Journal articles on the topic 'Opioid agonists'
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María Martín Orejas and Víctor Martín Mora. "AT-121, ¿el opioide perfecto?" Revista Electrónica AnestesiaR 12, no. 7 (August 3, 2020): 4. http://dx.doi.org/10.30445/rear.v12i7.862.
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Los opioides son los analgésicos más potentes y efectivos de que disponemos en la actualidad. Su cara oscura la encarna el creciente aumento de pacientes adictos a su consumo en todo el mundo, principalmente en Estados Unidos. Desde el descubrimiento de los primeros opioides sintéticos, la industria farmacéutica se halla en busca de un analgésico que no genere tolerancia ni dependencia, ni efectos adversos respiratorios. La mayoría de los opiáceos son agonistas del receptor mu, cuya activación aumenta la disponibilidad sináptica de dopamina, neurotransmisor vehicular en circuitos de recompensa. Sin embargo, un cuarto receptor opioide ha sido descrito recientemente: el receptor de nociceptina/orfanina. Su activación inhibe la liberación de dopamina, evitando el refuerzo positivo que ocurre tras el consumo del fármaco. AT-121 es un agonista bifuncional MOP/NOP que ha sido probado en primates no humanos con resultados prometedores en cuanto a potencia analgésica, menores efectos secundarios sistémicos y menor tasa de adicción y abuso. Tales características hacen de esta molécula un arma esperanzadora en el tratamiento del dolor crónico o de la propia adicción a fármacos opioides. En los últimos años se han explorado distintos agonistas bifuncionales en roedores y primates no humanos con interesantes resultados; quedamos pues a la espera de futuras investigaciones en humanos. ABSTRACT Is AT121 the perfect opioid? Opioids are the most powerful and effective analgesics available today. Their dark side is reflected in the growing number of patients addicted to their use around the world, mainly in the United States. Since the discovery of the first synthetic opioids, the pharmaceutical industry has been searching for an analgesic that does not generate tolerance or dependence, nor adverse respiratory effects. Most opioids are mu receptor agonists, whose activation increases the synaptic availability of dopamine, a neurotransmitter that is a carrier in reward circuits. However, a fourth opioid receptor has recently been described: the nociceptin/orphanine receptor. Its activation inhibits the release of dopamine, preventing the positive reinforcement that occurs after drug consumption. AT-121 is a bifunctional MOP/NOP agonist that has been tested in non-human primates with promising results in terms of analgesic potency, fewer systemic side effects, and lower rate of addiction and abuse. Such characteristics make this molecule a hopeful weapon in the treatment of chronic pain or addiction to opioid drugs. In recent years, different bifunctional agonists have been explored in rodents and non-human primates with interesting results; we are therefore awaiting future research in humans.
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Colson, James. "Office-Based Opioid Dependence Treatment." July 2012 3S;15, no. 3S;7 (July 14, 2012): ES231—ES236. http://dx.doi.org/10.36076/ppj.2012/15/es231.
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Background: Opioid misuse and abuse occurring in association with the treatment of chronic non-cancer pain are not new phenomena, but their increasing prevalence in recent years is unprecedented. Advancements in pharmaceutical technologies have provided opioid-related drugs, which lack the pure mu agonist activity characteristic of the typical opioid congeners. This absent or altered mu receptor activity imparts an opioid receptor antagonistic or partial agonistic pharmacologic action, which serves to modulate the development of opioid-induced tolerance and physical dependence and facilitate detoxification and withdrawal from opioids. Opioid antagonists and partial agonists are being used in abuse deterrent strategy regimens to prevent opioid tolerance and the development of dependence, as well as in the management of opioid detoxification and treatment of withdrawal. The specific opioid antagonists and partial agonists used in these various therapeutic modalities will be the focus of this review. Objectives: Evaluate the comparative therapeutic utility of opioid antagonists and partial agonists in preventing the development of opioid tolerance and treating opioid dependence, detoxification, and withdrawal. A primary focus is the use of opioid antagonists and partial agonists within an office-based practice. Methods: A narrative review of the current literature involving the therapeutic use of opioid antagonists and partial agonists in the management of opioid tolerance, dependence, detoxification, and withdrawal. A computerized literature search in the PubMed, EMBASE, BioMed, and Cochrane Library review databases from 2008 through 2010 was performed. This search included systematic and narrative reviews, prospective and retrospective studies, as well as cross-references from bibliographies of notable primary and review articles and abstracts from scientific meetings. US Food and Drug Administration records and pharmaceutical manufacturers’ product literature were also used in the search. Conclusion: Opioid dependency, whether it results from the misuse or abuse of prescription or street drugs, continues to be a significant public health issue. Passage of DATA 2000 and US Food and Drug Administration approval of buprenorphine and buprenorphine/ naloxone has revolutionized opioid dependence therapy. The traditional addiction medicine therapy regimen of methadone maintenance, with its inherent legal limitations and restrictions, has been challenged by an office-based dependence practice with buprenorphine serving as a prominent therapeutic tool. Key words: opioid antagonist, opioid partial agonist, tolerance, dependence, detoxification, withdrawal, hyperalgesia, buprenorphine, suboxone, naloxone, naltrexone, methylnaltrexone, nalmefene, tramadol, butorphanol, nalbupine, pentazocine.
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Haddad, G. G., H. J. Jeng, and T. L. Lai. "Effect of endorphins on heart rate and blood pressure in adult dogs." American Journal of Physiology-Heart and Circulatory Physiology 250, no. 5 (May 1, 1986): H796—H805. http://dx.doi.org/10.1152/ajpheart.1986.250.5.h796.
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To investigate the role of opioids in regulating cardiovascular function, we administered delta-opioid receptor agonists D-Ala-D-Leu enkephalin (DADLE) and D-Ala-Met enkephalinamide (DAME), and mu-opioid receptor agonist, a morphiceptin analogue (MA), intracisternally in 13 unanesthetized, chronically instrumented adult dogs in 2 doses (25 and 125 micrograms/kg). After an initial transient drop, the R-R interval increased (peak approximately 25–60 min) postadministration of opioids. The time course and the magnitude of the change in R-R interval depended on the agonist: delta-agonists induced a more prolonged and marked change in R-R interval than mu-agonists at both doses. Mean arterial blood pressure (MAP) increased initially but dropped toward or even below base line 30 min after opioids administration. Atropine, given intravenously or intra-arterially at peak action of agonist in relatively low doses (0.02 mg/kg), induced an AV block followed by a marked decrease in R-R interval. There was also an increase in MAP after atropine. Naloxone, given intracisternally, reversed both delta- and mu-opioid effects but did not induce changes in the R-R interval without prior administration of opioids. We conclude that in unanesthetized adult dogs 1) both mu- and delta-receptor opioid agonists prolong the R-R interval, and this depends on the type of receptor stimulated; 2) opioids induce slowing in heart rate, possibly by increasing parasympathetic activity to the heart; 3) enkephalin and morphiceptin analogues induce a biphasic response in MAP; and 4) endorphins do not modulate cardiovascular function tonically; we speculate that they can alter the R-R interval and MAP in the presence of stimuli.
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Trescot, Andrea M. "Opioid Pharmacology." Pain Physician 2s;11, no. 3;2s (March 14, 2008): S133—S153. http://dx.doi.org/10.36076/ppj.2008/11/s133.
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Background: Mu agonists have been an important component of pain treatment for thousands of years. The usual pharmacokinetic parameters (half-life, clearance, volume of distribution) of opioids have been known for some time. However, the metabolism has, until recently, been poorly understood, and there has been recent interest in the role of metabolites in modifying the pharmacodynamic response in patients, in both analgesia and adverse effects. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages and disadvantages of various opioids in the management of chronic pain are discussed. Objective: This review looks at the structure, chemistry, and metabolism of opioids in an effort to better understand the side effects, drug interactions, and the individual responses of patients receiving opioids for the treatment of intractable pain. Conclusion: Mu receptor agonists and agonist-antagonists have been used throughout recent medical history for the control of pain and for the treatment of opiate induced side effects and even opiate withdrawal syndromes. Key words: Opioid metabolism, opioid interactions, morphine, codeine, hydrocodone, oxycodone, hydromorphone, methadone, intractable pain, endorphins, enkephalins, dynorphins, narcotics, pharmacology, propoxyphene, fentanyl, oxymorphone, tramadol
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Zappi, Lucia, Francesco Nicosia, Danilo Rocchi, Pingfang Song, and Kai Rehder. "Opioid Agonists Modulate Release of Neurotransmitters in Bovine Trachealis Muscle." Anesthesiology 83, no. 3 (September 1, 1995): 543–51. http://dx.doi.org/10.1097/00000542-199509000-00013.
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Background Stimulation of opioid receptors in the airways can modulate cholinergic neurotransmission and thereby reduce bronchoconstriction. This protecting effect of opioids against bronchoconstriction may be of clinical interest. Inhalation of opioids as a method of analgesia is likely to result in an opioid concentration at airway receptors sufficient to protect against bronchoconstriction; the concentration may be insufficient when opioids are administered by conventional techniques. In addition, new selective opioids may be developed that could more selectively protect the airways against bronchoconstriction. Methods The effect of three selective opioid agonists on the contractile response to electric field stimulation (EFS) was studied in isolated muscle strips from four regions of the bovine trachea (upper, or laryngeal; upper middle; lower middle; lower, or carinal). Results The selective kappa agonist trans-3,4-dichloro-N-methyl-N-(2-1-pyrrolidinyl) cyclohexyl benzene acetamide (U-50488 H) and the selective mu-opioid agonist D-Ala2-N-MePhe4-Gly-ol5-enkephalin (DAMGO) reduced significantly (P < 0.001 and P < 0.001, respectively) the contractile response to EFS. The attenuation of the contractile response by U-50488 H was concentration-dependent (P < 0.0001) and tended to be larger at low stimulating frequencies (P = 0.055). The attenuation of the contractile response by DAMGO was frequency-dependent (P < 0.01). The selective delta-opioid agonist D-penicillamine2-D-penicillamine5-enkephalin had no significant effect on the contractile response to EFS (P = 0.71). There were no significant differences among the four regions of the trachea in their responses to the selective opioid agonists U-50488 H (P = 0.50) and DAMGO (P = 0.44). Neither U-50488 H nor DAMGO altered the contractile response to acetylcholine P > 0.11, P > 0.21, respectively), suggesting that the opioid agonists have a prejunctional effect. The attenuation of the contractile response to EFS by U-50488 H was partially but significantly antagonized by 10(-5) M naloxone (P < 0.01) and by 10(-5) and 10(-6) M of the selective kappa-opioid antagonist 2,2'-[1,1'-biphenyl] 4,4'-diyl- bis [2-hydroxy-4,4-dimethyl-morpholinium] (P < 0.05). Naloxone (10(-5) M) abolished the inhibitory effect of DAMGO, suggesting that opioid receptors are involved in the attenuation of the contractile response to EFS afforded by DAMGO and U-50488 H. Conclusions We conclude that prejunctional kappa- and mu-opioid receptors attenuate the contractile response of isolated bovine trachealis muscle to EFS by inhibiting cholinergic neurotransmission. This effect is uniform throughout the trachealis muscle. delta-Opioid receptors are apparently not present in the bovine trachealis muscle. Caution must be used in extrapolating these results to the intact human. In this study little or no inhibitory effect of the opioids was observed at concentrations expected at airway receptor sites when administered by conventional techniques. However, the effect may be large enough to protect against bronchoconstriction when nebulized opioids are administered by inhalation.
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El-Sharkawy, T. Y., M. F. Al-Shireida, and C. W. T. Pilcher. "Vascular effects of some opioid receptor agonists." Canadian Journal of Physiology and Pharmacology 69, no. 6 (June 1, 1991): 846–51. http://dx.doi.org/10.1139/y91-128.
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Opioid peptides have been implicated in shock-associated hypotension. Our aim was to find out whether opioid agonists have direct vasodilator actions on vascular smooth muscle. The study was conducted on rat abdominal aortic rings. In rings precontracted with either norepinephrine, prostaglandin F2α, or high potassium Krebs (HPK), the effects of the opioid agonists tested (morphine, U50488H, ethylketocyclazocine (EKC), and bremazocine) depended on the precontracting agent used. HPK-precontracted rings were relaxed by all agonists tested. In norepinephrine-precontracted rings, all caused contraction at low concentrations and relaxation at high concentrations except bremazocine, which caused only relaxation. In prostaglandin F2α-precontracted rings, U50488H produced contraction at low concentrations and relaxation at high concentrations while EKC caused only relaxation and morphine or bremazocine caused only contraction. All relaxant responses were endothelium-independent and were antagonized by verapamil but not by a number of antagonists including naloxone, MR2266, propranolol, diphenhydramine, cimetidine, and indomethacin. They may reflect calcium channel blockade. Morphine-induced vasoconstriction was antagonized by high concentrations of naloxone or mepyramine and may be due to release of histamine by a naloxone-sensitive mechanism. We conclude that (a) the opioid agonists tested exert direct actions on vascular smooth muscle; (b) the nature of the response depended not only on the agonist used and its concentration but also on the agent used to precontract the tissue; and (c) it is unlikely that direct actions of endogenous opioids contribute to the shock-associated hypotension because high doses were needed to elicit them.Key words: vascular smooth muscle, opioids, neurohormonal peptides, circulatory shock.
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Sandner-Kiesling, Andreas, and James C. Eisenach. "Estrogen Reduces Efficacy of μ- but Not κ-Opioid Agonist Inhibition in Response to Uterine Cervical Distension." Anesthesiology 96, no. 2 (February 1, 2002): 375–80. http://dx.doi.org/10.1097/00000542-200202000-00024.
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Background Although the uterine cervix is a common source of acute and chronic visceral pain in women, there is practically no neurobiological investigation of nociception from this visceral organ. With use of a novel model of uterine cervical distension nociception in rats, the estrogen dependency of opioid agonist-induced inhibition was investigated. Methods Sprague Dawley rats were anesthetized with halothane and bilateral ovariectomy was performed, after which placebo or estrogen treatment was administered for 1 week. Animals were reanesthetized and fine metal rods were inserted into the uterine cervix for manual distension. Reflex contraction of the rectus abdominis in response to distension was recorded before and after cumulative dosing with the mu-opioid agonist morphine and the kappa-opioid agonist (-)U50488. Results Uterine cervical distension increased reflex abdominal muscle contraction with a threshold of 75 g, regardless of estrogen treatment. Morphine and (-)U50488 reduced the reflex response to cervical distension in a dose-dependent manner. Estrogen reduced the inhibitory effect of morphine but not that of (-)U50488. Conclusions It has been suggested that mu-opioid agonists are less potent in females than males, whereas kappa-opioid agonists are more potent in females than males. These data suggest that estrogen may influence the action of opioids, at least against visceral pain, which may explain this sex difference. In addition, these data suggest that kappa-opioid agonists may be effective in the treatment of pain originating from the uterine cervix, regardless of estrogen status.
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Webster, Lynn, and William K. Schmidt. "Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach." Pain Medicine 21, no. 5 (June 5, 2019): 992–1004. http://dx.doi.org/10.1093/pm/pnz122.
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Abstract Objective Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist. Results Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested. Conclusions CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.
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Herz, Albert. "Opioid reward mechanisms: a key role in drug abuse?" Canadian Journal of Physiology and Pharmacology 76, no. 3 (March 1, 1998): 252–58. http://dx.doi.org/10.1139/y98-017.
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There is increasing evidence to implicate the mesolimbic dopamine system in the rewarding effects of drugs of abuse such as opioids, psychostimulants, and alcohol, and in addition endogenous opioids may play a key role in the underlying adaptive mechanisms. Opioid agonists with affinity for µ and delta opioid receptors are rewarding, whereas opioid agonists with affinity for kappa receptors are aversive. These opposing motivational effects are paralleled by an increase and decrease, respectively, of dopamine release in the nucleus accumbens. Opposite effects are induced in response to selective antagonists for these different receptor types, pointing to tonically active endogenous opioid reward mechanisms. Withdrawal from chronic morphine results in sensitization for opioid reward; an effect that is counteracted by kappa opioid agonists. The rewarding effects of psychostimulants such as cocaine and amphetamine, mediated by the mesolimbic dopamine pathway, are modulated by opioid mechanisms in both directions: sensitization by morphine pretreatment, inhibition by kappa receptor agonists. A modulatory role of endogenous opioids is also suggested from biochemical data, showing increased dynorphin and kappa receptor expression after chronic cocaine treatment. Alcohol reward involves the mesolimbic reward system also, and opioids modulate this behaviour. Naltrexone as well as selective µ and delta opioid receptor antagonists decrease alcohol consumption in operant conditioning models. Biochemical approaches point to a functional deficit of endogenous opioids in genetic models exhibiting high prevalence for alcohol intake. The therapeutic implications of these data are discussed.Key words: reward mechanisms, endogenouos opioid systems, psychostimulants, alcohol.
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Ikoma, Miho, Tatsuro Kohno, and Hiroshi Baba. "Differential Presynaptic Effects of Opioid Agonists on Aδ- and C-afferent Glutamatergic Transmission to the Spinal Dorsal Horn." Anesthesiology 107, no. 5 (November 1, 2007): 807–12. http://dx.doi.org/10.1097/01.anes.0000286985.80301.5e.
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Background Although intrathecal administration of opioids produces antinociceptive effects in the spinal cord, it has not been established whether intrathecal opioid application more effectively terminates C fiber-mediated pain than A fiber-mediated pain. Here, the authors focus on the differences in opioid actions on Adelta- and C-afferent responses. Methods Using the whole cell patch clamp technique, the authors investigated the presynaptic inhibitory actions of micro-, delta-, and kappa-opioid receptor agonists on primary afferent-evoked excitatory postsynaptic currents (EPSCs) in substantia gelatinosa neurons of adult rat spinal cord slices. Results The micro agonist DAMGO (0.1, 1 microM) reduced the amplitude of glutamatergic monosynaptic Adelta- or C fiber-evoked EPSCs. C fiber-evoked EPSCs were inhibited to a greater extent than Adelta fiber-evoked EPSCs. The delta agonist DPDPE (1, 10 microM) produced modest inhibition of Adelta- or C fiber-evoked EPSCs. In contrast, the kappa agonist U69593 (1 microM) did not affect the amplitude of either Adelta or C fiber-evoked EPSCs. Conclusions These results indicate that opioids suppress excitatory synaptic transmission mainly through activation of micro receptors on primary afferent C fibers. Given that the substantia gelatinosa is the main termination of Adelta and C fibers transmitting nociceptive information, the current findings may partially explain the different potency of opioid agonists.
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Grider, J. R., and G. M. Makhlouf. "Identification of opioid receptors on gastric muscle cells by selective receptor protection." American Journal of Physiology-Gastrointestinal and Liver Physiology 260, no. 1 (January 1, 1991): G103—G107. http://dx.doi.org/10.1152/ajpgi.1991.260.1.g103.
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Opioid receptors on isolated gastric smooth muscle cells were characterized pharmacologically by a technique in which synthetic selective opioid agonists and antagonists were used to protect and thus enrich a specific receptor type while all other receptors were inactivated by N-ethylamaleimide. Treatment of the cells with the selective mu-receptor agonist DAGO or antagonist CTAP preserved only the response to DAGO; treatment with the selective delta-receptor agonist DPDPE or antagonist naltrindole preserved only the response to DPPE; and treatment with the selective kappa-receptor agonist U50,488H or antagonist nor-binaltorphimine preserved only the response to U50,488H. The results established the presence of distinct kappa-, delta-, and mu-opioid receptors capable of mediating contraction of isolated gastric muscle cells. The pattern of interaction of endogenous opioid peptides with protected receptors implied that dynorphin-(1-13) and Met-enkephalin were selective agonists for kappa- and delta-opioid receptors, respectively, and Leu-enkephalin a preferential agonist of mu-opioid receptors. The results were confirmed by a reverse approach in which opioid receptors were inactivated by site-directed irreversible antagonists. beta-Funaltrexamine, a mu-selective antagonist, abolished the response to mu-receptor agonists, whereas beta-chlornaltrexamine, a mu- and kappa-selective antagonist, abolished the response to mu-receptor agonists and partially inhibited the response to kappa-receptor agonists.
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Hirayama, Shigeto, and Hideaki Fujii. "δ Opioid Receptor Inverse Agonists and their In Vivo Pharmacological Effects." Current Topics in Medicinal Chemistry 20, no. 31 (December 3, 2020): 2889–902. http://dx.doi.org/10.2174/1568026620666200402115654.
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The discovery of δ opioid receptor inverse agonist activity induced by ICI-174,864, which was previously reported as an δ opioid receptor antagonist, opened the door for the investigation of inverse agonism/constitutive activity of the receptors. Various peptidic or non-peptidic δ opioid receptor inverse agonists have since been developed. Compared with the reports dealing with in vitro inverse agonist activities of novel compounds or known compounds as antagonists, there have been almost no publications describing the in vivo pharmacological effects induced by a δ opioid receptor inverse agonist. After the observation of anorectic effects with the δ opioid receptor antagonism was discussed in the early 2000s, the short-term memory improving effects and antitussive effects have been very recently reported as possible pharmacological effects induced by a δ opioid receptor inverse agonist. In this review, we will survey the developed δ opioid receptor inverse agonists and summarize the possible in vivo pharmacological effects by δ opioid receptor inverse agonists. Moreover, we will discuss important issues involved in the investigation of the in vivo pharmacological effects produced by a δ opioid receptor inverse agonist.
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Claff, Tobias, Jing Yu, Véronique Blais, Nilkanth Patel, Charlotte Martin, Lijie Wu, Gye Won Han, et al. "Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists." Science Advances 5, no. 11 (November 2019): eaax9115. http://dx.doi.org/10.1126/sciadv.aax9115.
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Selective activation of the δ-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to μ-opioid receptor (MOP) agonists that are in the spotlight of the current “opioid crisis.” Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.
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Su, X., J. N. Sengupta, and G. F. Gebhart. "Effects of Kappa Opioid Receptor-Selective Agonists on Responses of Pelvic Nerve Afferents to Noxious Colorectal Distension." Journal of Neurophysiology 78, no. 2 (August 1, 1997): 1003–12. http://dx.doi.org/10.1152/jn.1997.78.2.1003.
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Su, X., J. N. Sengupta, and G. F. Gebhart. Effects of kappa opiois receptor-selective agonists on responses of pelvic nerve afferents to noxious colorectal distension. J. Neurophysiol. 78: 1003–1012, 1997. The aim of this study was to examine the effects of κ-opioid receptor selective agonists on responses of mechanosensitive afferent fibers in the pelvic nerve. Single-fiber recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root of the rat. A total of 572 afferent fibers in the S1 dorsal root were identified by electrical stimulation of the pelvic nerve; 252 (44%) responded to noxious colorectal distension (CRD; 80 mmHg). Of these 252 fibers that responded to CRD, 100 were studied further. All 100 fibers gave monotonic increases in firing to increasing pressures of CRD. Eighty-eight fibers had low thresholds for response (mean: 3 mmHg) and 12 fibers had high-thresholds for response (mean: 28 mmHg). Responses of 17 fibers also were tested after instillation of 5% mustard oil (MO) into the colon. The resting activity of 16/17 fibers significantly increased after MO instillation; 13 (77%) also exhibited sensitization of responses to graded CRD when tested 30 min after intracolonic MO instillation. The effects of κ1-opioid receptor preferring agonists (U50,488H, U69,593 and U62,066), the κ2-opioid receptor preferring agonist bremazocine, and the κ3-opioid receptor preferring agonist naloxone benzoylhydrazone (nalBzoH) were tested on responses of 64 mechanosensitive afferent fibers to noxious CRD. All five agonists dose-dependently inhibited afferent fiber responses to noxious CRD. Doses producing inhibition to 50% of the control response to CRD did not differ among the five agonists, ranging from ∼4 to 15 mg/kg. The effects of κ1, κ2, and κ3 receptor agonists were attenuated by naloxone; two κ-opioid receptor-selective antagonists were ineffective. There were no differences in the dose-response relationships of these drugs for fibers recorded from untreated and irritant-treated colons. Conduction velocities of the fibers remained unaffected after high doses of all tested agonists. In an in vitro study, U50,488 (10−4 M) did not produce any significant change in the tension of colonic smooth muscle. These results document that responses of mechanosensitive pelvic nerve afferent fibers innervating the colon are inhibited by κ-opioid receptor agonists having varying affinities for putative κ-opioid receptor subtypes. The inhibitory effects of these drugs likely are mediated by an action at receptors associated with the afferent fibers. The receptor at which these effects are produced is κ-opioid-like but clearly different from the κ-opioid receptor characterized in the CNS and is perhaps an orphan receptor.
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Kiguchi, Norikazu, Huiping Ding, Shiroh Kishioka, and Mei-Chuan Ko. "Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics." Current Topics in Medicinal Chemistry 20, no. 31 (December 3, 2020): 2878–88. http://dx.doi.org/10.2174/1568026620666200508082615.
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Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.
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Pham, Thao, Louis Carrega, Nicole Sauze, Odile Fund-Saunier, Christiane Devaux, Jean-Claude Peragut, Alain Saadjian, and Régis Guieu. "Supraspinal Antinociceptive Effects of μ and δ Agonists Involve Modulation of Adenosine Uptake." Anesthesiology 98, no. 2 (February 1, 2003): 459–64. http://dx.doi.org/10.1097/00000542-200302000-00027.
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Background The modulation of extracellular adenosine concentration by opioids provides evidence that the antinociceptive effects of these compounds involve endogenous adenosine. The aim of this study was to determine whether there is a relation between the inhibition of brain synaptosome adenosine uptake by opioid agonists and the analgesic effects of these compounds. Methods The authors used the hot plate and tail-pinch tests to evaluate in mice (C57BL/6 females; weight, 25-30 g) the effects of caffeine, a nonspecific adenosine receptor antagonist, on the antinociceptive effect induced by the intracerebroventricular administration of oxymorphone as a mu agonist, SNC80 as a delta agonist, or U69593 as a kappa agonist. They also investigated the effect of these opioid receptor agonists on the uptake of adenosine by whole brain synaptosomes. Results Caffeine decreased the analgesic effects induced by oxymorphone or SNC80 but not those induced by U69593. Oxymorphone and SNC80 inhibited adenosine uptake by brain cells, but U69593 did not. Conclusion The antinociceptive effects obtained with mu or delta (but not kappa) agonists administered supraspinally were indicative of the involvement of modulation of adenosine uptake.
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Sloan, MD, Paul, and Scott Hamann, PhD, MD. "Ultra-low-dose opioid antagonists to enhance opioid analgesia." Journal of Opioid Management 2, no. 5 (September 1, 2006): 295. http://dx.doi.org/10.5055/jom.2006.0044.
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This article will review decades of science contributing to current interest in opioid excitatory pharmacology. A long history of clinical confusion provided the stimulus for recent, detailed in vivo and in vitro investigations of the neuropharmacologic mechanisms involved in analgesic and hyperalgesic actions of opioid agonists and antagonists. Following the discovery of central nervous system opioid excitatory-hyperalgesic processes in animals, detailed neuronal cell culture experiments established opioid receptor/G protein/adenylate cyclase neurobiochemical mechanisms for bimodal inhibitory versus excitatory actions of opioids. Once this novel model was available to explain the cellular mechanisms responsible for the duality of opioid actions, clinical translation of this technology began to emerge, with a primary focus on selective antagonism of opioid excitatory actions with concomitant low-dose opioid antagonists. Encouraging results from recent animal and clinical studies will be discussed as further evidence that therapeutic pain management may be improved through enhancement of opioid agonist analgesia by cotreatment with ultra-low-dose opioid antagonists that selectively attenuate opioid-mediated hyperalgesia.
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Rech, Richard H., David J. Mokler, and Shannon L. Briggs. "Effects of Combined Opioids on Pain and Mood in Mammals." Pain Research and Treatment 2012 (March 21, 2012): 1–11. http://dx.doi.org/10.1155/2012/145965.
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The authors review the opioid literature for evidence of increased analgesia and reduced adverse side effects by combining mu-opioid-receptor (MOR) agonists, kappa-opioid-receptor (KOR) agonists, and nonselective low-dose-opioid antagonists (LD-Ant). We tested fentanyl (MOR agonist) and spiradoline (KOR agonist), singly and combined, against somatic and visceral pain models. Combined agonists induced additive analgesia in somatic pain and synergistic analgesia in visceral pain. Other investigators report similar effects and reduced tolerance and dependence with combined MOR agonist and KOR agonist. LD-Ant added to either a MOR agonist or KOR agonist markedly enhanced analgesia of either agonist. In accordance with other place-conditioning (PC) studies, our PC investigations showed fentanyl-induced place preference (CPP) and spiradoline-induced place aversion (CPA). We reduced fentanyl CPP with a low dose of spiradoline and reduced spiradoline CPA with a low dose of fentanyl. We propose combined MOR agonist, KOR agonist, and LD-Ant to produce superior analgesia with reduced adverse side effects, particularly for visceral pain.
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Sehgal, Nalini. "Peripherally Acting Opioids and Clinical Implications for Pain Control." Pain Physician 3;14, no. 3;5 (May 14, 2011): 249–58. http://dx.doi.org/10.36076/ppj.2011/14/249.
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Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues. Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides. Research has revealed that local application of exogenous opioid agonists produces a potent analgesic effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central nervous system (CNS), and therefore centrally mediated side effects, such as respiratory depression, mental clouding, altered consciousness, or addiction, are not associated with peripheral opioid activity. This discovery has stimulated research on developing peripherally restricted opioid agonists that lack CNS effects. In addition, it has been recognized that opioid receptors modulate inflammation, and that opioids have antiinflammatory effects. The anti-inflammatory actions of opioids are not well known or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid analgesia and describe current research directed at developing novel treatments for pain with improved side effect profiles. Key words: Opioids, opioid receptors, opioid agonists, peripheral nervous system, peripheral opioid receptors
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Vankova, Miriana E., Matthew B. Weinger, Dong-Yi Chen, J. Brian Bronson, Valerie Motis, and George F. Koob. "Role Central Mu, Delta-1, and Kappa-1 Opioid Receptors in Opioid-induced Muscle Rigidity in the Rat." Anesthesiology 85, no. 3 (September 1, 1996): 574–83. http://dx.doi.org/10.1097/00000542-199609000-00017.
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Background Opioids appear to produce their physiologic effects by binding to at least three types of opioid receptors, the mu (mu), delta (delta), and kappa (kappa) receptors. Muscle rigidity occurs after administration of supra-analgesic doses of potent mu-preferring agonists like alfentanil. The role of different supraspinal opioid receptors in this rigidity has been addressed only recently. To elucidate the contribution of central mu, delta, and kappa receptors to muscle rigidity, the effects of intracerebroventricularly administered opioid receptor-selective agonists and antagonists on alfentanil-induced muscle rigidity were examined in rats. Methods Rats in which chronic intracerebroventricular cannulae had been implanted received an intracerebroventricular infusion of either saline or a mu (D-Ala2,N-Me-Phe4-Gly5-olenkephalin; DAMGO), delta(1) (D-Pen2,D-Pen5-enkephalin; DPDPE), or kappa(1) (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)- cyclohexyl)-benzene-acetamide methane sulfonate; U50,488H) opioid agonist. Ten minutes later, they received either saline or the mu-agonist alfentanil subcutaneously. Muscle rigidity was assessed using hindlimb electromyographic activity. Different groups of animals were pretreated with an intracerebroventricular infusion of either saline or a mu (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2; CTAP), delta (naltrindole), or kappa(1) (norbinaltorphimine) opioid antagonist before administration of either saline or a selective intracerebroventricular agonist. Results The mu agonist DAMGO alone dose-dependently induced muscle rigidity. This effect was antagonized by pretreatment with the mu-selective antagonist CTAP. Neither DPDPE nor U50,488H, when administered alone, affected muscle tone. However, both the delta(1) and kappa(1) agonists dose-dependently attenuated alfentanil-induced rigidity. This antagonism of alfentanil rigidity was abolished after pretreatment with the delta (naltrindole) and kappa(1) (nor-binaltorphimine) antagonists, respectively. Conclusions The present data demonstrate that whereas systemic opiate-induced muscle rigidity is primarily due to the activation of central mu receptors, supraspinal delta(1) and kappa(1) receptors may attenuate this effect. This finding is consistent with previous demonstrations of functional interactions between different central opioid receptor populations in other opiate effects, and could have important pharmacotherapeutic implications.
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Sadee, Wolfgang, John Oberdick, and Zaijie Wang. "Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management." Molecules 25, no. 18 (September 11, 2020): 4163. http://dx.doi.org/10.3390/molecules25184163.
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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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Takeda, Shinhiro, Lars I. Eriksson, Yuji Yamamoto, Henning Joensen, Hiroshi Onimaru, and Sten G. E. Lindahl. "Opioid Action on Respiratory Neuron Activity of the Isolated Respiratory Network in Newborn Rats." Anesthesiology 95, no. 3 (September 1, 2001): 740–49. http://dx.doi.org/10.1097/00000542-200109000-00029.
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Background Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists. Methods Newborn rat brainstem-spinal cord preparations were used and superfused with mu-, kappa-, and delta-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory). Results Mu- and kappa-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of mu- and kappa-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by mu- and kappa-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses. Conclusions Mu- and kappa-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.
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Almeida, O. F. X., K. E. Nikolarakis, and A. Herz. "Neuropharmacological analysis of the control of LH secretion in gonadectomized male and female rats: altered hypothalamic responses to inhibitory neurotransmitters in long-term castrated rats." Journal of Endocrinology 119, no. 1 (October 1988): 15–21. http://dx.doi.org/10.1677/joe.0.1190015.
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ABSTRACT The control of LHRH and LH by neurotransmitters and neuromodulators such as the endogenous opioid peptides is essentially the same in intact adult male and female rats: adrenergic and dopaminergic agonists stimulate LH release and opioid agonists inhibit it. Several weeks after gonadectomy, however, the contribution of the endogenous ligands of adrenergic, dopaminergic and opioidergic receptors to the control of LHRH is altered. A detailed pharmacological analysis in long-term ovariectomized females confirmed previous reports that adrenergic and dopaminergic agonists still enhance secretion of LHRH and LH and opioid receptor agonists still suppress it. A similar investigation in long-term castrated males also confirmed previous reports that opioid agonists fail to block LH secretion. In addition, we have found that while adrenergic and dopaminergic agonists cause increases in serum concentrations of LH, adrenoreceptor and dopamine receptor antagonists do not inhibit LH release in long-term castrates. Furthermore, the opioid antagonist naloxone does not raise serum LH levels in either sex after long-term gonadectomy. These observations therefore imply reduced opioidergic, dopaminergic and adrenergic transmission, in relation to LHRH release, after longterm castration. In addition, opioid receptor activity (assessed by responsiveness to an opioid receptor agonist) of female rats is maintained, whereas that of male rats is lost, after long-term gonadectomy. J. Endocr. (1988) 119, 15–21
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Ju, Ji Youn, Kye-Min Kim, and Sangseok Lee. "Effect of preoperative administration of systemic alpha-2 agonists on postoperative pain: a systematic review and meta-analysis." Anesthesia and Pain Medicine 15, no. 2 (April 30, 2020): 157–66. http://dx.doi.org/10.17085/apm.2020.15.2.157.
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Background: Alpha-2 agonists have sedative, analgesic, and opioid-sparing effects. Moreover, intraoperative or postoperative systemic administration of alpha-2 adrenergic agonists is known to reduce postoperative pain and opioid consumption. This meta-analysis investigated whether preoperative administration of alpha-2 agonists can affect postoperative pain and opioid consumption.Methods: We searched the MEDLINE, EMBASE, Cochrane Library (CENTRAL), KoreaMed, and KMbase databases through March 2019 to identify relevant randomized controlled trials (RCTs) on the effect of preoperative systemic administration of alpha-2 agonists on postoperative pain and opioid consumption. We conducted a meta-analysis according to the Cochrane Collaboration guidelines. Standardized mean differences (SMDs) of postoperative pain intensity or dose of opioid consumption in the alpha-2 agonist group were extracted and combined using a random-effect model and were compared to those of the control group.Results: Eleven RCTs involving 748 participants were included in this meta-analysis. Preoperative administration of systemic alpha-2 agonists significantly reduced cumulative opioid consumption up to 6 h (SMD, –0.52; 95% confidence interval [–0.90 to –0.14]) and 24 h (SMD, –0.68 [–1.27 to –0.09]) after surgery. Moreover, preoperative administration of alpha-2 agonists significantly reduced postoperative pain intensity at 6 h (SMD, –0.50 [–0.78 to –0.21]) and 24 h (SMD, –0.44 [–0.86 to –0.03]).Conclusions: In this meta-analysis, high degree of heterogeneity limits the preoperative administration of alpha-2 agonists in reducing postoperative opioid consumption and pain intensity. Future powered large RCTs are required to increase the certainty of evidence on the effect in reducing postoperative opioid consumption and pain intensity.
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Chaturvedi, Kirti, Persis Bandari, Norihiro Chinen, and Richard D. Howells. "Proteasome Involvement in Agonist-induced Down-regulation of μ and δ Opioid Receptors." Journal of Biological Chemistry 276, no. 15 (January 10, 2001): 12345–55. http://dx.doi.org/10.1074/jbc.m008054200.
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This study investigated the mechanism of agonist-induced opioid receptor down-regulation. Incubation of HEK 293 cells expressing FLAG-tagged δ and μ receptors with agonists caused a time-dependent decrease in opioid receptor levels assayed by immunoblotting. Pulse-chase experiments using [35S]methionine metabolic labeling indicated that the turnover rate of δ receptors was accelerated 5-fold following agonist stimulation. Inactivation of functional Giand Goproteins by pertussis toxin-attenuated down-regulation of the μ opioid receptor, while down-regulation of the δ opioid receptor was unaffected. Pretreatment of cells with inhibitors of lysosomal proteases, calpain, and caspases had little effect on μ and δ opioid receptor down-regulation. In marked contrast, pretreatment with proteasome inhibitors attenuated agonist-induced μ and δ receptor down-regulation. In addition, incubation of cells with proteasome inhibitors in the absence of agonists increased steady-state μ and δ opioid receptor levels. Immunoprecipitation of μ and δ opioid receptors followed by immunoblotting with ubiquitin antibodies suggested that preincubation with proteasome inhibitors promoted accumulation of polyubiquitinated receptors. These data provide evidence that the ubiquitin/proteasome pathway plays a role in agonist-induced down-regulation and basal turnover of opioid receptors.
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Borkowski, Kazimierz R. "κ-Opioid agonist induced diuresis. Is it mediated by a blood-borne factor of adrenomedullary origin?" Canadian Journal of Physiology and Pharmacology 67, no. 10 (October 1, 1989): 1219–24. http://dx.doi.org/10.1139/y89-193.
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Intravenous administration of the κ-opioid agonists U50488H, tifluadom, and ethylketocyclazocine induced a characteristic diuresis in conscious, intact, saline-loaded rats. Naloxone pretreatment antagonized U50488H-induced diuresis. The diuretic response to the κ-opioid agonists was significantly attenuated in adrenal demedullated rats. However, basal urine output, the diuretic response to furosemide, and the antidiuretic response to the μ-opioid agonist buprenorphine were unaffected. Transfusion studies established that 1 mL of blood, from intact donor rats treated with U50488H, induced a diuretic response when administered to intact or demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50488H was unable to induce diuresis in intact or demedullated recipients. The results indicate that κ-opioid agonist induced diuresis appears to be mediated by a nonopioid blood-borne "diuretic factor" of adrenomedullary origin and that this factor might be responsible for the dependence of the diuretic response upon an intact and functional adrenal medulla in conscious rats.Key words: kappa-opioid agonists, diuresis, adrenal medulla, conscious rats.
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James, Arul, and John Williams. "Basic Opioid Pharmacology — An Update." British Journal of Pain 14, no. 2 (March 20, 2020): 115–21. http://dx.doi.org/10.1177/2049463720911986.
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Opioids are a group of analgesic agents commonly used in clinical practice. The three classical opioid receptors are MOP, DOP and KOP. The NOP (N/OFQ) receptor is considered to be a non-opioid branch of the opioid receptor family. Opioid receptors are G-protein-coupled receptors which cause cellular hyperpolarisation when bound to opioid agonists. Opioids may be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds. Opioid use disorder (OUD) is an emerging issue and important lessons can be learnt from the United States where opioid epidemic was declared as a national emergency in 2017.
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Srejic, Una, and Faried Banimahd. "Haunting of the phantom limb pain abolished by buprenorphine/naloxone." BMJ Case Reports 14, no. 2 (February 2021): e237009. http://dx.doi.org/10.1136/bcr-2020-237009.
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Neuropathic opioid refractory phantom limb pain (PLP) following amputation can be a life long debilitating chronic pain syndrome capable of completely destroying a patient’s life. The pain, its associated depression and sleep deprivation can make many patients suicidal. Ever changing and relentless, it is notoriously unresponsive to traditional cocktails of strong opioids, adjuvant pain medications, antidepressants, local anaesthetics, nerve stimulators, hypnotics and psychotropics. Drug effects are seldom more effective than placebo. We describe a successful sustained rescue of a difficult 2-year-long PLP case with sublingual buprenorphine/naloxone using the drug’s potent multimodal mechanisms of action: potent long-acting mu agonist/antagonist, kapa receptor antagonist, delta receptor antagonist and novel opioid receptor-like 1 (OR-L1) agonist effects. Traditional escalating pure mu-opioid receptor agonists and adjuvant neuropathic pain cocktails often have disappointing efficacy in the treatment of resistant PLP. We suggest introducing buprenorphine/naloxone as an early effective opioid choice in PLP management.
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Ferreira, Diana H., Jason W. Boland, Jane L. Phillips, Lawrence Lam, and David C. Currow. "The impact of therapeutic opioid agonists on driving-related psychomotor skills assessed by a driving simulator or an on-road driving task: A systematic review." Palliative Medicine 32, no. 4 (January 4, 2018): 786–803. http://dx.doi.org/10.1177/0269216317746583.
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Background: Driving cessation is associated with poor health-related outcomes. People with chronic diseases are often prescribed long-term opioid agonists that have the potential to impair driving. Studies evaluating the impact of opioids on driving-related psychomotor skills report contradictory results likely due to heterogeneous designs, assessment tools and study populations. A better understanding of the effects of regular therapeutic opioid agonists on driving can help to inform the balance between individual’s independence and community safety. Aim: To identify the literature assessing the impact of regular therapeutic opioid agonists on driving-related psychomotor skills for people with chronic pain or chronic breathlessness. Design: Systematic review reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis statement; PROSPERO Registration CRD42017055909. Data sources: Six electronic databases and grey literature were systematically searched up to January, 2017. Inclusion criteria were as follows: (1) empirical studies reporting data on driving simulation, on-the-road driving tasks or driving outcomes; (2) people with chronic pain or chronic breathlessness; and (3) taking regular therapeutic opioid agonists. Critical appraisal used the National Institutes of Health’s quality assessment tools. Results: From 3809 records screened, three studies matched the inclusion criteria. All reported data on people with chronic non-malignant pain. No significant impact of regular therapeutic opioid agonists on people’s driving-related psychomotor skills was reported. One study reported more intense pain significantly worsened driving performance. Conclusion: This systematic review does not identify impaired simulated driving performance when people take regular therapeutic opioid agonists for symptom control, although more prospective studies are needed.
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Gui, Chloe, and Sean Wong. "Biased mu-opioid receptor agonists confer analgesia with reduced side effects." University of Western Ontario Medical Journal 87, no. 1 (April 24, 2018): 62–64. http://dx.doi.org/10.5206/uwomj.v87i1.1910.
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Opioids are considered mainstay treatments for acute and terminal pain. In recent decades, however, overprescription and the increasing prevalence of illicit opioids has propelled North America into a state of “opioid crisis.” Along with the analgesic benefits, opioid use also commonly induces a number of side effects. Respiratory depression is an especially dangerous and potentially lethal example. The development of painkillers with improved safety profiles is thus a priority. Downstream to the mu-opioid receptor, which is responsible for the analgesic effects of opioids, β-arrestin-2 signaling has been suggested to be important for the manifestation of side effects, including respiratory depression. Two novel mu-opioid receptor agonists, TRV130 and PMZ21, have recently been reported to preferentially promote G protein-coupling over β-arrestin-2 signaling, thereby promoting analgesia with reduced side effects. TRV130 has been found in clinical trials to be more potent than morphine but safer in the setting of acute moderate-to-severe pain and is currently under New Drug Application review in the U.S. PMZ21 has shown promising and unique pain-relieving effects in mouse models, but further investigation is warranted to examine whether its therapeutic effects and safety profile are translatable to humans.
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Jones, MD, Mark R., Alan David Kaye, MD, PhD, Aaron J. Kaye, BA, and Richard D. Urman, MD, MBA. "The emerging therapeutic roles of κ-opioid agonists." Journal of Opioid Management 12, no. 2 (March 1, 2016): 101. http://dx.doi.org/10.5055/jom.2016.0321.
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The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the κ-opioid (KOP) receptor, have long been known to play a role in pain relief.Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established κ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.
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Helm II, Standiford. "Opioid Antagonists, Partial Agonists, and Agonists/Antagonists: The Role of OfficeBased Detoxification." Pain Physician 2;11, no. 3;2 (March 14, 2008): 225–35. http://dx.doi.org/10.36076/ppj.2008/11/225.
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Background: The opioid receptor antagonists naloxone and naltrexone are competitive antagonists at the mu, kappa, and sigma receptors with a higher affinity for the mu receptor and lacking any mu receptor efficacy. Buprenorphine is classified as a partial agonist. It has a high affinity, but low efficacy at the mu receptor where it yields a partial effect upon binding. It also, however, possesses kappa receptor antagonist activity making it useful not only as an analgesic, but also in opioid abuse deterrence, detoxification, and maintenance therapies. Naloxone is added to sublingual buprenorphine (Suboxone®) to prevent the intravenous abuse of buprenorphine. The same product (sublingual buprenorphine) when used alone (i.e. without naloxone) is marketed as Subutex®. Objective: To evaluate and update the available evidence regarding the use of agonist/antagonists to provide office-based opioid treatment for addiction. Methods: A review using databases of EMBASE and MEDLINE (1992 to December 2007). These included systematic reviews, narrative reviews, prospective and retrospective studies, as well as cross-references from other articles. Outcome Measures: The primary outcome measure was treatment retention. Other outcome measures included opioid-free urine drug testing, opioid craving, intensity of withdrawal, pain reduction, adverse effects, addiction severity index, and HIV risk behavior. Results: The results found 17 studies, 1 systematic review, 12 RCTs, and 4 observational series, which document the efficacy and safety of buprenorphine alone and in combination with naloxone in detoxifying and maintaining abstinence from illicit drugs in patients with opioid addiction. Conclusion: Based on the present evaluation, it appears that opioid antagonists, partial agonists, and antagonists are useful in office-based opioid treatment for addiction. Key words: Opioid, antagonist, partial agonist, tolerance, dependence, detoxification, withdrawal, hyperalgesia, buprenorphine, naloxone, naltrexone, methylnaltrexone, butorphanol, nalbuphine, pentazocine
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Mann, Anika, Lionel Moulédous, Carine Froment, Patrick R. O’Neill, Pooja Dasgupta, Thomas Günther, Gloria Brunori, et al. "Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists." Science Signaling 12, no. 574 (March 26, 2019): eaau8072. http://dx.doi.org/10.1126/scisignal.aau8072.
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Agonists of the nociceptin/orphanin FQ opioid peptide (NOP) receptor, a member of the opioid receptor family, are under active investigation as novel analgesics, but their modes of signaling are less well characterized than those of other members of the opioid receptor family. Therefore, we investigated whether different NOP receptor ligands showed differential signaling or functional selectivity at the NOP receptor. Using newly developed phosphosite-specific antibodies to the NOP receptor, we found that agonist-induced NOP receptor phosphorylation occurred primarily at four carboxyl-terminal serine (Ser) and threonine (Thr) residues, namely, Ser346, Ser351, Thr362, and Ser363, and proceeded with a temporal hierarchy, with Ser346 as the first site of phosphorylation. G protein–coupled receptor kinases 2 and 3 (GRK2/3) cooperated during agonist-induced phosphorylation, which, in turn, facilitated NOP receptor desensitization and internalization. A comparison of structurally distinct NOP receptor agonists revealed dissociation in functional efficacies between G protein–dependent signaling and receptor phosphorylation. Furthermore, in NOP-eGFP and NOP-eYFP mice, NOP receptor agonists induced multisite phosphorylation and internalization in a dose-dependent and agonist-selective manner that could be blocked by specific antagonists. Our study provides new tools to study ligand-activated NOP receptor signaling in vitro and in vivo. Differential agonist-selective NOP receptor phosphorylation by chemically diverse NOP receptor agonists suggests that differential signaling by NOP receptor agonists may play a role in NOP receptor ligand pharmacology.
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Kumar, V., M. J. Clark, J. R. Traynor, J. W. Lewis, and S. M. Husbands. "Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists." Bioorganic & Medicinal Chemistry 22, no. 15 (August 2014): 4067–72. http://dx.doi.org/10.1016/j.bmc.2014.05.065.
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Rosow, Carl E. "5 Newer opioid agonists." Baillière's Clinical Anaesthesiology 9, no. 1 (March 1995): 67–82. http://dx.doi.org/10.1016/s0950-3501(95)80053-0.
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Henthorn, Thomas K., and Susan K. Mikulich-Gilbertson. "μ-Opioid Receptor Agonists." Anesthesiology 128, no. 5 (May 1, 2018): 867–70. http://dx.doi.org/10.1097/aln.0000000000002177.
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Dmytriiev, D. V., O. A. Zaletska, and D. I. Bortnik. "Opioids in the treatment of non-specific acute and chronic pain." Pain medicine 4, no. 1 (April 29, 2019): 22–36. http://dx.doi.org/10.31636/pmjua.v4i1.3.
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After reading this article, the reader will be familiar with the general classes of opioid agonists and partial agonists, the basics of the pharmacokinetics and pharmacodynamics of opioids, the risks of opioid therapy and the requirements for the safe and effective use of opioids in acute and chronic pain. The use of opioids during surgical procedures or anesthesia is not discussed. Also, there is no discussion about various available opioid antagonists that are used to treat overdose and the various disorders associated with their use (including naloxone and naltrexone). Opioids are available, the most powerful and effective analgesics, and have become acceptable drugs for the treatment of acute and cancerous pain. However, there is concern about their use in case of chronic pain, if there is no cancer, because they are long-range ineffective but best suited for stopping this pain. Opioid prescription must be monitored for better use. Chronic pain creates discomfort for these patients, reducing their productivity and efficiency, which, in turn, can lead to economic problems in the country. The choice of Nalbuphine is due to the following reasons: the opioid, which is comparable to morphine by its analgesic potential, but has a better safety profile for nausea, vomiting and respiratory depression; not subject to strict quantitative accounting (extract on prescription form 1); the choice of opioid analgesics is significantly limited in Ukraine.
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Ozaki, Noriyuki, J. N. Sengupta, and G. F. Gebhart. "Differential Effects of μ-, δ-, and κ-Opioid Receptor Agonists on Mechanosensitive Gastric Vagal Afferent Fibers in the Rat." Journal of Neurophysiology 83, no. 4 (April 1, 2000): 2209–16. http://dx.doi.org/10.1152/jn.2000.83.4.2209.
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Single-fiber recordings were made from the decentralized right cervical vagus nerve (hyponodosal) of the rat. A total of 56 afferent fibers that responded to gastric distension (GD) were studied: 6 fibers were stimulated by phasic balloon GD, 50 by fluid GD. All fibers gave increasing responses to increasing pressures of GD (5–60 mmHg). The effects of μ-opioid (morphine), δ-opioid (SNC80), and κ-opioid (EMD61,753, U62,066) receptor agonists were tested on responses of afferent fibers to GD. Morphine, administered systemically over a broad dose range (10 μg to 31 mg/kg, cumulative), had no effect on either resting activity or responses of vagal afferent fibers to GD. Similarly, the δ-opioid receptor agonist SNC80 (0.05–3.2 mg/kg) did not affect resting activity or responses to GD. In contrast, cumulative intra-arterial doses of the κ-opioid receptor agonist EMD61,753 or U62,066 dose dependently attenuated afferent fiber responses to GD. Doses producing inhibition to 50% of the control response to GD of EMD61,753 (8.0 mg/kg) and U62,066 (8.8 mg/kg) did not differ. The effect of U62,066 was moderately attenuated by a nonselective dose (4 mg/kg) of naloxone hydrochloride; the κ-opioid receptor-selective antagonist nor-BNI (20 mg/kg) was ineffective. These results demonstrate that κ-, but not μ- or δ-opioid receptor agonists modulate visceral sensation conveyed by vagal afferent fibers innervating the stomach. Given that κ-opioid receptor agonists effects were only modestly antagonized by naloxone and not at all by nor-BNI, the results point to a novel site of action.
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Belvisi, M. G., C. D. Stretton, G. M. Verleden, S. J. Ledingham, M. H. Yacoub, and P. J. Barnes. "Inhibition of cholinergic neurotransmission in human airways by opioids." Journal of Applied Physiology 72, no. 3 (March 1, 1992): 1096–100. http://dx.doi.org/10.1152/jappl.1992.72.3.1096.
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Opioids reduce the cholinergic responses to electrical field stimulation (EFS) in guinea pig and canine airways by a prejunctional effect. We determined whether a similar effect operates in human airways in vitro. [D-Ala2-NMePhe4-Gly-ol5]enkephalin (DAMGO) (10(-8)-10(-6) M), a selective mu-opioid receptor agonist, inhibited the response to EFS in a dose- and frequency-dependent manner. DAMGO (10(-6) M) produced 86% inhibition at 0.5 Hz and 38% inhibition at 4 Hz, but at 32 Hz there was no significant inhibition. Another selective mu-opioid receptor agonist H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH2 diacetate (BW 443C) also inhibited responses to EFS, producing 57.7% inhibition at 4 Hz at a concentration of 10(-6) M. The inhibitory effect on EFS was blocked by the opioid receptor antagonist naloxone (10(-5) M), indicating that opioid receptors are involved. DAMGO (10(-6) M) had no effect on the contractile response to exogenous acetylcholine, indicating a prejunctional effect. We conclude that mu-opioid agonists inhibit cholinergic neurotransmission in human airways in vitro, and this could have therapeutic potential in the treatment of airway disease.
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ALLOUCHE, Stéphane, Jocelyne POLASTRON, Ahmed HASBI, Vincent HOMBURGER, and Philippe JAUZAC. "Differential G-protein activation by alkaloid and peptide opioid agonists in the human neuroblastoma cell line SK-N-BE." Biochemical Journal 342, no. 1 (August 10, 1999): 71–78. http://dx.doi.org/10.1042/bj3420071.
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Differences in the specificity of coupling of δ-opioid receptor with G-protein have been reported in the literature. We have observed a differential desensitization of δ-opioid receptors, endogenously expressed in the neuroblastoma cell line SK-N-BE, induced by peptide and alkaloid agonists. By combining photoaffinity labelling of receptor-activated G-proteins with [α-32P]azidoanilide-GTP and an anti-sense oligodeoxynucleotide strategy, we examined whether the chemical nature of opioid agonists, alkaloid or peptide, has a critical role in determining a Giα/Goα-protein-selective activation by the human δ-opioid receptors. Etorphine, a non-selective alkaloid agonist, was shown to stimulate the incorporation of [α-32P]azidoanilide-GTP into Giα1, Giα2, Giα3 and pertussis-toxin-insensitive Gα subunits. In contrast, [D-Pen2,D-Pen5]enkephalin (DPDPE; Pen is penicillamine) and Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I), selective peptide agonists, mainly activated Giα2 and Goα2 subunits. The ‘knock-down’ of Goα2 subunits by anti-sense oligodeoxynucleotides selectively decreased the inhibition of adenylate cyclase induced by DPDPE and deltorphin I, whereas anti-sense oligodeoxynucleotides directed against Giα2 subunits only decreased the potency of etorphine in inhibiting cAMP accumulation. These results suggest that the nature of the agonist, peptide or alkaloid is critical in determining the interaction between human δ-opioid receptors and Gα subunits.
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Faouzi, Abdelfattah, Balazs R. Varga, and Susruta Majumdar. "Biased Opioid Ligands." Molecules 25, no. 18 (September 16, 2020): 4257. http://dx.doi.org/10.3390/molecules25184257.
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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.
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KAY, B. "POTENCY RATIO BETWEEN OPIOID AGONISTS AND PARTIAL AGONISTS." British Journal of Anaesthesia 59, no. 6 (June 1987): 810. http://dx.doi.org/10.1093/bja/59.6.810.
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ROSEN, M., and I. KLEPPER. "POTENCY RATIO BETWEEN OPIOID AGONISTS AND PARTIAL AGONISTS." British Journal of Anaesthesia 59, no. 6 (June 1987): 810. http://dx.doi.org/10.1093/bja/59.6.810-a.
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Nagase, Hiroshi, and Akiyoshi Saitoh. "Research and development of κ opioid receptor agonists and δ opioid receptor agonists." Pharmacology & Therapeutics 205 (January 2020): 107427. http://dx.doi.org/10.1016/j.pharmthera.2019.107427.
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Chan ge Chien, George C. "Is Kratom the New ‘Legal High’ on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential." January 2018 1, no. 21;1 (January 14, 2017): E195—E198. http://dx.doi.org/10.36076/ppj.2017.1.e195.
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Kratom is an unscheduled herbal extract that contains alkaloids with opioid receptor agonist activity. It is currently available in the form of dietary supplements and is used and abused by chronic pain patients on prescription opioids. Active alkaloids isolated from Kratom such as mitragynine and 7-hydroxymitragynine are thought to act on mu and delta opioid receptors as well as alpha 2 adrenergic and 5-HT2A receptors. Animal studies suggest that Kratom may be more potent than morphine. Consequently, Kratom consumption produces analgesic and euphoric feelings among users. Some chronic pain patients on opioids take Kratom to counteract the effects of opioid withdrawal. Although the Food and Drug Administration has banned its use as a dietary supplement, Kratom continues to be widely available and easily accessible on the internet at much lower prices than other opioid replacement therapies like buprenorphine. There are no Federal regulations monitoring the sale and distribution of this substance. Consumption of Kratom has been associated with hallucination, delusion, depression, myalgia, chill, nausea/vomiting, respiratory depression, hepatotoxicity, seizure, coma and death. A search of the pain literature shows past research has not described the use and potential deleterious effects of this extract. Many pain physicians are not familiar with Kratom. As providers who take care of high-risk chronic pain patients using prescribed opioids, knowledge of all current substances with opioid receptor agonists with abuse potential is of paramount importance. The goal of this article is to introduce Kratom to pain specialists and identify issues for further studies that will be required to help better understand the clinical and long-term effects of Kratom use among chronic pain patients. Key words: Opioid receptor agonist, Kratom, Mitragynine, opioid overdose, chronic pain, substance abuse :
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Honey, Brooke L., Russell J. Benefield, Jamie L. Miller, and Peter N. Johnson. "α2-Receptor Agonists for Treatment and Prevention of Iatrogenic Opioid Abstinence Syndrome in Critically Ill Patients." Annals of Pharmacotherapy 43, no. 9 (August 18, 2009): 1506–11. http://dx.doi.org/10.1345/aph.1m161.
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Objective: To review the literature regarding the use of α2-agonists in the treatment and prevention of iatrogenic opioid abstinence syndrome (IOAS) in critically ill patients. Data Sources: Primary literature was identified through a search of MEDLINE (1950–June 2009), EMBASE (1988–June 2009), International Pharmaceutical Abstracts (1970–June 2009), and the Cochrane Library (1996–June 2009), using the names of individual α2-agonists and the following key words: children, opioid withdrawal, opioid, and adult. Relevant abstracts from the Society of Critical Care Medicine, reference citations from selected articles, and manufacturers’ product information were also reviewed. Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. Three retrospective studies and 6 case reports/series representing 44 patients were included for analysis. Data Synthesis: Central α2-agonists are thought to minimize symptoms of IOAS by decreasing presynaptic outflow of catecholamines. Successful use of clonidine and dexmedetomidine for management of IOAS has been reported. Lofexidine, an α2-agonist not yet approved in the US, may offer similar withdrawal symptom relief but has yet to be studied in the intensive care setting. Although the quality of studies identified was limited, preliminary evidence does provide some support for the use of transdermal clonidine and injectable dexmedetomidine in the treatment and prevention of IOAS. These agents were shown to facilitate discontinuation of opioids and to minimize withdrawal symptoms with few reported adverse events. Conclusions: Central α2-agonists appear to be effective and safe second-line agents for treatment and prevention of IOAS. Further studies should be conducted to determine their role in the therapy of patients with IOAS.
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Knapman, Alisa, Marina Santiago, Yan Ping Du, Philip R. Bennallack, Macdonald J. Christie, and Mark Connor. "A Continuous, Fluorescence-based Assay of µ-Opioid Receptor Activation in AtT-20 Cells." Journal of Biomolecular Screening 18, no. 3 (September 26, 2012): 269–76. http://dx.doi.org/10.1177/1087057112461376.
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Opioids are widely prescribed analgesics, but their use is limited due to development of tolerance and addiction, as well as high variability in individual response. The development of improved opioid analgesics requires high-throughput functional assays to assess large numbers of potential opioid ligands. In this study, we assessed the ability of a proprietary “no-wash” fluorescent membrane potential dye to act as a reporter of µ–opioid receptor (MOR) activation and desensitization via activation of G-protein-coupled inwardly rectifying potassium channels. AtT-20 cells stably expressing mouse MOR were assayed in 96-well plates using the Molecular Devices FLIPR membrane potential dye. Dye emission intensity decreased upon membrane hyperpolarization. Fluorescence decreased in a concentration-dependent manner upon application of a range of opioid ligands to the cells, with high-efficacy agonists producing a decrease of 35% to 40% in total fluorescence. The maximum effect of morphine faded in the continued presence of agonist, reflecting receptor desensitization. The effects of opioids were prevented by prior treatment with pertussis toxin and blocked by naloxone. We have demonstrated this assay to be an effective method for assessing ligand signaling at MOR, which may potentially be scaled up as an additional high-throughput screening technique for characterizing novel opioid ligands.
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Mansikka, Heikki, Chengshui Zhao, Rishi N. Sheth, Ichiro Sora, George Uhl, and Srinivasa N. Raja. "Nerve Injury Induces a Tonic Bilateral μ-Opioid Receptor–mediated Inhibitory Effect on Mechanical Allodynia in Mice." Anesthesiology 100, no. 4 (April 1, 2004): 912–21. http://dx.doi.org/10.1097/00000542-200404000-00022.
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Background Mice lacking the mu-opioid receptor gene have been used to characterize the role of mu-opioid receptors in nociception and the analgesic actions of opioid agonists. In this study, the authors determined the role of mu-opioid receptors in neuropathic pain behaviors and the effectiveness of mu- and kappa-opioid receptor agonists on this behavior in mice. Methods The authors studied the behavioral responses of mu-opioid receptor knockout and wild-type mice to thermal and mechanical stimuli before and after neuropathic pain induced by unilateral ligation and section of the L5 spinal nerve. Response to mechanical stimuli was evaluated by determining the frequency of hind paw withdrawal to repetitive stimulation using a series of von Frey monofilaments. Thermal hyperalgesia was assessed by determining the paw withdrawal latencies to radiant heat and frequency of hind paw withdrawal to cooling stimuli. The effects of systemic morphine, the kappa-opioid agonist U50488H, and naloxone on responses to mechanical and thermal stimuli were also studied in spinal nerve-injured mice. Results After spinal nerve injury, wild-type mice developed increased responsiveness to mechanical, heat, and cooling stimuli ipsilateral to nerve injury. mu-Opioid receptor knockout mice not only had more prominent mechanical allodynia in the nerve-injured paw, but also expressed contralateral allodynia to mechanical stimuli. Hyperalgesia to thermal stimuli was similar between mu-opioid knockout and wild-type animals. Morphine decreased mechanical allodynia dose dependently (3-30 mg/kg subcutaneous) in wild-type mice--an effect that was attenuated in the heterozygous mice and absent in the homozygous mu-opioid knockout mice. The kappa-opioid agonist U50488H (3-10 mg/kg subcutaneous) attenuated mechanical allodynia in wild-type, heterozygous, and homozygous mu-opioid mice. Naloxone in wild-type mice resulted in enhanced ipsilateral and contralateral allodynia to mechanical stimuli that resembled the pain behavior observed in mu-opioid receptor knockout mice. Conclusions The authors' observations indicate that (1) unilateral nerve injury induces a bilateral tonic activation of endogenous mu-opioid receptor-mediated inhibition that attenuates mechanical allodynia but not thermal hyperalgesia, (2) both mu- and kappa-opioid agonists attenuate neuropathic pain in mice, and (3) the antihyperalgesic actions of morphine are mediated primarily via mu-opioid receptors.
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Gach, Katarzyna, Mariola Piestrzeniewicz, Jakub Fichna, Barbara Stefanska, Janusz Szemraj, and Anna Janecka. "Opioid-induced regulation of µ-opioid receptor gene expression in the MCF-7 breast cancer cell line." Biochemistry and Cell Biology 86, no. 3 (April 2008): 217–26. http://dx.doi.org/10.1139/o08-001.
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The aim of the study was to investigate the presence of opioid receptor types in human breast adenocarcinoma MCF-7 cells and to characterize the changes in MOR expression induced by opioid agonist and antagonist treatment. We have shown that all three types of opioid receptors, but predominantly MOR, are expressed in MCF-7 cells. Selective MOR agonists, morphine, endomorphin-1, and endomorphin-2 downregulated MOR mRNA levels in a concentration- and time-dependent manner, but the effect produced by endomorphins was much stronger. Downregulation was blocked by the opioid antagonist naloxone. Naloxone alone produced a slight increase in MOR gene expression. Immunoblotting with antiserum against MOR-1 confirmed these results at the protein level. The results of our study indicate that, in MCF-7 cells, MOR gene expression is downregulated by opioid agonists and upregulated by opioid antagonists. We propose that the opioid-induced regulation of MOR mRNA expression is mediated by reduced binding of the transcription factors NFκB and AP-1 to the promoter region on the MOR gene.
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Lalley, Peter M. "D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289, no. 1 (July 2005): R45—R51. http://dx.doi.org/10.1152/ajpregu.00868.2004.
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Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D1 receptor (D1R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D1R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 ± 3.4 μg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO2), elevated end-tidal carbon dioxide (ETCO2), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 μg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D1R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO2 and ETCO2 to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 ± 4.3 μg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D1R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.