Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat pups become immobile and analgesic when exposed to an adult male rat. The aim of this study was to determine whether these reactions are under the control of endogenous opioids and to determine the role of the midbrain periaqueductal gray (PAG), which mediates stress-induced immobility and analgesia in adult animals. In Experiment 1, 14-day-old rats were injected systemically with the general opioid receptor antagonist naltrexone (1 mg/kg), which blocked male-induced analgesia to thermal stimulation but did not affect immobility. In Experiment 2, the selective mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 50 or 100 ng/200 nl) was microinjected into the ventrolateral and lateral PAG. CTOP suppressed male-induced analgesia when injected into the ventrolateral PAG. Male-induced immobility was not affected by CTOP. Male proximity therefore seems to induce analgesia in rat pups by releasing endogenous opioids that bind to mu opioid receptors in the ventrolateral PAG.
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PMID:Mu opioid receptors in the ventrolateral periaqueductal gray mediate stress-induced analgesia but not immobility in rat pups. 1071 68

We studied the acute tolerance liability of peripheral opioid analgesia in mice. The analgesia was assessed by the inhibition of bradykinin (BK)-induced nociceptive action by using a newly developed flexor reflex paradigm. Morphine [intraplantarly (i.pl.)] given ipsilaterally to BK showed a dose-dependent reduction of the BK (2 pmol) responses, whereas the administration of 10 nmol of morphine into the contralateral side failed to show any significant analgesic effects. Furthermore, DAMGO ([D-Ala(2),MePhe(4), Gly-ol(5)]-enkephalin), a mu-opioid receptor (MOR) agonist, and U-69593, a kappa-opioid receptor (KOR) agonist, but not DSLET ([D-Ser(2)]Leu-enkephalin-Thr(6)), a delta-opioid receptor agonist, showed similar analgesia on the BK responses. The morphine- or U-69593 [(5alpha,7alpha, 8beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec -8yl] benzeneacetamide]-induced analgesia was markedly attenuated by the intrathecal injection of each antisense oligodeoxynucleotide for the MOR or KOR, respectively, suggesting that these peripheral analgesia are mediated through MORs and KORs located on nociceptor endings, respectively. As BK response was completely recovered to the control level 4 h after morphine (3 nmol i.pl.) or U-69593 (10 nmol i.pl.) administration, these compounds were challenged again to see the inhibition of BK responses. Although morphine analgesia by the second challenge was markedly attenuated, U-69593 analgesia was not. The attenuated morphine analgesia was completely reversed by the pretreatment of calphostin C, Go6976, or HBDDE, a protein kinase C inhibitor, but not by KT-5720, a protein kinase A inhibitor. These results suggest that selective acute tolerance of peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs located on polymodal nociceptors, respectively, in the bradykinin-nociception test in mice was mediated through protein kinase C activation.
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PMID:Protein kinase C-mediated acute tolerance to peripheral mu-opioid analgesia in the bradykinin-nociception test in mice. 1077 42

This work was designed to examine whether brain endomorphins (EM1 and EM2), the endogenous mu-opioid ligands, are involved in electroacupuncture (EA)-induced analgesia in the mice. C57BL/6J mice were given EA for 30 min and the effect of EA-induced analgesia was assessed by radiant heat tail flick latency (TFL). Intracerebroventricular (i.c.v.) injection of mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Tyr-Orn-Thr-Pen-Thr-NH(2) (CTOP), or antiserum against EM1 or EM2 was performed to see whether EA analgesia could be blocked. The results showed that: (1) i.c.v. injection of CTOP at 25-100 ng dose-dependently antagonized the analgesia induced by EA of 2 Hz, but not 100 Hz. (2) Intracerebroventricular injection of EM1 antiserum (5 ml, 1:1 or 1:10 dilution) dose-dependently antagonized 2 Hz, but not 100 Hz EA analgesia. (3) EM2 antiserum showed similar effect at 1:1 dilution. The results are interpreted to mean that endogenously released EM1 and EM2 and the cerebral mu-receptors are involved in mediating 2 Hz but not 100 Hz EA analgesia in the mice.
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PMID:Endomorphin and mu-opioid receptors in mouse brain mediate the analgesic effect induced by 2 Hz but not 100 Hz electroacupuncture stimulation. 1107 39

Central effects of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr), a fragment from wheat gluten, were studied on the pain-inhibitory system, emotionality and learning/memory processes in mice. Orally administered gluten exorphin A5 produced neither an antinociceptive effect nor an effect on morphine analgesia. Intracerebroventricularly (i.c.v.) administered gluten exorphin A5 produced mild but significant antinociception in a dose-depepndent manner, while not affecting the morphine analgesia. On the other hand, oral gluten exorphin A5 suppressed the endogenous pain-inhibitory system, i.e., antinociception induced by socio-psychological- (PSY-) stress (SIA) using a communication box; intraperitoneal gluten exorphin A5 abolished both footshock- (FS-) stress-induced antinociception (SIA) and PSY-SIA; and i.c.v. gluten exorphin A5 suppressed FS-SIA, but rather potentiated PSY-SIA. This peptide given by these routes was without effect on forced swim-SIA. In addition, oral gluten exorphin A5 tended to prolong the retention time on open arms in the elevated plus-maze test. Finally, oral gluten exorphin A5 when given during the post-training period of learning/memory processes significantly increased the latency into the dark compartment in the one-trail step-though type passive avoidance test, indicating that the peptide also facilitates the acquire/consolidation process of learning/memory. Thus, gluten exorphin A5 has been found to produce various effects not only in the peripheral nervous systems but also in the central nervous system.
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PMID:Behavioral and pharmacological studies on gluten exorphin A5, a newly isolated bioactive food protein fragment, in mice. 1113 26

The synthesis of 18 N-alpha-FMOC-amino acid glycosides for solid-phase glycopeptide assembly is reported. The glycosides were synthesized either from the corresponding O'Donnell Schiff bases or from N-alpha-FMOC-amino protected serine or threonine and the appropriate glycosyl bromide using Hanessian's modification of the Koenigs-Knorr reaction. Reaction rates of D-glycosyl bromides (e.g., acetobromoglucose) with the L- and D-forms of serine and threonine are distinctly different and can be rationalized in terms of the steric interactions within the two types of diastereomeric transition states for the D/L and D/D reactant pairs. The N-alpha-FMOC-protected glycosides [monosaccharides Xyl, Glc, Gal, Man, GlcNAc, and GalNAc; disaccharides Gal-beta(1-4)-Glc (lactose), Glc-beta(1-4)-Glc (cellobiose), and Gal-alpha(1-6)-Glc (melibiose)] were incorporated into 22 enkephalin glycopeptide analogues. These peptide opiates bearing the pharmacophore H-Tyr-c[DCys-Gly-Phe-DCys]- were designed to probe the significance of the glycoside moiety and the carbohydrate-peptide linkage region in blood-brain barrier (BBB) transport, opiate receptor binding, and analgesia.
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PMID:Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin. 1128 73

Dynorphin A(1-17) given intrathecally releases spinal cholecystokinin to produce an antianalgesic action against spinal morphine in the tail-flick test in CD-1 mice. The present study showed that following the cholecystokinin step, a delta(2)-opioid inverse agonist action of Leu-enkephalin (LE), was involved. Pretreatment with intrathecal LE antiserum eliminated dynorphin and cholecystokinin-8s antianalgesia. A small dose of LE intrathecally produced antianalgesia that like that from dynorphin A(1-17) and cholecystokinin was eliminated by naltriben but not 7-benzylidenenaltrexone (delta(2)- and delta(1)-opioid receptor antagonist, respectively). This LE step was followed by N-methyl-D-aspartate (NMDA) receptor activation. MK801, an NMDA receptor antagonist, eliminated the antianalgesia from dynorphin A(1-17), cholecystokinin-8s, and LE. Furthermore, none of the three were effective against morphine analgesia in 129S6/SvEv mice possibly because of their deficiency in NMDA receptor response. In 129S6/SvEv mice, [D-Ser(2)]-Leu-enkephalin-Thr analgesia was not attenuated by LE; thus, this delta(2)-analgesic agonist and LE inverse agonist action did not occur through competition at the same delta(2)-receptor in CD-1 mice. In CD-1 mice, a linear sequence of dynorphin A(1-17) --> cholecystokinin --> LE --> NMDA receptors was indicated: cholecystokinin antiserum inhibited cholecystokinin but not LE; naltriben inhibited LE but not NMDA. The uniqueness of LE in linking dynorphin A(1-17), cholecystokinin, delta(2)-opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine.
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PMID:Inverse agonist action of Leu-enkephalin at delta(2)-opioid receptors mediates spinal antianalgesia. 1130 46

Neuropeptide pharmaceuticals have potential for the treatment of neurological disorders, but the blood-brain barrier (BBB) limits entry of peptides to the brain. Several strategies to improve brain delivery are currently under investigation, including glycosylation. In this study we investigated the effect of O-linked glycosylation on Ser(6) of a linear opioid peptide amide Tyr-D-Thr-Gly-Phe-Leu-Ser-NH(2) on metabolic stability, BBB transport, and analgesia. Peptide stability was studied in brain and serum from both rat and mouse by high-performance liquid chromatography. BBB transport properties were investigated by rat in situ perfusion. Tail-flick analgesia studies were performed on male ICR mice, injected i.v. with 100 microg of peptide ligand. Glycosylation of Ser(6) of the peptide led to a significant increase in enzymatic stability in both serum and brain. Glycosylation significantly increased the BBB permeability of the peptide from a value of 1.0 +/- 0.2 microl x min(-1) x g(-1) to 2.2 +/- 0.2 microl x min(-1) x g(-1) (p < 0.05), without significantly altering the initial volume of distribution. Analgesia studies showed that the glycosylated peptide gave a significantly improved analgesia after i.v. administration compared with nonglycosylated peptide. The improved analgesia profile shown by the glycosylated peptide is due in part to an improvement in bioavailability to the central nervous system. The bioavailability is increased by improving stability and transport into the brain.
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PMID:Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. 1171 84

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via a mu-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear. In this study, spinally applied BLF produced analgesia that was reversed by coadministration with a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester, during phases 1 and 2 in the formalin test. Spinal coadministration of a mu-opioid receptor agonist, morphine, with a subeffective dose of BLF produced a much more highly potentiated analgesia than that produced by morphine alone during phases 1 and 2 in the formalin test. This potentiated analgesia by morphine with BLF was reversed by a mu-opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2, or by NG-nitro-l-arginine methyl ester. In the tail-flick test, continuous spinal infusion of morphine via an osmotic minipump over 6 days resulted in development of tolerance by day 4, but no tolerance of BLF was observed throughout the experiment. These results suggest that BLF acts as an enhancer of the spinal opioidergic system via an NO-mediated mechanism.
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PMID:Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord. 1285 13

Four enkephalin analogues (Tyr-D-Thr-Gly-Phe-Leu-Ser-CONH(2), 1, and the related O-linked glycopeptides bearing the monosaccharide beta-glucose, 2, the disaccharide beta-maltose, 3, and the trisaccharide beta-maltotriose, 4) were synthesized, purified by HPLC, and biophysical studies were conducted to examine their interactions with membrane model systems. Glycopeptide 2 has been previously reported to penetrate the blood-brain barrier (BBB), and produce potent analgesia superior to morphine in mice (J. Med. Chem.2000, 43, 2586-90 and J. Pharm. Exp. Ther. 2001, 299, 967-972). The parent peptide and its three glycopeptide derivatives were studied in aqueous solution and in the presence of micelles using 2-D NMR, CD, and molecular mechanics (Monte Carlo studies). Consistent with previous conformational studies on cyclic opioid agonist glycopeptides, it was seen that glycosylation did not significantly perturb the peptide backbone in aqueous solution, but all four compounds strongly associated with 5-30 mM SDS or DPC micelles, and underwent profound membrane-induced conformational changes. Interaction was also observed with POPC:POPE:cholesterol lipid vesicles (LUV) in equilibrium dialysis experiments. Although the peptide backbones of 1-4 possessed random coil structures in water, in the presence of the lipid phase they each formed a nearly identical pair of structures, all with a stable beta-turn motif at the C-terminus. Use of spin labels (Mn(2+) and 5-DOXYL-stearic acid) allowed for the determination of the position and orientation of the compounds relative to the surface of the micelle.
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PMID:Glycopeptide-membrane interactions: glycosyl enkephalin analogues adopt turn conformations by NMR and CD in amphipathic media. 1273 23

The aim of the present study was to investigate the effect of a micro-opioid receptor agonist DAMGO (Tyr-d-Ala-Gly-NMe-Phe-Gly-ol) on the excitability of trigeminal root ganglion (TRG) neurons, projecting onto the superficial layer of the cervical dorsal horn, by using the perforated-patch technique and to determine whether TRG neurons show the expression of mRNA or functional protein for micro-opioid receptors by using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. TRG neurons projecting onto the superficial layer of the cervical dorsal horn were retrogradely labeled with Fluorogold (FG). The cell diameter of FG-labeled TRG neurons was small (<30 microm). Under voltage-clamp (V(h)=-60 mV), voltage-dependent K(+) currents were recorded in the TRG neurons and isolated by blocking Na(+) and Ca(2+) currents with appropriate ion replacement. Separation of the K(+) current components was achieved by the response to variation in the conditioning voltage. Two distinct K(+) current components, a transient (I(A)) and sustained (I(K)), were identified. DAMGO significantly increased I(A) by 57% (20 microM) and in a dose-dependent manner (1-50 microM). Similarly, I(K) was also enhanced by DAMGO administration (42%, 20 microM). The augmentation of both I(A) and I(K) was antagonized by a micro-opioid receptor antagonist, CTOP (d-Phe-Cys-Thr-d-Trp-Orn-Thr-Pen-Thr-NH(2)). Hyperpolarization of the membrane potential was elicited by DAMGO (20 microM) and the response was associated with a decrease in the input resistance. DAMGO induced hyperpolarization was blocked by CTOP. DAMGO-sensitive I(A) and I(K) currents were antagonized by K(+) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA). In the presence of both 4-AP and TEA, no significant changes in membrane potential induced by DAMGO application were observed. In the presence of BaCl(2), DAMGO evoked hyperpolarization with decreased resistance was observed. The firing rate of action potentials and the first spike duration induced by depolarizing step pulses were decreased in the presence of DAMGO. RT-PCR analysis demonstrated the expression of mRNA for micro-opioid receptors in the trigeminal ganglia. The micro-opioid receptor immunoreactivity was expressed in the small diameter FG-labeled TRG neurons. These results suggest that the activation of micro-opioid receptors inhibits the excitability of rat small diameter TRG neurons projecting on the superficial layer of the cervical dorsal horn and this inhibition is mediated by potentiation of voltage-dependent K(+) currents. We therefore concluded that modulation of nociceptive transmission in the trigeminal system, resulting in the functional activation of micro-opioid receptors, occurs at the level of small TRG cell bodies and/or their primary afferent terminals, which contribute to opioid analgesia in the trigeminal pain.
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PMID:Opioidergic modulation of excitability of rat trigeminal root ganglion neuron projections to the superficial layer of cervical dorsal horn. 1512 Aug 59


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