UMLS:C0344307 - FACTA Search

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of amlodipine, a selective L-type voltage dependent Ca(2+) channel (VDCC) blocker, and mibefradil, a selective T-type VDCC blocker on the antinociceptive effects of morphine, and mu, delta and kappa opioid receptor selective agonist-induced antinociception at the spinal level. Intrathecally administered amlodipine and mibefradil potentiated morphine and [D-Ala(2), N mePhe(4), Gly-ol(5)] enkephalin (DAMGO)-induced antinociception by shifting their dose response curves to the left. However, intrathecally administered amlodipine and mibefradil did not affect [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl] benzene acetamide (U-50, 488H)-induced antinociception. These data indicate that L-type and T-type VDCC blockers synergistically potentiate the analgesic effects of mu opioid receptor agonists, but not delta and kappa opioid receptor agonists, at the spinal level. Additionally, these data suggest that there is an important functional interaction between L-type and/ or T-type VDCC and mu opioid receptors in the process of analgesia.
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PMID:L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice. 1140 39

Opioids have been thought to induce analgesia by activating the descending pain control system, especially at the level of periaqueductal gray, and regulate the neurotransmitter release through the inhibition of calcium channel. In the present study, the modulatory effects of protein kinase C and protein kinase A on the mu-opioid agonist-induced inhibition of the high-voltage activated calcium current were examined in the acutely dissociated rat periaqueductal gray neurons with the nystatin-perforated patch-clamp technique. Among 505 neurons tested, the barium current passing through the high-voltage activated calcium channels of 172 neurons (34%) were inhibited by 32+/-3% with the application of an mu-opioid agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO, 1 microM). The barium currents itself and the DAMGO-induced inhibitory effects were not affected by the application of either an adenylate cyclase activator (forskolin, 1 microM) or a protein kinase inhibitor (staurosporin, 10 nM) for 2 min. The DAMGO inhibition was completely and irreversibly antagonized by the application of a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA, 1 microM) for 2 min without any alteration of the barium current itself. However, the antagonizing effect of PMA was completely abolished by the application of 10 nM staurosporin for 2 min. After then, PMA did not show the antagonizing effect any more. Inversely, when staurosporin was applied before PMA, the antagonizing effect of PMA was also not shown. These results demonstrate that the mu-opioid agonist-induced inhibition of the periaqueductal gray neuronal high-voltage activated calcium current can be antagonized by protein kinase C activation. This finding may provide us a significant clue to understand the action mechanism of opioid-induced analgesia in the periaqueductal gray.
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PMID:Antagonizing effect of protein kinase C activation on the mu-opioid agonist-induced inhibition of high voltage-activated calcium current in rat periaqueductal gray neuron. 1159 91

Ohmefentanyl is a very potent and highly selective agonist for mu-opioid receptors. We now study analgesia, in vitro activity and opioid receptor affinity of the stereoisomers of ohmefentanyl isothiocyanate. We found that some isomers of ohmefentanyl isothiocyanate had a potent analgesic effect and that all isomers except (3R,4S,2'S)-ohmefentanyl isothiocyanate had a more potent inhibitory action on the electrically evoked contractions of mouse vas deferens than of guinea pig ileum. The inhibitory actions could be antagonized by naloxone. However, compared with the activity of the corresponding stereoisomers of ohmefentanyl, these ohmefentanyl isothiocyanates had significantly reduced analgesia and in vitro activity. They also inhibited the binding of [3H]DPDPE ([D-Pen(2),D-Pen(5)]enkephalin) and [3H]DAGO ([D-Ala(2),Mephe(4),Gly-ol(5)]enkephalin) to opioid receptors in mouse brain membranes. The inhibitory effect of stereoisomers of ohmefentanyl isothiocyanate at mu-opioid receptors was markedly lower than that of their parent compounds. The affinity of stereoisomers of ohmefentanyl isothiocyanate for delta-opioid receptors was, however, greater than or equal to that of their corresponding stereoisomers of ohmefentanyl. The results showed that the introduction of an isothiocyanato group into the phenyl ring in position-1 of ohmefentanyl reduced bioactivity and affinity to mu-opioid receptors but that the selectivity of these compounds for delta-opioid receptors was enhanced. Isomer (3R,4S,2'R)-ohmefentanyl isothiocyanate showed highest selectivity for delta-opioid receptors (K(i)(mu)/K(i)(delta)=13.6) and potent analgesic activity (ED(50)=0.25 mg/kg).
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PMID:Analgesic activity and opioid receptor selectivity of stereoisomers of ohmefentanyl isothiocyanate. 1167 62

A novel member of the opioid related receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was identified and demonstrated to be involved in many physiological functions including pain regulation. [Nphe(1)]N/OFQ-(1-13)-NH(2) (Nphe) is a novel peptide antagonist of NOP receptors, developed using peripheral preparations. We have quantitatively investigated the interaction of Nphe with N/OFQ, the endogenous ligand of NOP receptors, in the midbrain ventrolateral periaqueductal gray (PAG), a crucial brain region for N/OFQ-induced reversal of opioid analgesia, using the patch-clamp recording technique in brain slices. N/OFQ concentration-dependently activated an inwardly rectifying K(+) current in response to hyperpolarization ramps from -60 to -140 mV. Nphe concentration-dependently attenuated the K(+) current activated by N/OFQ without changing its reversal potential. The presence of Nphe right-shifted the concentration-response curve to N/OFQ in a parallel manner. The Schild plot analysis yielded a slope of 1.16 and a pA(2) value of 6.64 that is similar to those obtained in peripheral preparations. At concentrations up to 3 microM, Nphe affected neither the membrane current per se, nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It is concluded that Nphe acts as a pure, selective and competitive antagonist at native NOP receptors of ventrolateral PAG neurons.
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PMID:[Nphe(1)]N/OFQ-(1-13)-NH(2) is a competitive and selective antagonist at nociceptin/orphanin FQ receptors mediating K(+) channel activation in rat periaqueductal gray slices. 1180 21

Opioid agonists produce analgesia in mammals through the activation of mu, kappa, or delta opioid receptors. Previous behavioral and binding studies from our laboratory using an amphibian model suggested that mu, kappa, or delta opioid agonists may activate a single type of opioid receptor in the grass frog, Rana pipiens. In the present study, kinetic, saturation, and competitive binding profiles for three opioid radioligands, [(3)H]DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin) (mu-selective), [(3)H]U65953 [(5 alpha, 7 alpha,8 beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide] (kappa-selective), and [(3)H]DPDPE ([D-Pen(2),D-Pen(5)]-enkephalin) (delta-selective) were determined using frog whole brain homogenates. Kinetic analyses and experimentally derived values from saturation experiments gave affinity constants (K(D)) in the low nanomolar range. The density of opioid binding sites (B(max)) was 224.4, 118.6, and 268.9 fmol/mg for mu, kappa, and delta opioid radioligands, respectively. The affinity values did not significantly differ among the three opioid radioligands, but the kappa radioligand bound to significantly fewer sites than did the mu or delta radioligands. K(i) values for unlabeled mu, kappa, and delta competitors, including highly selective opioid antagonists, were consistent with each radioligand selectivity profile. The present data suggest that mu, kappa, and delta opioid radioligands bind to distinct opioid receptors in amphibians that are surprisingly similar to those found in mammalian brain.
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PMID:Characterization of mu, kappa, and delta opioid binding in amphibian whole brain tissue homogenates. 1190 94

Intracellular recordings were made from neurones in laminae I and II of the dorsal horn of a longitudinal, parasagittal spinal cord slice from the neonatal rat. Their responses to peripheral nerve stimulation were first tested. Then the responses to bath application of [Sar(9),Met(O(2))(11)]-substance P and [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin, neurokinin 1 (NK(1)) and mu-opioid receptor agonists respectively, were studied. Finally, the structure of each neurone was investigated by injecting neurobiotin intracellularly following recording, and immunocytochemical studies were performed on post-fixed tissues to reveal whether they expressed the NK(1) receptor. Nine lamina I neurones where shown to express NK(1) receptor and these were depolarised by [Sar(9),Met(O(2))(11)]-substance P. These neurones typically received a powerful C-fibre input that was strongly inhibited, presynaptically, by the mu-opioid receptor agonist.The structure, afferent input, opioid sensitivity and intrinsic properties of these neurones are all consistent with the view that they are a major relay for nociceptive information leading to intense pain. The characteristics of 10 other neurones studied in which the NK(1) receptor was not found to be expressed at levels detectable by immunocytochemistry are briefly described for comparison. These results contribute to the emergent view that the large neurones in the most dorsal neuronal layer (lamina I) of the spinal cord, which express the principal receptor for substance P (NK(1)) over their entire soma and dendrites, are a major relay for information leading to intense pain. Inhibition of the relay of information by these neurones would be predicted to result in analgesia and hence, a detailed knowledge of their unique neurochemical characteristics is of paramount importance.
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PMID:Spinal lamina I neurones that express neurokinin 1 receptors: II. Electrophysiological characteristics, responses to primary afferent stimulation and effects of a selective mu-opioid receptor agonist. 1198 27

A novel opioid receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, has been identified to be involved in many physiological functions including pain regulation. CompB (also known as J-113397) is the first non-peptide antagonist of NOP receptors. Using the patch-clamp recording technique in brain slices, we have quantitatively studied the interactions of CompB with N/OFQ at native NOP receptors of ventrolateral neurons of the midbrain periaqueductal gray (PAG), a crucial region for N/OFQ-induced reversal of opioid analgesia. N/OFQ concentration-dependently activated inwardly rectifying K(+) channels in response to hyperpolarization ramps from -60 to -140 mV. CompB attenuated the magnitude but not the reversal potential of the K(+) current activated by N/OFQ in a concentration-dependent manner. The presence of CompB produced a parallel right-shift of the concentration-response curve to N/OFQ. The Schild plot analysis yielded a pA(2) value of 8.37. At concentrations up to 1 microM, CompB affected neither the membrane current per se nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It appears that CompB, at nanomolar concentrations, is a pure, selective and competitive antagonist of postsynaptic NOP receptors that mediate inwardly rectifying K(+) channel activation in ventrolateral PAG neurons.
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PMID:CompB (J-113397), selectively and competitively antagonizes nociceptin activation of inwardly rectifying K(+) channels in rat periaqueductal gray slices. 1206 9

Chronic opioid agonist treatment produces tolerance and in some cases opioid receptor internalization and down-regulation. Both morphine and etorphine induce tolerance; however, only etorphine produces mu-opioid receptor (muOR) down-regulation. In vitro studies implicate dynamin-2 (DYN-2) and G-protein receptor kinase-2 (GRK-2) in these processes. Therefore, we examined etorphine and morphine effects on regulation of GRK-2 and DYN-2 in mouse spinal cord. Mice were treated for 7 days with etorphine (200 microg/kg/day infusion) or morphine (40 mg/kg/day infusion + one 25-mg implant pellet). Controls were implanted with a placebo pellet. On the 7th day after implantation mice were tested for i.t. [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) analgesia. In other mice, spinal cord was removed for [(3)H]DAMGO binding studies or GRK-2 and DYN-2 protein and mRNA abundance were determined. Both etorphine and morphine produced significant tolerance (ED(50) shift = 7.6- and 7.3-fold for morphine and etorphine, respectively). Etorphine decreased spinal muOR density by approximately 30%, whereas morphine did not change muOR density. Etorphine increased ( approximately 70%) DYN-2 protein abundance and decreased its mRNA (31%), whereas it had no effect on GRK-2 protein and mRNA abundance. Morphine had no effect on either DYN-2 or GRK-2 protein or mRNA abundance. These data raise the possibility that unequal receptor regulation by etorphine and morphine might be due to differential regulation of trafficking proteins. Overall, receptor down-regulation associated with chronic etorphine treatment may accelerate dynamin-related activity. Finally, the decrease in DYN-2 mRNA may be related to stabilization of DYN-2 protein abundance, which might inhibit transcription.
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PMID:Opioid agonists differentially regulate mu-opioid receptors and trafficking proteins in vivo. 1243 15

A lanthionine enkephalin derivative, Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (DV(L)(2)DA(L)(5)LanEnk), where Val(L) and Ala(L) denote the lanthionine amino acid ends linked via a monosulfide bridge to form the lanthionine structure, was synthesized. It was found to possess selectivity for and potency at the delta versus mu opioid receptor as defined by binding studies and by its respective activity on the mouse vas deferens compared with the guinea pig ileum. The agent produced a potent analgesia after intrathecal and intraperitoneal delivery with ED(50) values being, respectively, 0.19 mucrog and 0.49 mg/kg. The effects of the agent were reversed by the delta-selective antagonist naltrindole. These analgesic actions occurred at doses that had no effect upon general behavior or motor function. These results suggest a potent delta-preferring agent suitable for development as a systemic delta opioid analgesic.
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PMID:Systemic and spinal analgesic activity of a delta-opioid-selective lanthionine enkephalin analog. 1253 39

The opioid receptor-like 1 receptor is a novel member of the opioid receptor family and its endogenous peptide ligand has been termed nociceptin and orphanin FQ. Activation of the opioid receptor-like 1 receptor by nociceptin/orphanin FQ in vivo produces hyperalgesia when this peptide is given supraspinally but analgesia at the spinal level. Nociceptin/orphanin FQ also reverses stress-induced analgesia, suggesting that the peptide has anti-opioid properties. Nociceptin/orphanin FQ knockout mice show alterations in pain sensitivity and stress responses and display increased morphine dependence, suggesting an interaction of the nociceptin/orphanin FQ system with classical opioid receptor function. To determine if the behavioural phenotype of nociceptin/orphanin FQ knockout mice reflects changes in either opioid receptor-like 1 or classical opioid receptor expression, we have carried out quantitative autoradiography of the opioid receptor-like 1, mu-, delta- and kappa-opioid receptors in the brains of these animals. Receptor density was measured on coronal sections from wild-type, heterozygous and homozygous mice using [(3)H]nociceptin, [(3)H][D-Ala(2)-N-methyl-Phe(4)-Gly(5) ol] enkephalin, [(3)H]deltorphin-I, or [(3)H](-)-N-methyl-N-[7-(1-pyrrodinyl)-1-oxospiro[4,5]dec-8-yl]-4-benzofuranacetamide to label opioid receptor-like 1, mu-, delta- and kappa-receptors, respectively. A region-specific up-regulation of the opioid receptor-like 1 receptor (up to 135%) was seen in brains from homozygous mice. Mu-Receptors also showed significant differences between genotypes whilst changes in delta- and kappa- receptors were minor. In conclusion the region-specific up-regulation of the opioid receptor-like 1 receptor indicates a tonic role for nociceptin/orphanin FQ in some brain structures and may suggest the peptide regulates the receptor expression in these regions. The changes in the opioid receptor-like 1 receptor may relate to the anxiogenic phenotype of these animals but the observed change in mu-receptors does not correlate with altered morphine responses.
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PMID:Nociceptin/orphanin FQ knockout mice display up-regulation of the opioid receptor-like 1 receptor and alterations in opioid receptor expression in the brain. 1260 2

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