted craving in the laboratory and in the natural environment (P's ≤ 0.04), and altered subjective responses to alcohol consumption (P's ≤ 0.01). Naltrexone was generally well tolerated by participants. This study provides the first experimentally controlled evidence that naltrexone reduces drinking and craving, and alters subjective responses to alcohol in a sample of adolescent problem drinkers, and suggests larger clinical trials with long-term follow-ups are warranted.

Opiate Receptor Antagonists for Treatment of Severe Pruritus Associated with Advanced Cholestatic Liver Disease

Journal of Palliative MedicineVol. 16, No. 2 Letters to the EditorOpiate Receptor Antagonists for Treatment of Severe Pruritus Associated with Advanced Cholestatic Liver DiseaseNilay Kumar, Neetika Garg, and Amos BaileyNilay KumarDepartment of Internal Medicine, University of Alabama at Birmingham, Birmingham, Alabama.Search for more papers by this author, Neetika GargDepartment of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.Search for more papers by this author, and Amos BaileyDivision of Palliative care and Hospice Medicine, Birmingham VA Medical Center, Birmingham, Alabama.Search for more papers by this authorPublished Online:7 Feb 2013https://doi.org/10.1089/jpm.2012.0452AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Opiate Receptor Antagonists for Treatment of Severe Pruritus Associated with Advanced Cholestatic Liver Disease." , 16(2), pp. 122–123FiguresReferencesRelatedDetailsCited byAnalgetikaNaltrexone for cholestatic itch: a systematic review10 March 2021 | BMJ Supportive & Palliative Care, Vol. 11, No. 2Therapeutics for Pruritus in Cholestatic Liver Disease: Many Treatments but Few Cures6 April 2018 | Current Hepatology Reports, Vol. 17, No. 2AnalgetikaHepatitis C virus-associated pruritus: Etiopathogenesis and therapeutic strategiesWorld Journal of Gastroenterology, Vol. 23, No. 5Methylnaltrexone to Palliate Pruritus in Terminal Hepatic Disease13 November 2017 | Journal of Palliative Care, Vol. 31, No. 2AnalgetikaAzithromycin22 March 2014 | Reactions Weekly, Vol. 1493, No. 1Opioid AntagonistsJournal of Pain and Symptom Management, Vol. 47, No. 2 Volume 16Issue 2Feb 2013 InformationCopyright 2013, Mary Ann Liebert, Inc.To cite this article:Nilay Kumar, Neetika Garg, and Amos Bailey.Opiate Receptor Antagonists for Treatment of Severe Pruritus Associated with Advanced Cholestatic Liver Disease.Journal of Palliative Medicine.Feb 2013.122-123.http://doi.org/10.1089/jpm.2012.0452Published in Volume: 16 Issue 2: February 7, 2013PDF download

Vitamin D receptor activation and downregulation of renin-angiotensin system attenuate morphine-induced T cell apoptosis

Opiates have been reported to induce T cell loss. We evaluated the role of vitamin D receptor (VDR) and the activation of the renin-angiotensin system (RAS) in morphine-induced T cell loss. Morphine-treated human T cells displayed downregulation of VDR and the activation of the RAS. On the other hand, a VDR agonist (EB1089) enhanced T cell VDR expression both under basal and morphine-stimulated states. Since T cells with silenced VDR displayed the activation of the RAS, whereas activation of the VDR was associated with downregulation of the RAS, it appears that morphine-induced T cell RAS activation was dependent on the VDR status. Morphine enhanced reactive oxygen species (ROS) generation in a dose-dependent manner. Naltrexone (an opiate receptor antagonist) inhibited morphine-induced ROS generation and thus, suggested the role of opiate receptors in T cell ROS generation. The activation of VDR as well as blockade of ANG II (by losartan, an AT(1) receptor blocker) also inhibited morphine-induced T cell ROS generation. Morphine not only induced double-strand breaks (DSBs) in T cells but also attenuated DNA repair response, whereas activation of VDR not only inhibited morphine-induced DSBs but also enhanced DNA repair. Morphine promoted T cell apoptosis; however, this effect of morphine was inhibited by blockade of opiate receptors, activation of the VDR, and blockade of the RAS. These findings indicate that morphine-induced T cell apoptosis is mediated through ROS generation in response to morphine-induced downregulation of VDR and associated activation of the RAS.

Serotonin Influences the Endogenous Opiate Peptides in the Rat Spinal Cord to Participates in Pain Modulation

Spinal cord is a necessary pathway that transfers the body nociceptive inputs to the brain. Endogenous opiate peptides have been proven to participate in the nociceptive process at spinal level. It has reported that serotonin (5-HT, 5-hydroxytryptamine) in spinal cord plays a role in pan modulation, which can be blocked by opiate receptor antagonists. The present study was designed to investigate the interaction between 5-HT and endogenous opiate peptides at rat spinal level effecting on pain modulation. The results showed that 1) pain stimulation increased not only leucine-enkephalin (L-Ek), β-endorphin (β-Ep) and dynorphin A1-13 (DynA1-13) concentrations but also 5-HT and 5-hydorxyindoleace acid (5-HIAA, the 5-HT main metabolic product) concentrations in spinal cord significantly; 2) 5-HT could increase L-Ek, β-Ep and DynA1-13 concentrations in spinal cord in a dose-dependent manner, whereas cypotolamine (a 5-HT receptor antagonist) decreased L-Ek, β-Ep and DynA1-13 concentrations in spinal cord. The data suggested that 5-HT antinociceptive role might be involved in the endogenous opiate peptide system through 5-HT receptors at spinal level.

Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides

Periaqueductal gray (PAG) plays a very important role in pain modulation through endogenous opiate peptides including leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek), β-endorphin (β-Ep) and dynorphin A 1–13 (DynA 1–13). Our pervious study has demonstrated that intra-PAG injection of oxytocin (OXT) increases the pain threshold, and local administration of OXT receptor antagonist decreases the pain threshold, in which the antinociceptive role of OXT can be reversed by pre-PAG administration of OXT receptor antagonist. The experiment was designed to investigate the effect of OXT on endogenous opiate peptides in the rat PAG during the pain process. The results showed that (1) the concentrations of OXT, L-Ek, M-Ek and β-Ep, not DynA 1–13 in the PAG perfusion liquid were increased after the pain stimulation; (2) the concentrations of L-Ek, M-Ek and β-Ep, not DynA 1–13 in the PAG perfusion liquid were decreased by the OXT receptor antagonist; (3) the increased pain threshold induced by the OXT was attenuated by naloxone, an opiate receptor antagonist; and (4) the concentrations of L-Ek, M-Ek and β-Ep, not DynA 1–13 in the PAG perfusion liquid were increased by exogenous OXT administration. The data suggested that OXT in the PAG could influence the L-Ek, M-Ek and β-Ep rather than DynA 1–13 to participate in pain modulation, i.e. OXT in the PAG participate in pain modulation by influencing the L-Ek, M-Ek and β-Ep rather than DynA 1–13.

Pruritus: an overview of current concepts

Pruritus is an integral part of the patient's symptoms in numerous dermatological and systemic diseases in humans and animals. Comparable to chronic pain, pruritus can have a dramatic impact on the quality of life of the patient. In recent years, pruritus has been defined as an autonomous, pain-independent sensation, and itch-specific neurons, mediators, spinal neurons and cortical areas have been identified. These observations have not only improved our understanding of the neurobiology of itch but will also lead to improved diagnosis and to the development of new and more efficient therapeutic options. This article reviews the role of itch fibres and their response to various mediators of pruritus including histamine, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and substance P (SP), and opioids. Substances that may be involved in the induction or modulation of itch may be termed pruritogenic mediators and examples discussed include proteases, lipid mediators, neuropeptides, opioids and various cytokines. There is no single, generally accepted clinical classification of chronic pruritus. In the past pruritus has been classified on the basis of the neuroanatomical origin and on the potential underlying disease. Therapeutic options for the management of pruritus are discussed including topical and systemic therapies, assuming that trigger factors have been eliminated where possible. Topical agents may include capsaicin, the calcineurin inhibitors tacrolimus and pimecrolimus, and cannabinoid agonists such as N-palmitoyl ethanolamine. Systemic therapies may include antihistamines, anticonvulsants, opiate receptor antagonist or agonists, antidepressants, ciclosporin, and UV light.

Discovery and pharmacological characterization of a selective delta opiate receptor antagonist (CP-646,777)

CP-646,777 (compound 2a) is identified as a potent and selective delta opioid receptor antagonist. The synthesis, pharmacological evaluation, disposition characteristics and pharmacokinetic properties of this compound are reported herein. An approach for reducing clearance as measured by human liver microsomes is demonstrated. The significance of p-glycoprotein efflux on CNS disposition and on the pharmacological action of CP-646,777 is also discussed.

89. The effects of opiate receptor agonists and antagonists on spontaneous seizure activity in hippocampal slices

89. The effects of opiate receptor agonists and antagonists on spontaneous seizure activity in hippocampal slices

Medial forebrain stimulation enhances intracranial nociception and attenuates morphine analgesia suggesting the existence of an endogenous opioid antagonist

The purpose of this experiment was to test in the rat the hypotheses that activation of the brain reward system would attenuate the effects of intracranial nociceptive stimulation and would potentiate the antinociceptive effects of morphine. In this experiment pain (nociception) was generated by electrical stimulation of a brain pain pathway, the mesencephalic reticular formation (MRF) of the rat. Reward pathway stimulation was to the medial forebrain bundle at the level of the lateral hypothalamus (MFB-LH). Current thresholds for escape from MRF stimulation were determined using a modification of the psychophysical methods of limits. MRF stimulation was delivered concurrently with different intensities of non-contingent MFB-LH stimulation. The effects of morphine and saline were determined under all stimulation conditions. Contrary to expectation MFB-LH stimulation significantly lowered MRF stimulation escape thresholds. Morphine administration elevated MRF thresholds in the absence of MFB-LH stimulation. However, this effect was blocked by concurrent MFB-LH stimulation. These findings, which mimic the effects of the opiate antagonist naloxone, i.e., potentiating of pain and antagonism of morphine's analgesic effects, suggest the presence of an endogenous opiate receptor antagonist.

Opioid-Like Activity of Naltrexone on Natural Killer Cell Cytolytic Activity and Cytokine Production in Splenocytes: Effects of Alcohol

Chronic alcohol consumption has been shown to decrease the activity of natural killer (NK) cell cytolytic function and the production of various cytokines from the spleen. We have recently shown that naltrexone, an opiate receptor antagonist, when administered for a period of 2 weeks suppresses micro-opiate receptor binding but increases partial differential-opiate receptor activity in rat splenocytes. However, the effects of long-term naltrexone treatment on alcohol-induced alteration of NK cell cytolytic activity and cytokines production in splenocytes have not been determined. Male rats were pair-fed an isocaloric liquid diet or fed an ethanol-containing liquid diet for a period of 3 weeks. These rats were additionally treated after a week with a subcutaneous implant of either a naltrexone pellet or placebo pellet for 2 weeks. Splenocytes were isolated and used for determination of various cytokines interleukin (IL)-2, IL-4, and IL-6, and interferon-gamma (IFN-gamma) using enzyme-linked immunosorbent assay (ELISA), and the basal and IL-2-, IL-12-, or IL-18-induced NK cytolytic activity was measured using a standard 4-h (51)Cr release assay against YAC-1 lymphoma target cells. Ethanol consumption resulted in a reduction of the production of IL-2, IL-4, and IL-6 as well as the basal and cytokine-activated NK cell cytolytic activity and IFN-gamma production in splenocytes. Naltrexone administration increased the production of IL-2, IL-4, and IL-6 and the basal and cytokine-activated NK cell cytolytic activity and IFN-gamma production in the splenocytes of pair-fed and alcohol-fed rats. These results indicated that naltrexone treatment increases NK cell cytolytic activity and cytokine production in the spleen in vivo. Furthermore, these results identify the potential of the use of naltrexone in the treatment of immune deficiency in alcoholic and non-alcoholic patients.

How to Reduce Medication Nonadherence in Heroin Dependence

The opiate receptor antagonist naltrexone reduces heroin use in narcotic-dependent patients, but its real-life usefulness is limited because patients

Design, synthesis and biological evaluation of a bivalent μ opiate and adenosine A1 receptor antagonist

The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A 1 adenosine and μ opiate receptors with a K i of 0.8 ± 0.05 and 0.7 ± 0.03 μM, respectively. This hybrid molecule increases cAMP production in cells that over express the μ receptor as well as those over expressing the A 1 adenosine receptor and reverses the antalgic effects of μ and A 1 adenosine receptor agonists in animals.

Naloxone Effects on Behavior of Inbred Mice with Different Response to Emotional Stress in Open Field Test

Effects of nonspecific opiate receptor antagonist naloxone in doses of 0.1, 0.5, 1.0, 5.0, 10.0 mg/kg on open field behavior and spontaneous motor activity were studied in male BALB/c and C57Bl/6 mice. Differently directed effects of naloxone on behavioral parameters of emotional-stress reaction in BALB/c and C57Bl/6 mice were observed. Naloxone increased motor activity in the open field test in BALB/c mice, but decreased it in C57Bl/6 mice. In the absence of stress, naloxone in the studied dose range did not affect spontaneous motor activity in C57Bl/6 mice, and significantly reduced activity in BALB/c mice in doses 0.5 and 1.0 mg/kg.

Stress-dependent enhancement and impairment of retention by naloxone: Evidence for an endogenous opioid-based modulatory system protective of memory

The opiate-receptor antagonist naloxone was administered to rats after passive-avoidance training either alone or in combination with forced-swim stress. A retention test revealed that while naloxone enhanced retention when administered alone, it impaired retention when administered in combination with forced-swim stress. The findings provide evidence for a “protective” endogenous opioid-based system that, when not blocked pharmacologically, limits enhancement or impairment of retention under conditions of mild and intense stress, respectively.

Dual Roles for Endothelin-B Receptors in Modulating Adjuvant-Induced Inflammatory Hyperalgesia in Rats

Injection of endothelin-1 (ET-1) into the plantar rat hindpaw causes acute pain at high concentrations and tactile sensitization at low concentrations. The pro-nociceptive actions are driven through ET(A) receptors for both levels of [ET-1], but the ET(B) receptors are only pro-nociceptive for allodynia from low [ET-1] and anti-nociceptive for pain from high [ET-1]. The goal of the present work was to discriminate the roles of the ET receptors in the acute hyperalgesia from inflammation by complete Freund's adjuvant (CFA, 20 mg/paw) into the rat hindpaw. Selective antagonists were injected l0 min before and then together with CFA. An ET(A) receptor antagonist, BQ-123, reduced CFA-induced thermal hyperalgesia (by up to 50%), as did an ET(B) receptor antagonist, BQ-788 (by up to 66%). BQ-123 and BQ-788 also delayed the onset (by 1.5 - 2 h) but insignificantly reduced the maximum degree of CFA-induced allodynia (~10%). Surprisingly, an ET(B) receptor agonist, IRL-1620, also reduced maximum thermal hyperalgesia induced by CFA, suppressed peak allodynia and delayed its occurrence by ~ 3 h. The latter actions of IRL-1620 were reversed by co-administration of BQ-788, naloxone hydrochloride and the peripherally restricted opiate receptor antagonist naloxone methiodide, and by antiserum against β-endorphin. These findings demonstrate an important role for endogenous ET-1 in acute inflammatory pain and a dual action of ET(B) receptors, including a pro-algesic action along with the important activation of a local analgesic pathway, implying that at least two different ET(B) receptors contribute to modulation of inflammatory pain.

Effect of Simultaneous Local Injection of 6-Hydroxydopamine and Naloxone on the Testis of Neonatal Rats/Der Einfluß einer gleichzeitigen lokalen Injektion von 6-Hydroxydopamin und Naloxon auf den Hoden neugeborener Ratten

The effect of simultaneous intratesticular injection of the opiate receptor antagonist naloxone and the neurotoxic drug 6-hydroxydopamine (6-OHDA) on testicular growth, compensatory testicular hypertrophy, serum testosterone level and basal testosterone secretion in vitro was studied in neonatal rats. In animals with two testes unilateral intratesticular administration of naloxone alone enhanced, while 6-OHDA alone decreased the weight of the treated gonad. In animals treated simultaneously with these two agents the decrease in testicular weight induced by 6-OHDA was partially prevented by naloxone. In hemicastrated animals intratesticular treatment with naloxone enhanced the extent of compensatory testicular hypertrophy. Treatment of the remaining testis with 6-OHDA + naloxone did not interfere with the diminished compensatory testicular hypertrophy observed following 6-OHDA treatment. Data indicate that naloxone can counteract the degenerative effect of 6-OHDA in animals with two testes but not in hemicastrates.

Studies of 3-O-acyl derivatives of naloxone as its potential prodrugs

An efficient method has been proposed for the preparation of a series of 3-O-acyl derivatives of naloxone. The features of the steric structure and NMR spectra are discussed. Pharmaceutical investigation has shown the promise within the synthesized compounds of creating opiate receptor antagonist compounds with prolonged action.

OxyContin® Abuse and Overdose

Background: OxyContin® (controlled-release oxycodone hydrochloride) (Purdue Pharma, Stamford, CT) was approved in 1995 by the US Food and Drug Administration (FDA) for moderate-to-severe chronic pain. Crushing and snorting the delayed-release tablets results in a rapid release of the drug, increased absorption, and high peak serum concentrations. The propensity for addiction to OxyContin® and the trend of increased prescription drug abuse have made it imperative for physicians and health care providers to recognize the clinical presentation of overdose and know how to manage associated complications. Objectives: In this review of OxyContin®, we discuss current trends in its abuse and the clinical presentation of overdose. We review the specific effects of the drug on body systems and the recognition of symptomatology, differential diagnosis, and management. Discussion: Many of the clinical findings in acute opioid overdoses are nonspecific, making diagnosis difficult. OxyContin® overdose presents with a typical opiate toxidrome, including decreased respirations, miosis, hypothermia, bradycardia, hypotension, and altered mental status. The presence of coingestants can cloud the clinical picture. If OxyContin® overdose is suspected, early ventilation and oxygenation should be administered, which is generally sufficient to prevent death. Even in the absence of a confirmation, cautious administration of naloxone–the opiate receptor antagonist and antidote for opioid overdoses–may have both diagnostic and therapeutic effects. Summary: With increasing rates of prescription drug abuse, OxyContin® will continue to present challenges to physicians and health care providers. Physicians should be aware of potential patients who are seeking OxyContin® for recreational use.