Journal articles: 'Delta-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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Loriga, Giovanni, Paolo Lazzari, Ilaria Manca, Stefania Ruiu, Matteo Falzoi, Gabriele Murineddu, Mirko Emilio Heiner Bottazzi, Giovanni Pinna, and Gérard Aimè Pinna. "Novel diazabicycloalkane delta opioid agonists." Bioorganic & Medicinal Chemistry 23, no. 17 (September 2015): 5527–38. http://dx.doi.org/10.1016/j.bmc.2015.07.036.

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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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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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Negus, S. Stevens, Ember M. Morrissey, John E. Folk, and Kenner C. Rice. "Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys." Pain Research and Treatment 2012 (May 14, 2012): 1–8. http://dx.doi.org/10.1155/2012/867067.

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Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine). Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg). SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

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Zhang, L., Z. F. Gu, T. Pradhan, R. T. Jensen, and P. N. Maton. "Characterization of opioid receptors on smooth muscle cells from guinea pig stomach." American Journal of Physiology-Gastrointestinal and Liver Physiology 262, no. 3 (March 1, 1992): G461—G469. http://dx.doi.org/10.1152/ajpgi.1992.262.3.g461.

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On the basis of opioid-stimulated contraction of dispersed gastric smooth muscle cells it has been suggested that these cells possess opioid receptors of three subtypes: kappa (kappa), mu (mu), and delta (delta). We have used selective peptidase-resistant radioligands, agonists and antagonists, to examine receptor subtypes on dispersed gastric smooth muscle cells from guinea pigs prepared by collagenase digestion. The kappa-agonist U-50488H, the mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO), and the delta-agonist [D-Pen2,Pen5]enkephalin (DPDPE) each caused muscle contraction. The concentrations required to caused half-maximal contraction were U50488H (6 pM) greater than DAGO (13 pM) greater than DPDPE (6 nM). The abilities of these agonists to inhibit binding of [3H]U-69593 (kappa-preferring) by 50% were U50488H (43 nM) greater than DAGO (43 microM) greater than DPDPE (200 microM). Their abilities to inhibit binding of [3H]naloxone (mu-preferring) by 50% were DAGO (0.2 microM) greater than U50488H (10 microM) greater than DPDPE (greater than 100 microM). No binding could be detected with the delta-selective ligand [3H]DPDPE. The kappa-preferring antagonist Mr2266 (10 nM) preferentially inhibited contraction stimulated by the kappa-agonist U50488H, and naltrexone (10 nM) (mu-selective antagonist) preferentially inhibited contraction stimulated by the mu-agonist DAGO. ICI 174864 (200 microM; delta-selective antagonist) had no effect on contraction stimulated by mu-, kappa-, or delta-agonists. Contraction stimulated by the delta-agonist DPDPE was inhibited by both kappa- and mu-receptor antagonists. Studies on the effect of the antagonists on binding of [3H]naloxone and [3H]U69593 also provided evidence for kappa- and mu-sites but nor for delta-sites.(ABSTRACT TRUNCATED AT 250 WORDS)

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Schaeffer, J. I., and G. G. Haddad. "Regulation of ventilation and oxygen consumption by delta- and mu-opioid receptor agonists." Journal of Applied Physiology 59, no. 3 (September 1, 1985): 959–68. http://dx.doi.org/10.1152/jappl.1985.59.3.959.

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To study the effect of endorphins on metabolic rate and on the relationship between O2 consumption (VO2) and ventilation, we administered enkephalin analogues (relatively selective delta-receptor agonists) and a morphiceptin analogue (a highly selective mu-receptor agonist) intracisternally in nine unanesthetized chronically instrumented adult dogs. Both delta- and mu-agonists decreased VO2 by 40–60%. delta-Agonists induced a dose-dependent decrease in mean instantaneous minute ventilation (VT/TT) associated with periodic breathing. The decrease in VT/TT started and resolved prior to the decrease and returned to baseline of VO2, respectively. In contrast, the mu-agonists induced an increase in VT/TT associated with rapid shallow breathing. Arterial PCO2 increased and arterial PO2 decreased after both delta- and mu-agonists. Low doses of intracisternal naloxone (0.002–2.0 micrograms/kg) reversed the opioid effect on VT/TT but not on VO2; higher doses of naloxone (5–25 micrograms/kg) reversed both. Naloxone administered alone had no effect on VT/TT or VO2. These data suggest that 1) both delta- and mu-agonists induce alveolar hypoventilation despite a decrease in VO2, 2) this hypoventilation results from a decrease in VT/TT after delta-agonists but an increase in dead space ventilation after mu-agonists, and 3) endorphins do not modulate ventilation and metabolic rate tonically, but we speculate that they may do so in response to stressful stimulation.

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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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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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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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Harada, Y., K. Nishioka, L. M. Kitahata, K. Kishikawa, and J. G. Collins. "Visceral Antinociceptive Effects of Spinal Clonidine Combined with Morphine, [D-Pen sup 2, D-Pen sup 5] Enkephalin, or U50,488H." Anesthesiology 83, no. 2 (August 1, 1995): 344–52. http://dx.doi.org/10.1097/00000542-199508000-00015.

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Background Visceral pain is an important component of many clinical pain states. The perispinal administration of drug combinations rather than a single agent may reduce side effects while maximizing analgesic effectiveness. The purpose of this study was to examine the nature of interactions between an alpha 2-adrenergic agonist (clonidine) and a mu-opioid agonist (morphine), a delta-opioid agonist ([D-Pen2, D-Pen5] enkephalin [DPDPE]), or a kappa-opioid agonist (U50,488H). Methods Colorectal distension was used to elicit a nociceptive visceromotor response (contraction of abdominal musculature) in rats. The ability of intrathecally administered clonidine alone or in combination with morphine, DPDPE, or U50,488H to alter thresholds for the production of the visceromotor response was examined. Results Clonidine produced dose-dependent reduction in threshold. U50,488H, at the doses tested, showed no synergistic interaction with clonidine. Conclusions Spinal combinations of alpha 2-adrenergic and mu- or delta- but not kappa-opioid agonists may be beneficial in the control of visceral pain.

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Grudt, T. J., and J. T. Williams. "kappa-Opioid receptors also increase potassium conductance." Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11429–32. http://dx.doi.org/10.1073/pnas.90.23.11429.

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Decrease of calcium conductance induced by opioid agonists has been reported by others for mu-, delta-, and kappa-opioid receptors. On the other hand, only mu- and delta-opioid receptors have been reported to increase potassium conductance. Intracellular recordings were made from guinea pig substantia gelatinosa neurons in a brain slice. A subset of cells (29 of 83) were hyperpolarized by the kappa-opioid receptor agonist U69593 with an EC50 of 23 nM. The kappa-opioid receptor antagonist norbinaltorphimine (10 nM) blocked the hyperpolarization by U69593 but had no effect on the mu-opioid hyperpolarization present in these cells. Naloxone (300 nM) shifted the U69593 dose-response curve to the right, giving an estimated Kd for naloxone of 7.5 and 8.1 nM measured in two cells. The hyperpolarization caused by U69593 was mediated by a potassium conductance as determined with voltage clamp experiments. This demonstrates, depending on the cell type, that all three major opioid receptors (mu, delta, and kappa) can increase potassium conductance as well as decrease calcium conductance.

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Fujii, Hideaki, Kohei Hayashida, Akiyoshi Saitoh, Akinobu Yokoyama, Shigeto Hirayama, Takashi Iwai, Eriko Nakata, et al. "Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure." ACS Medicinal Chemistry Letters 5, no. 4 (January 30, 2014): 368–72. http://dx.doi.org/10.1021/ml400491k.

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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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Zappi, Lucia, Pingfong Song, Siriana Nicosia, Francesco Nicosia, and Kai Rehder. "Inhibition of Airway Constriction by Opioids Is Different down the Isolated Bovine Airway." Anesthesiology 86, no. 6 (June 1, 1997): 1334–41. http://dx.doi.org/10.1097/00000542-199706000-00015.

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Background Opioid agonists attenuate in isolated airways contractile responses to electrical field stimulation (EFS), and this attenuation is mediated by opioid receptors. Differences exist in the density of muscarinic and beta-adrenergic receptors between large and small airways. The authors hypothesized that the density of opioid receptors may also be different down the airway. Methods The effects of three selective opioid agonists (mu, kappa, delta) on EFS-induced contractions were compared between isolated bovine sublobar (4- or 5-mm inner diameter) and segmental (2- or 3-mm inner diameter) bronchial rings and between trachealis strips and bronchial rings. Results D-Ala2-N-MePhe4-Gly-ol5 enkephalin (DAMGO; 10(-5) M), a mu-opioid agonist, attenuated EFS-induced contractions of isolated sublobar and segmental bronchial rings at low stimulating frequencies of 0.5 Hz (P < 0.001), 2 Hz (P < 0.001), and 8 Hz (P < 0.001), but not at 32 Hz (P = 0.071). The inhibitory effect of DAMGO was antagonized by naloxone (10(-5) M) (P = 0.025). The selective kappa-opioid agonist U-50488 H (10(-5) m) attenuated EFS-induced contractions at 32 Hz (P = 0.008) and 8 Hz (P = 0.045), but not at 2-Hz (P = 0.893) or 0.5-Hz (P = 0.145) contractions. The inhibitory effects of 10(-5) M U-50488 H were not antagonized by the highly selective kappa-antagonist 2,2'-[1,1'-biphenyl] 4,4'-diyl-bis [2-hydroxy-4,4-dimethyl]-morpholinium (nor-BNI; 10(-5) M; P = 0.216) or naloxone (10[-5]) M; P = 0.065). The selective delta-agonist D-penicillamine2-D-penicillamine5-enkephalin (DPDPE) (10(-5) M) had no inhibitory effects (P = 0.256). The inhibitory effects of the selective mu-opioid agonist DAMGO were smaller (P < 0.001) and those of U-50488 H larger (P < 0.001) in trachealis strips compared with bronchial rings. Conclusions The attenuation of EFS-induced contractions by DAMGO in isolated bovine bronchi was mediated by prejunctional opioid receptors. In contrast, the inhibitory effect of U-50488 H was probably not mediated by opioid receptors in the bronchi.

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Hayashida, Kohei, Shigeto Hirayama, Takashi Iwai, Yoshikazu Watanabe, Toshihiro Takahashi, Junichi Sakai, Eriko Nakata, Tomio Yamakawa, Hideaki Fujii, and Hiroshi Nagase. "Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities." Bioorganic & Medicinal Chemistry Letters 27, no. 12 (June 2017): 2742–45. http://dx.doi.org/10.1016/j.bmcl.2017.04.059.

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Jutkiewicz, E. M. "The Antidepressant -like Effects of Delta-Opioid Receptor Agonists." Molecular Interventions 6, no. 3 (June 1, 2006): 162–69. http://dx.doi.org/10.1124/mi.6.3.7.

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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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Zhao, Min, and Daisy T. Joo. "Enhancement of Spinal N -Methyl-d-aspartate Receptor Function by Remifentanil Action at δ-Opioid Receptors as a Mechanism for Acute Opioid-induced Hyperalgesia or Tolerance." Anesthesiology 109, no. 2 (August 1, 2008): 308–17. http://dx.doi.org/10.1097/aln.0b013e31817f4c5d.

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Background Intraoperative remifentanil infusions have been associated with postoperative opioid-induced hyperalgesia and tolerance. Using a previously identified subpopulation of spinal neurons that displays an augmentation in N-methyl-D-aspartate (NMDA) receptor current after chronic morphine, investigations were undertaken to determine whether remifentanil induces acute increases in NMDA responses that are concentration dependent and receptor subtype dependent. Methods Electrophysiologic recordings of NMDA current were made from cultured rat dorsal horn neurons treated with remifentanil at various concentrations for 60 min. Selective mu- or delta-opioid receptor inhibitors and agonists were used to determine the site of action of remifentanil. Results Remifentanil at 4, 6, and 8 nM, but not higher or lower concentrations, caused significant mean increases in NMDA peak current amplitude of 37.30% (P < 0.001), 30.19% (P < 0.001), and 23.52% (P = 0.025), respectively, over control conditions. This occurred by 36 min of remifentanil perfusion and persisted throughout its washout. Inhibition by 100 nM naloxone or 1 nM naltrindole attenuated the remifentanil-induced NMDA response increase. Selective delta-opioid agonists [D-Pen(2), D-Pen(5)]enkephalin and deltorphin II displayed a similar bell-shaped concentration-response relation for the enhancement of NMDA responses, and 10 nM deltorphin II occluded the effects of 4 nM remifentanil on NMDA responses. Conclusions Clinically relevant concentrations of remifentanil induce rapid, persistent increases in NMDA responses that mirror the development of remifentanil-induced hyperalgesia and tolerance. NMDA enhancement by remifentanil is dependent on the activation of both mu- and delta-opioid receptors and is inducible solely by delta-opioid receptor activation. Therefore, selective delta-opioid inhibition may attenuate acute paradoxical increases in pain and tolerance to opioids.

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Ehrlich, George K., Matthew L. Andria, Xin Zheng, Brigitte Kieffer, Theresa L. Gioannini, Jacob M. Hiller, Jeremy E. Rosenkranz, Boris M. Veksler, R. Suzanne Zukin, and Eric J. Simon. "Functional significance of cysteine residues in the δ opioid receptor studied by site-directed mutagenesis." Canadian Journal of Physiology and Pharmacology 76, no. 3 (March 1, 1998): 269–77. http://dx.doi.org/10.1139/y98-018.

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Previous work suggested that sulfhydryl groups and disulfide bridges have important functions in opioid binding to the delta opioid receptor. The question regarding which cysteines are essential for ligand binding was approached by replacement of cysteine residues in the cloned delta opioid receptor using site-directed mutagenesis. The wild-type and mutant receptors were expressed stably in Chinese hamster ovary cells. The two extracellular cysteine residues and the six located in transmembrane domains were mutated to serine or alanine, one at a time. Replacement of either of the extracellular cysteines produced a receptor devoid of delta agonist and antagonist binding activity. Immunofluorescence cytochemistry, performed with anti delta opioid receptor antibodies in washed cell monolayers in one of these mutants (Cys-Ser121), and immunoblots, performed on cell extracts, indicate that the receptor was expressed and seems to be associated with the cell membrane. The existence of an essential extracellular disulfide bridge, previously postulated by analogy to other G protein coupled receptors, is strongly supported by our results. Replacement of any one of the six transmembrane cysteines was virtually without effect on the ability of the receptor to bind delta agonists and antagonists. Since there is strong evidence that the transmembrane domains are involved in ligand binding, these results suggest that the cysteine residues, even those near or at the binding site, are not essential for receptor binding. Furthermore, these results support the idea that the striking effects of sulfhydryl reagents on ligand binding of opioid receptors are likely to be due to steric hindrance by the large moieties transferred to the sulfhydryl groups of cysteine residues by these reagents.Key words: opioid receptor, cysteine, sulfhydryl, site-directed mutagenesis.

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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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Reinoso-Barbero, Francisco, and Isabel de Andres. "Effects of Opioid Microinjections in the Nucleus of the Solitary Tract on the Sleep-Wakefulness Cycle States in Cats." Anesthesiology 82, no. 1 (January 1, 1995): 144–52. http://dx.doi.org/10.1097/00000542-199501000-00019.

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Background Previous studies have shown that the region of the nucleus of the solitary tract (NST) is involved in the control of electrocortical activity and in sleep mechanisms. It also is well known that this region contains the highest concentration of opioid receptors within the medullary brainstem. The involvement of the NST opioid system in sleep-wakefulness states were evaluated. Methods Ten cats were implanted with electrodes for chronic polygraphic recordings of their sleep-wakefulness states and provided with an implanted guide cannula stereotaxically aimed at the NST region. Microinjections of saline, morphine sulfate, morphiceptin (specific mu agonist), D-pen-2-D-pen-5-enkephalin (delta agonist), and U-50488H (kappa agonist) were given to the freely moving animals (doses 0.8-2.4 x 10(-9) M, in a volume of 0.05 microliters of saline). After microinjections, sleep-wakefulness recordings were obtained for 8 h. Results Morphine microinjections in NST provoked a dose-dependent enhancement of all the polygraphic and behavioral manifestations of slow wave sleep. This effect was blocked by the prior intraperitoneal administration of naloxone. The mu and delta agonists also produced a hypnotic effect by enhancing slow wave sleep. By contrast, the kappa agonist caused no changes in sleep-wakefulness states. Conclusions These results indicate that endogenous opioids could be involved in controlling electrocortical activity generated by NST and that activation of mu and delta NST opioid receptors enhanced the electroencephalographic synchronization associated with behavioral slow wave sleep in cats.

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Qian, Xinhua, Katalin E. Koever, Mark D. Shenderovich, Bih-Show Lou, Aleksandra Misicka, Teresa Zalewska, Robert Horvath, Peg Davis, and E. J. Bilsky. "Newly discovered stereochemical requirements in the side-chain conformation of .delta. opioid agonists for recognizing opioid .delta. receptors." Journal of Medicinal Chemistry 37, no. 12 (June 1994): 1746–57. http://dx.doi.org/10.1021/jm00038a004.

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CADONI, C., L. SPINA, R. LONGONI, and A. MULAS. "BEHAVIOURAL AND BIOCHEMICAL EFFECTS OF NON-PEPTIDE DELTA OPIOID AGONISTS." Behavioural Pharmacology 7, Supplement 1 (May 1996): 12. http://dx.doi.org/10.1097/00008877-199605001-00026.

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Peppin, J. F., and R. B. Raffa. "Delta opioid agonists: a concise update on potential therapeutic applications." Journal of Clinical Pharmacy and Therapeutics 40, no. 2 (March 2, 2015): 155–66. http://dx.doi.org/10.1111/jcpt.12244.

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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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Cheng, P. Y., D. Wu, Y. Soong, S. McCabe, J. A. Decena, and H. H. Szeto. "Role of mu 1- and delta-opioid receptors in modulation of fetal EEG and respiratory activity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 265, no. 2 (August 1, 1993): R433—R438. http://dx.doi.org/10.1152/ajpregu.1993.265.2.r433.

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Recent evidence suggests that administration of low doses of morphine causes respiratory stimulation, along with a more active electroencephalogram (EEG) in the fetal lamb. The present study used selective opioid agonists and antagonists to determine the role mu 1- and delta-opioid receptor subtypes play in the response as well as determine if endogenous opioid peptides exert a tonic influence at the mu 1- and delta-opioid receptors to maintain normal EEG and respiratory activity under control, physiological conditions. Both morphine (2.5 mg/h iv) and [D-Pen2,D-Pen5]enkephalin (DPDPE) (46 nmol/h icv) resulted in a significant activation of fetal EEG, which was blocked by naloxonazine (NALZ, mu 1-opioid antagonist) and naltrindole (NTI, delta-opioid antagonist), respectively. Administration of NALZ alone, but not NTI, resulted in a slowing of the EEG. Morphine and [D-Ala2]deltorphin I (0.36 nmol/h icv) significantly increased breath number and were blocked by NALZ and NTI respectively. Both NALZ and NTI alone resulted in a reduction in breath number. These results suggest that the activation of the delta- or mu 1-opioid receptors will stimulate fetal respiratory and EEG activity. Furthermore, the endogenous opioids play a tonic role at both the delta- and mu 1-opioid receptors in the regulation of respiratory timing and EEG activity.

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Portoghese, P. S., S. T. Moe, and A. E. Takemori. "A selective .delta.1 opioid receptor agonist derived from oxymorphone. Evidence for separate recognition sites for .delta.1 opioid receptor agonists and antagonists." Journal of Medicinal Chemistry 36, no. 17 (August 1993): 2572–74. http://dx.doi.org/10.1021/jm00069a017.

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Corazziari, Enrico. "Role of Opioid Ligands in the Irritable Bowel Syndrome." Canadian Journal of Gastroenterology 13, suppl a (1999): 71A—75A. http://dx.doi.org/10.1155/1999/598659.

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Endogenous opioid peptides – enkephalins, beta-endorphin and dynorphins – are located in specific sites of the brain, the spinal cord, the autonomic ganglia and the enteric nervous system. Endogenous opioids participate in the regulation of nervous visceral afference and sensitivity as well as of several visceral motor function induced by the central nervous system and through the enteroenteric and the myoenteric reflexes. Their final effect on gut physiology is the net and harmonically balanced result of their binding to mu, delta and kappa opioid receptor subtypes. Exogenous opioid receptor ligands with different affinities for the opioid receptor subtypes have been effectively used to modify and normalize altered gut functions. Themureceptor agonists – morphine and, to a greater extent, the meperidine congeners diphenoxylate and loperamide – have been shown to slow gastrointestinal transit by their effects on the circular and longitudinal muscle of the intestine. Diphenoxylate and, more efficiently, loperamide, for the lack of any effect on the central nervous system, have been usefully employed in the treatment of diarrhea in irritable bowel syndrome (IBS) patients. Unlike the mu receptor agonists morphine and loperamide, which invariably stimulate colonic motility, trimebutine, which has almost equal affinity for mu, delta and kappa receptors, has no effect on normal colonic activity but reduces the abnormal increase in postprandial motor activity in IBS patients and accelerates slow large bowel transit in constipated patients. Opioid ligands can be usefully employed to normalize altered visceral sensitivity in IBS patients. The kappa receptor agonist fedotozine exerts its antinociceptive effect by acting on peripheral nerve endings of sensory vagal and nonvagal afferent pathways. Fedotozine has been shown to increase the threshold of perception to colonic distension in experimental conditions and to affect favourably symptoms of IBS in clinical trials.

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McIntosh, C. H., X. Jia, and Y. N. Kowk. "Characterization of the opioid receptor type mediating inhibition of rat gastric somatostatin secretion." American Journal of Physiology-Gastrointestinal and Liver Physiology 259, no. 6 (December 1, 1990): G922—G927. http://dx.doi.org/10.1152/ajpgi.1990.259.6.g922.

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The opioid peptides are potent inhibitors of gastric somatostatin-like immunoreactivity (SLI) secretion from the isolated perfused rat stomach. In addition, inhibition of SLI secretion induced by vagal stimulation is partially blocked by naloxone, indicating that endogenously released opioid peptides probably play a physiological role in the regulation of SLI release. The opioid peptides exert their effects by interacting with a number of different receptor types. In the present study, the effect of the selective delta-opioid receptor agonists [D-Pen2.5]enkephalin and [D-Pen2,L-Pen5]enkephalin and the mu-receptor agonist [D-Ala2, N-methyl (NMe)-Phe4,Gly5-ol]enkephalin on gastric inhibitory polypeptide (GIP)-stimulated SLI secretion from the isolated perfused rat stomach have been studied. Responses to the less selective delta-agonist [D-Ala2,D-Leu5]enkephalin, dynorphins 1-8, 1-13, and 1-17, and the extended enkephalin forms Met-enkephalin-Arg6-Phe7,Met- enkephalin-Arg6-Gly7-Leu8, and Met-enkephalin-Arg6-Arg7-Val8-NH2 (metorphamide), have also been investigated. [D-Ala2,NMe-Phe4,Gly5-ol]enkephalin induced a concentration-dependent inhibition of GIP-stimulated SLI secretion, with 50% of maximal inhibition at 10 nM. Neither [D-Pen2.5]enkephalin nor [D-Pen2,L-Pen6]enkephalin (10 nM to 1 microM) had any effect on SLI release, and [D-Ala2,D-Leu5] enkephalin inhibited SLI release only at high concentrations. Met-enkephalin-Arg6-Phe7 and metorphamide both inhibited SLI release, whereas Met-enkephalin-Arg6-Gly7-Leu8 and the dynorphins had little or no effect. In conclusion, the strong inhibition of SLI secretion produced by [D-Ala2,NMe-Phe4,Gly5-ol] enkephalin and lack of major effect of [D-Pen2.5]-enkephalin, [D-Pen2,L-Pen5]enkephalin, and the dynorphins indicate that opioid peptide-induced inhibition was mediated by interaction with mu-receptors and that neither delta or kappa-receptors play a significant role.

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Saitoh, Akiyoshi, and Mitsuhiko Yamada. "Antidepressant-like Effects of δ Opioid Receptor Agonists in Animal Models." Current Neuropharmacology 10, no. 3 (September 1, 2012): 231–38. http://dx.doi.org/10.2174/157015912803217314.

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Pradhan, Amynah A. A., Jérôme A. J. Becker, Grégory Scherrer, Petra Tryoen-Toth, Dominique Filliol, Audrey Matifas, Dominique Massotte, Claire Gavériaux-Ruff, and Brigitte L. Kieffer. "In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists." PLoS ONE 4, no. 5 (May 1, 2009): e5425. http://dx.doi.org/10.1371/journal.pone.0005425.

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Berthiaume, Sophie, Khaled Abdallah, Véronique Blais, and Louis Gendron. "Alleviating pain with delta opioid receptor agonists: evidence from experimental models." Journal of Neural Transmission 127, no. 4 (March 18, 2020): 661–72. http://dx.doi.org/10.1007/s00702-020-02172-4.

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Goicoechea, C., M. J. Alfaro, M. J. Ormazábal, and M. I. Martín. "Salmon calcitonin potenciates analgesia induced by delta and kappa opioid agonists." Pharmacological Research 31 (January 1995): 118. http://dx.doi.org/10.1016/1043-6618(95)86730-9.

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Peng, Youyi, Qiang Zhang, Sonia Arora, Susan M. Keenan, Sandhya Kortagere, Kenneth M. Wannemacher, Richard D. Howells, and William J. Welsh. "Novel delta opioid receptor agonists exhibit differential stimulation of signaling pathways." Bioorganic & Medicinal Chemistry 17, no. 17 (September 1, 2009): 6442–50. http://dx.doi.org/10.1016/j.bmc.2009.07.007.

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Ford, Christopher P., Michael J. Beckstead, and John T. Williams. "Kappa Opioid Inhibition of Somatodendritic Dopamine Inhibitory Postsynaptic Currents." Journal of Neurophysiology 97, no. 1 (January 2007): 883–91. http://dx.doi.org/10.1152/jn.00963.2006.

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In the midbrain, dopamine neurons can release dopamine somatodendritically. This results in an inhibitory postsynaptic current (IPSC) within adjacent dopamine cells that occurs by the activation of inhibitory D2 autoreceptors. Kappa, but not mu/delta, opioid receptors inhibit this IPSC. The aim of the present study was to determine the mechanism by which κ-opioid receptors inhibit the dopamine IPSC. In both the ventral tegmental area (VTA) and substantia nigra compacta (SNc) the κ-receptor agonist U69593 inhibited the IPSC, but not the current induced by the exogenous iontophoretic application of dopamine. The endogenous peptide dynorphin A (1–13) also inhibited IPSCs in the VTA and SNc, but also the dopamine iontophoretic current in the VTA. Although both kappa agonists induced a postsynaptic outward current in the VTA, the current induced by dynorphin was dramatically larger. This suggests that the decrease in iontophoretic dopamine current was the result of occlusion. Occlusion alone, however, could not completely account for suppression of the IPSC. The kappa opioid inhibition of the IPSC was not affected by global increases or decreases in dopamine cell activity within the slice. These findings suggest that, although kappa opioid receptors can hyperpolarize dopamine neurons, they also suppress dopamine release by direct actions at the release site. The results thus demonstrate both pre- and postsynaptic actions of kappa receptor agonists. The actions of dynorphin indicate that VTA dopamine cells are selectively regulated by kappa receptors.

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Ostermeier, Andreas M., Beate Schlösser, Dirk Schwender, and Bernd Sutor. "Activation of μ- and δ-Opioid Receptors Causes Presynaptic Inhibition of Glutamatergic Excitation in Neocortical Neurons." Anesthesiology 93, no. 4 (October 1, 2000): 1053–63. http://dx.doi.org/10.1097/00000542-200010000-00029.

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Background The mechanism underlying the depressant effect of opioids on neuronal activity within the neocortex is still not clear. Three modes of action have been suggested: (1) inhibition by activation of postsynaptic potassium channels, (2) interaction with postsynaptic glutamate receptors, and (3) presynaptic inhibition of glutamate release. To address this issue, the authors investigated the effects of mu- and delta-receptor agonists on excitatory postsynaptic currents (EPSCs) and on membrane properties of neocortical neurons. Methods Intracellular recordings were performed in rat brain slices. Stimulus-evoked EPSCs mediated by different glutamate receptor subtypes were pharmacologically isolated, and opioids were applied by addition to the bathing medium. Possible postsynaptic interactions between glutamate and opioid receptors were investigated using microiontophoretic application of glutamate on neurons functionally isolated from presynaptic input. Results delta-Receptor activation by d-Ala2-d-Leu5-enkephalin (DADLE) reduced the amplitudes of EPSCs by maximum 60% in a naltrindole-reversible manner (EC50: 6-15 nm). In 30-40% of the neurons investigated, higher concentrations (0.1-1 micrometer) of DADLE activated small outward currents. The mu-receptor selective agonist d-Ala2-N-MePhe5-Gly5-ol-enkephalin (0.1-1 micrometer) depressed the amplitudes of EPSCs by maximum 30% without changes in postsynaptic membrane properties. In the absence of synaptic transmission, inward currents induced by microiontophoretic application of glutamate were not affected by DADLE. Conclusions Activation of mu- and delta-opioid receptors depresses glutamatergic excitatory transmission evoked in neocortical neurons by presynaptic inhibition. A weak activation of a postsynaptic potassium conductance becomes evident only at high agonist concentrations. There is no evidence for a postsynaptic interaction between glutamate and opioid receptors.

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GAO, Wei-Min, Yan LI, Shu-Wei ZHANG, and Ling YANG. "Structural Feature Studies on Spiropiperidine Analogues as Agonists of Delta Opioid Receptors." Acta Agronomica Sinica 40, no. 7 (2013): 668. http://dx.doi.org/10.3724/sp.j.1206.2012.00537.

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Moye, Laura S., Alycia F. Tipton, Isaac Dripps, Zoie Sheets, Aimee Crombie, Jonathan D. Violin, and Amynah A. Pradhan. "Delta opioid receptor agonists are effective for multiple types of headache disorders." Neuropharmacology 148 (April 2019): 77–86. http://dx.doi.org/10.1016/j.neuropharm.2018.12.017.

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Hirayama, Shigeto, Eika Higashi, Jun Nikaido, Toru Nemoto, Hiroko Ikeda, Junzo Kamei, and Hideaki Fujii. "Development of Novel Delta Opioid Receptor Inverse Agonists and Their Antitussive Effects." Proceedings for Annual Meeting of The Japanese Pharmacological Society WCP2018 (2018): PO4–1–1. http://dx.doi.org/10.1254/jpssuppl.wcp2018.0_po4-1-1.

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Nagase, Hiroshi, Hisanori Wakita, Koji Kawai, Takashi Endoh, Hirotoshi Matsuura, Chiko Tanaka, and Yuko Takezawa. "Syntheses of Non-Peptidic Delta Opioid Agonists and Their Structure Activity Relationships." Japanese Journal of Pharmacology 64 (1994): 35. http://dx.doi.org/10.1016/s0021-5198(19)49890-9.

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Nagase, Hiroshi, Yumiko Osa, Toru Nemoto, Hideaki Fujii, Masayuki Imai, Takashi Nakamura, Toshiyuki Kanemasa, Akira Kato, Hiroaki Gouda, and Shuichi Hirono. "Design and synthesis of novel delta opioid receptor agonists and their pharmacologies." Bioorganic & Medicinal Chemistry Letters 19, no. 10 (May 2009): 2792–95. http://dx.doi.org/10.1016/j.bmcl.2009.03.099.

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van Rijn, Richard M., Daniela I. Brissett, and Jennifer L. Whistler. "Distinctive modulation of ethanol place preference by delta opioid receptor-selective agonists." Drug and Alcohol Dependence 122, no. 1-2 (April 2012): 156–59. http://dx.doi.org/10.1016/j.drugalcdep.2011.09.024.

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Nagasaka, Hiroshi, Hamdy Awad, and Tony L. Yaksh. "Peripheral and Spinal Actions of Opioids in the Blockade of the Autonomic Response Evoked by Compression of the Inflamed Knee Joint." Anesthesiology 85, no. 4 (October 1, 1996): 808–16. http://dx.doi.org/10.1097/00000542-199610000-00016.

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Background Three types of opioid receptors, mu, delta, and kappa, are present in the periphery and in the central nervous system. In contrast to the effects in the central nervous system, the antinociceptive action of opioids in the periphery is not as well characterized. The effects of intraarticular, spinal, and intramuscular injections of mu, delta, and kappa opioid agonists on the autonomic response evoked by compression of an inflamed knee joint were evaluated. Methods In halothane-anesthetized rats, arthritis was induced by injecting kaolin and carrageenan into the right knee joint. Standardized compression of the knee joint by inflation of a pediatric blood pressure cuff to 200 mmHg for 2 min produced a reliable stimulus-dependent hypertension (delta = 13 mmHg). Drugs were delivered intramuscularly, intrathecally through a chronic catheter, or intraarticularly into the right knee joint. The drug injection was performed 4 hr after induction of the inflammation. Results The intrathecal administration of mu, delta, and kappa agonists resulted in a dose-dependent blockade of the cuff-evoked increase in blood pressure. The order of intrathecal drug activity on the compression-evoked blood pressure responses with median effective dose (ED50) was sufentanil (0.02 nmol; mu) > PD117302 (0.5 nmol; kappa); spiradoline (1.5 nmol; kappa) morphine (2.4 nmol; mu) > DADL (15 nmol; delta); DPDPE (18 nmol; delta) > U-50,488H (620 nmol; kappa) > naloxone = 0. The intraarticular administration of mu and kappa, but not delta agonists, produced a dose-dependent blockade of a compression-evoked increase in blood pressure, with the order of drug activity (ED40) as follows: sufentanil (0.04 mumol) > PD117302 (0.3 mumol); spiradoline (0.8 mumol), morphine (0.9 mumol) > U-50,488H (0.9 mumol) > DPDPE (> 5 mumol); DADL (> 18 mumol) > naloxone = 0. Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED50) as follows: sufentanil (0.2 mumol) > PD117302 (2 mumol); spiradoline (11 mumol) morphine (9 mumol) > DPDPE (> 5 mumol); DADL (18 mumol) > U-50,488H (22 mumol) > naloxone = 0. All intraarticular effects were reversible by injecting naloxone intramuscularly, with the ordering of naloxone potency against equiactive doses of morphine > U50,488H. Conclusions The activity of the respective agonists and the intraarticular > intramuscular ordering of systemic potency in this model indicate that opioids, by an action at mu and kappa, can exert a direct antihyperalgesic action at the terminals of primary afferents projecting to a region of inflammation. These observations offer strong support for a peripheral action of opioids in certain states in inflammation-induced hyperalgesia.

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Xiao, R. P., S. Pepe, H. A. Spurgeon, M. C. Capogrossi, and E. G. Lakatta. "Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells." American Journal of Physiology-Heart and Circulatory Physiology 272, no. 2 (February 1, 1997): H797—H805. http://dx.doi.org/10.1152/ajpheart.1997.272.2.h797.

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Opioid peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (LE), a naturally occurring delta-opioid peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2+ transient, and contraction. The antiadrenergic effect of LE was pertussis toxin sensitive and abolished by naloxone, an opioid receptor antagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5'-cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.

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Jimenez-Vargas, Nestor N., Jing Gong, Matthew J. Wisdom, Dane D. Jensen, Rocco Latorre, Alan Hegron, Shavonne Teng, et al. "Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain." Proceedings of the National Academy of Sciences 117, no. 26 (June 16, 2020): 15281–92. http://dx.doi.org/10.1073/pnas.2000500117.

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Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gαi/oand β-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.

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Poole, Sarah L., Jim Deuchars, David I. Lewis, and Susan A. Deuchars. "Subdivision-Specific Responses of Neurons in the Nucleus of the Tractus Solitarius to Activation of Mu-Opioid Receptors in the Rat." Journal of Neurophysiology 98, no. 5 (November 2007): 3060–71. http://dx.doi.org/10.1152/jn.00755.2007.

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Abstract:

Microinjection of opioid receptor agonists into the nucleus tractus solitarius (NTS) has differential effects on cardiovascular, respiratory, and gastrointestinal responses. This can be achieved either by presynaptic modulation of inputs onto neurons or by postsynaptic activation of receptors on neurons in specific regions. Therefore we sought to determine whether responses of neurons to activation of opioid receptors were dependent on their location within the NTS. Using whole cell patch-clamp recordings from neurons within the NTS, the mu opioid receptor (MOR) agonist [d-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO, 100 nM) hyperpolarized a proportion of neurons in the medial, dorsomedial and dorsolateral NTS, whereas no postsynaptic responses were observed in remaining subdivisions. DAMGO reduced the amplitude of solitary tract-evoked excitatory postsynaptic potentials (EPSPs) in all neurons tested, regardless of subdivision. The kappa opioid receptor (KOR) agonist U69593 (10–20 μM) also hyperpolarized a small fraction of neurons (6/79) and decreased the amplitude of EPSPs in 50% of neurons. In contrast, the delta-opioid receptor agonist DPDPE (1–4 μM) had no presynaptic or postsynaptic effects on NTS neurons even after preincubation with bradykinin. Anatomical data at the light and electron microscopic level complemented electrophysiological observations with respect to MOR location and further showed that MORs were present at both presynaptic and postsynaptic sites in the dorsolateral NTS, often at the same synapse. These data demonstrate site specific responses of neurons to activation of MORs and KORs, which may underlie their ability to modulate different autonomic reflexes.

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WALLACE, D., S. DODSON, A. NATH, and R. BOOZE. "Delta opioid agonists attenuate TAT-induced oxidative stress in SK-N-SH cells." NeuroToxicology 27, no. 1 (January 2006): 101–7. http://dx.doi.org/10.1016/j.neuro.2005.07.008.

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Nagesi, Hiroshi, Hisanori Wakita, Koji Kawai, Akira Mizusuna, Takashi Endoh, Hirotoshi Matsuura, Chiko Tajima, et al. "Drug design of highly selective non-peptide opioid delta agonists, and their pharmacology." Japanese Journal of Pharmacology 71 (1996): 9. http://dx.doi.org/10.1016/s0021-5198(19)36299-7.

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Beaudry, H., A. Proteau-Gagné, Shuang Li, Y. Dory, C. Chavkin, and L. Gendron. "Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents." Neuroscience 161, no. 2 (June 2009): 381–91. http://dx.doi.org/10.1016/j.neuroscience.2009.03.053.

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Journal articles on the topic 'Delta-opioid agonists'

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