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)

Peptide hormones and neurotransmitters play crucial roles in the maintenance of physiological function at both the cellular and organ level. Although peptide neuropharmaceuticals have enormous potential in the treatment of disease states, the blood-brain barrier (BBB) generally prevents the entry of peptides into the brain either by enzyme degradation or by specific properties of the BBB. Peptides that act at opioid receptors are currently being designed for analgesia and to reduce the unwanted side effects associated with morphine, such as addiction and inhibition of gastric motility. It has been the focus of our group to produce stabile peptide analogues of Met-enkephalin, that lead to analgesia without side effects. In this paper we present the methodologies that have been used to elucidate the transport mechanisms of three peptides across the BBB. Using a primary endothelial cell culture model of the BBB, in situ perfusion, and kinetic analysis we show that D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) crosses the BBB via diffusion, [D-penicillamine2,5]enkephalin uses a combination of diffusion and a saturable transport mechanism, and biphalin ([Tyr-D-Ala-Gly-Phe-NH]2) uses diffusion and the large neutral amino acid carrier. Understanding BBB transport mechanisms for peptides will aid in the rational design of peptides targeted to the brain.
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PMID:Transport of opioid peptides into the central nervous system. 981 2

Neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) is able to modulate opioid analgesia. Intracerebroventricular treatment for 5 days with antisense-oligodeoxynucleotides complementary to the sequence of human SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) precursor gene or by mismatch-oligodeoxynucleotides did not change the antinociceptive activity of morphine in the mouse tail flick test. In contrast, antisense- but not mismatch-oligodeoxynucleotides attenuated significantly the tolerance to the analgesic activity of morphine and the withdrawal syndrome precipitated by naloxone in morphine-treated mice. These treatments with oligodeoxynucleotides did not modify neuropeptide FF-immunoreactivity content in whole brain but repeated injections of an agonist of neuropeptide FF receptors increased the intensity of morphine tolerance. These results demonstrate the important role of neuropeptide FF in opioid pharmacodependence.
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PMID:Antisense oligonucleotides to human SQA-neuropeptide FF decrease morphine tolerance and dependence in mice. 982 85

The purpose of this prospective cohort study was to compare metabolic effects of epidural or patient controlled analgesia (PCA) in patients undergoing major upper abdominal surgery. Seventeen patients undergoing major upper abdominal surgery were included: 10 received perioperative epidural analgesia (Group I) and the remainder received morphine via a PCA device for postoperative analgesia (Group II). A number of measures compared between one day preoperatively (day 1) and day 2 postoperatively included femoral arterial and venous blood concentrations of glucose, lactate, pyruvate and amino acids. In addition, the relevant flux values were measured from the products of the respective arteriovenous substrate concentration differences and calf blood flow. The efflux of lactate from peripheral tissues was greater in Group II than in Group I (P < 0.01): glucose and pyruvate efflux did not differ between groups. There was no difference between groups in mean individual and total flux of amino acids on day-1. However increased efflux between day-1 and day 2 was found for alanine, valine, isoleucine, leucine, phenylalanine, lysine, arginine in both groups, and for serine, glycine, tyrosine and histidine in Group II (P < 0.05). The efflux of glycine, methionine, amino benzoic acid, alanine, and lysine was less in Group I than Group II on day 2 (P < 0.05). There was a significant difference in the total amino acid flux on day 2 (Group I = -1.2 mumol. (100 ml tissue)-1.min-1 cf Group II = -2.5 mumol. (100 ml tissue)-1.min-1; P = 0.04). In conclusion, perioperative epidural analgesia was associated with a reduced postoperative amino acid efflux two days following major upper abdominal surgery.
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PMID:Epidural analgesia reduces the release of amino acids from peripheral tissues in the ebb phase of the metabolic response to major upper abdominal surgery. 1005 Feb 19

Systemic administration of sumatriptan and buspirone (20 mg/kg: 5-HT1A agonists) produced antinociception against acetic acid-induced writhing. The antinociceptive effect was potentiated by cholinomimetic physostigmine (0.05 mg/kg i.p.) and blocked by the muscarinic antagonist atropine (5 mg/kg i.p.). Naloxone, an opiate antagonist, failed to reverse the sumatriptan- or buspirone-induced antinociception, but pindolol (10 mg/kg), a nonselective 5-HT1A antagonist, blocked this response. Sumatriptan- or buspirone-induced antinociception was significantly potentiated by L-NAME (a nitric oxide [NO] synthase inhibitor) although L-NAME (20 mg/kg) given alone had no effect on the nociceptive threshold. Recent studies have suggested that the L-arginine/NO/cGMP pathway is involved in the modulation of pain perception. The present results suggest that NO may play a role in cholinergic antinociception-mediated 5-HT1A receptor stimulation and that NO exerts an inhibitory action on cholinergic analgesia.
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PMID:L-NAME, a nitric oxide synthase inhibitor, modulates cholinergic antinociception. 1038 17

Primary cultures of cerebral neurons of Sprague-Dawley rats increased cyclic GMP production in response to the stimulation of excitatory amino acids, including N-methyl-D-aspartate, quisqualate, kainate and (+/-)-1-aminocylopentane-trans-1,3-dicarboxylic acid. This increased cyclic GMP production was significantly inhibited by halothane or isoflurane at clinically relevant concentrations (0.5-2%). This inhibition was reversible by treatment with L-arginine, the substrate of nitric oxide synthase. However, the increase of cyclic GMP production stimulated by sodium nitroprusside, an activator of soluble guanylate cyclase, was not inhibited by halothane or isoflurane. Neither halothane nor isoflurane affected the basal cyclic GMP production. Activation of the excitatory amino acid neurotransmitter-stimulated nitric oxide-guanylate cyclase signaling pathway increases intracellular cyclic GMP content in neurons. Our results suggest that halothane or isoflurane inhibited this signaling pathway stimulated by selective agonists of each subtype of receptors for excitatory amino acid neurotransmitters. This inhibition may be involved in mechanisms of anesthesia and analgesia. The site(s) of the inhibition is (are) proximal to the activation of neuronal nitric oxide synthase.
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PMID:Inhibition of excitatory neurotransmitter-nitric oxide signaling pathway by inhalational anesthetics. 1047 81

The attenuation of opioid analgaesia is a well established effect of extremely low frequency (ELF) magnetic fields with light having a modulatory role in these effects such that when the ELF exposures are carried out in the dark, the inhibitory effects on analgesia are reduced. Here, we considered the light dependency of the effects of exposure to an ELF magnetic field prior to the induction of opioid analgesia. Brief exposure to a 60 Hz field potentiated in a light dependent manner the inhibitory effects of the nitric oxide (NO) precursor L-arginine on the level of subsequent opioid-induced analgesia in the land snail Cepaea nemoralis. This suggests a general light dependency of the actions of magnetic fields and the involvement of NO in the mediation of the effects of magnetic fields.
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PMID:Light-dependent effects of magnetic fields on nitric oxide activation in the land snail. 1050 22

The periaqueductal gray matter (PAG) is an important center in the modulation of behavioral responses during nociception and stress. In the present experiment, extracellular excitatory amino acid overflow in the PAG was measured every 30 s during noxious stimulation. A combination of in vivo brain microdialysis in freely moving rats and capillary zone electrophoresis with laser induced-fluorescence detection allowed us to detect short lasting changes of excitatory amino acid in dialysates. A formalin injection in the hindpaw of the rat increased glutamate, arginine and aspartate concentration in PAG dialysates. This increase was calcium and nerve impulse-dependent, suggesting neuronal and glial origin of glutamate and arginine, respectively. Handling, pinching or saline injection in the hind paw did not increase glutamate showing that this neurochemical phenomenon is related to painful and persistent noxious stimulation. The results suggest that a rapid excitation of the PAG occurs during noxious stimulation. The role of glutamate and arginine in analgesia is discussed.
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PMID:Noxious stimulation increases glutamate and arginine in the periaqueductal gray matter in rats: a microdialysis study. 1092 6

In the present study, we found that complement C3a exerted central effects after intracerebroventricular administration in mice. At doses of 3 and 10 pmol/mouse, the peptide showed an antagonistic effect on analgesia induced by morphine and U-50488H, known to be mu- and kappa-opioid receptor agonists, respectively. Moreover, complement C3a improved scopolamine- and ischemia-induced amnesia at a dose of 10 pmol/mouse. Anti-analgesia was not observed by C3a des-Arg at 10 pmol/mouse. The present findings suggest that complement C3a may act as a peptide with anti-opioid activity in the central nervous system.
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PMID:Anti-analgesic and anti-amnesic effect of complement C3a. 1105 63

The tetrapeptide DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) is a polar and selective mu agonist showing poor penetration of the placental and blood-brain barriers. In an effort to enhance the potency of DALDA, analogues containing 2',6'-dimethyltyrosine (Dmt), N,2',6'-trimethyltyrosine (Tmt), 2'-methyltyrosine (Mmt) or 2'-hydroxy,6'-methyltyrosine (Hmt) in place of Tyr1, or Orn or alpha,gamma-diaminobutyric acid (A2bu) in place of Lys4, were synthesized. All compounds displayed high mu receptor selectivity in the rat and guinea pig brain membrane binding assays and most of them were more potent mu agonists than DALDA in the mu receptor-representative guinea pig ileum assay, with [Dmt1]DALDA showing the highest potency. Because of its extraordinary mu agonist potency, high mu selectivity, polar character (charge of 3 + ) and metabolic stability, [Dmt1]DALDA has potential for use in obstetrical or peripheral analgesia.
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PMID:Synthesis and in vitro opioid activity profiles of DALDA analogues. 1112 15

Complement C3a is an anti-opioid peptide, having anti-analgesic and anti-amnesic effects after intracerebroventricular administration. However, the peptide is inactive after oral administration. Orally active C3a agonist peptide was designed based on the structure of oryzatensin, a C3a agonist peptide derived from rice albumin. Tyr-Pro-Leu-Pro-Arg, a pentapeptide at the carboxyl terminus of oryzatensin is the minimally essential structure for exerting C3a activity. Due to the affinity for mu-opioid receptor, both oryzatensin and Tyr-Pro-Leu-Pro-Arg showed analgesia after intracerebroventricular administration in mice which was blocked by the opioid antagonist naloxone. Tyr-Pro-Leu-Pro-Arg lost opioid activity by substitution the amino terminus tyrosine with other hydrophobic residues. Among the newly designed peptides, Trp-Pro-Leu-Pro-Arg was found to possess the strongest C3a activity. The peptide antagonized morphine-induced analgesia at 300 mg/kg after oral administration and also improved scopolamine- and ischemia-induced amnesia in a step-through passive avoidance test.
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PMID:Designing of an orally active complement C3a agonist peptide with anti-analgesic and anti-amnesic activity. 1117 94


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