Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antinociceptive effect of intracerebroventricular injection (icv) of Asn-Ala-Gly-Ala (NAGA), a partial sequence of beta-lipotropin, was studied in rats. The potassium iontophoresis-induced tail flick was used to measure the pain threshold. The antinociceptive effect of NAGA, which was dose-dependent (icv, 0.03-0.24 mumol/rat) and long-lasting (90 min), was reversed by naloxone (icv, 0.26 mg.kg-1) and inhibited by anti-MEK serum (titre: 1:5000, 5 microliters) or anti-LEK serum (titre: 1:5000, 5 microliters). NAGA-induced antinociception was scarcely affected by anti-beta-EP serum (titre: 1:30,000, 5 microliters) or anti-Dyn A1-13 serum (titre: 1:30,000, 5 microliters). It was suggested that the antinociceptive effect of NAGA may be associated with the release of met-enkephalin and leu-enkephalin in rat brain.
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PMID:Antinociceptive effect of intracerebroventricular injection of a tetrapeptide Asn-Ala-Gly-Ala in rats. 770 46

Peptides are of potential interest in the field of gene therapy but require modification by genetic engineering to facilitate their secretion. Amino terminal addition of a signal peptide is not always sufficient to achieve this goal, as found in this study for beta-endorphin. To overcome this problem, addition of the pre-pro-sequence of mouse nerve growth factor to beta-endorphin was tested. Retrovirus-mediated expression of a hybrid construct of the pre-pro-sequence of nerve growth factor and human beta-endorphin in primary fibroblasts resulted in the secretion of beta-endorphin immunoreactivity at a rate of 620 pg/h/10(6) cells. Analysis of the secreted beta-endorphin immunoreactivity with reverse-phase HPLC, immunoassays using three different antibodies, and an assay for the specific displacement of [3H][D-Ala2,N-MePhe4,Gly-ol5]enkephalin from mu-opioid receptors suggests that the pre-pro-sequence is cleaved off from the pre-pro-sequence/beta-endorphin construct prior to secretion, resulting in bona fide beta-endorphin. Transplantation of beta-endorphin-secreting cells into brain or spinal cord may provide a gene therapy approach for the treatment of chronic, opioid-sensitive pain states.
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PMID:Retrovirus-mediated expression of an artificial beta-endorphin precursor in primary fibroblasts. 783 38

Hybrids of amino-poly(ethylene glycol) (aPEG) and [D-Ala2,(N-Me)Phe4] enkephalin analogs, H-Tyr-D-Ala-Gly-(Me)Phe-aPEG, H-Tyr-D-Ala-Gly-(Me)Phe-Leu-aPEG and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-aPEG, were prepared by the solution method and their antinociceptive properties were examined in comparison with those of the peptides. H-Tyr-D-Ala-Gly-(Me)Phe-OH and H-Tyr-D-Ala-Gly-(Me)Phe-Leu-OH themselves at intracerebroventricular (i.c.v.) doses of 10-30 nmol/animal produced an antinociceptive effect which was less potent than that of i.c.v. morphine, 3 micrograms/animal, and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-OH did not have any marked effect. However, the antinociceptive effects of H-Tyr-D-Ala-Gly-(Me)Phe-Leu-OH and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-OH were remarkably potentiated by hybrid formation with aPEG to levels higher than that of 3 micrograms/mouse of morphine, and the effect lasted at least 120 min. In contrast, the effect of H-Tyr-D-Ala-Gly-(Me)Phe-OH was rather diminished by hybrid formation. In view of the low toxicity and weak immunogenic properties of aPEG, the hybrids could be useful in therapy of patients for relieving chronic and severe pain.
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PMID:Amino acids and peptides. XXIV. Preparation and antinociceptive effect of [D-Ala2,(N-Me)Phe4]enkephalin analog-poly(ethylene glycol) hybrids. 795 39

Combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or orchiectomy was administered to 268 patients with previously untreated metastatic stage D2 prostate cancer for an average of 1,191 d (3.26 y). Only 17 of the 268 evaluable patients (6.5%) showed no objective positive response to the combination therapy assessed according to the National Prostatic Cancer Project objective criteria of response. The median duration of the disease-free response was 2.23 y and median overall survival was 3.58 y. The median survival for patients with only 1-5 bone metastases was not yet reached at 8 y, but for patients with 6-10 bone lesions, 11-40 bone lesions, and multiple bone metastases (superscan), median survival was markedly reduced to 3.56, 2.36, and 1.76 y, respectively. Analysis of patients according to general symptomatology, pain, and performance status showed median survivals of 5.47, 2.71, and 2.1 y for minimal, moderate, and severe symptoms, respectively. The present data demonstrate that administration of combination therapy to stage D2 prostate cancer patients having 1-5 bone metastases adds a minimum of 4.4 y of good quality life compared with patients whose disease is slightly more advanced. Our findings clearly demonstrate the major importance of starting combination therapy as soon as possible after diagnosis of metastatic prostatic cancer.
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PMID:Major advantages of "early" administration of endocrine combination therapy in advanced prostate cancer. 801 54

Leucine enkephalin (Tyr-Gly-Gly-Phe-Leu; Leu-Enk) is a naturally occurring peptide that has been shown to have pain modulating properties. To evaluate the feasibility of using various absorptive mucosae as a route of systemic delivery, the stability of Leu-Enk and the effect of enzyme inhibitors (e.g., amastatin, EDTA, and thimerosal) on stabilization and permeation of Leu-Enk through rabbit mucosae in the presence of dihydrofusidates were investigated. Enzymes in the nasal, rectal, and vaginal mucosae were extracted and Leu-Enk (50 micrograms/mL) was added to each of the enzyme extracts and incubated to determine the kinetics and mechanism of degradation. The rate of degradation in the extracts in the absence of inhibitors followed the order: rectal > vaginal > nasal. Whereas EDTA had the best stabilizing effect on Leu-Enk, thimerosal was the best stabilizer for the degradation intermediates. A combination of amastatin (50 microM), EDTA (5 mM), and thimerosal (50 microM) had the greatest stabilizing effect on Leu-Enk and its degradation intermediates. For permeation studies, each mucosa was mounted onto a Valia-Chien permeation cell with Leu-Enk (200 micrograms/mL) in isotonic phosphate buffer (as donor solution). The enhancers used for the study were sodium tauro-dihydrofusidate (STDHF), sodium glycodihydrofusidate (SGDHF), and phosphato-dihydrofusidate (PHDHF). The greatest effect was achieved by PHDHF for all the mucosae. STDHF had a significant effect only on the rectal permeation, whereas SGDHF had significant effects on rectal and vaginal mucosae. Mechanisms by which the dihydrofusidates enhance permeating may involve micelle formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transmucosal delivery of leucine enkephalin: stabilization in rabbit enzyme extracts and enhancement of permeation through mucosae. 828 38

Two hexapeptides affecting pain sensitivity were isolated from the bone marrow cells supernatant, shown to have primary structure Leu-Val-Val-Tyr-Pro-Trp and Phe-Leu-Gly-Phe-Pro-Thr, and synthesized by the solid phase method. In physico-chemical and biological properties the synthetic peptides were identical to the peptides isolated.
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PMID:[Isolation and structure determination of biologically active peptides from the bone marrow]. 837 52

The effect of various doses of the selective delta agonist BUBU (Tyr-D-Ser(O-t-butyl)-Gly-Phe-Leu-Thr(O-t-butyl) on the vocalization threshold to paw pressure were compared in normal and arthritic rats, a suitable clinical model of chronic pain. In both group of rats, the intravenous administration of BUBU (6, 9, 12 mg/kg in normal and 1.5, 3, 6 mg/kg in arthritic rats) led to significant antinociceptive effects. The same dose of BUBU (6 mg/kg i.v.) produced a much more potent antinociceptive effect in arthritic than in normal rats, and a dose as low as 1.5 mg/kg produced a significant analgesic effect in the arthritic animal, whereas at 3 mg/kg BUBU was ineffective in normal rats. The analgesic effects of BUBU (9 mg/kg in normal and 3 mg/kg in arthritic rats) were completely prevented by the selective delta antagonist naltrindole (1 mg/kg i.v. a dose devoid of analgesic potency per se), while they were not affected by the selective mu antagonist naloxone (0.05 mg/kg i.v.). In addition, 3 mg/kg i.v. of BUBU remained effective in morphine tolerant arthritic rats. These results suggest that delta opioid receptor activation can modulate the transmission of cutaneous mechanical nociceptive information in rats, especially in inflammatory pain conditions.
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PMID:The highly selective delta agonist BUBU induces an analgesic effect in normal and arthritic rat and this action is not affected by repeated administration of low doses of morphine. 839 93

Neuropathic pains have often been classified as opioid-resistant. Here, spinal (intrathecal) actions of morphine and nonmorphine opioids have been studied in a nerve ligation model of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Nerve-injured animals exhibited allodynia that was stable for up to 6 weeks after the surgery. Morphine did not alter allodynia at doses up to 300 nmol (100 micrograms). In contrast, [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), a high-efficacy mu opioid agonist, produced a significant, dose-related antiallodynic action. [D-Ala2, Glu4]deltorphin (delta agonist) produced a significant antiallodynic effect only at 300 nmol, reaching approximately 70% of the maximum. Coadministration of morphine with a dose of [D-Ala2, Glu4]deltorphin, which was inactive alone, produced a significant and long-lasting antiallodynic action that was antagonized by NTI (delta receptor antagonist); NTI alone had no effect. Although blockade of cholecystokinin-B (CCKB) receptors with L365,260 did not produce effects alone, a significant antiallodynic action was observed when coadministered with morphine; this elevation of nociceptive threshold was abolished by NTI. The finding that DAMGO, but not very large doses of morphine, produced antiallodynic actions suggests that the ability of mu opioids to alleviate the allodynia is related, in part, to efficacy at postsynaptic mu receptors. At an inactive dose, a delta agonist or a CCKB antagonist enhanced morphine antiallodynic efficacy in an NTI-sensitive fashion. CCKB receptor blockade may enhance endogenous enkephalin actions, resulting in enhancement of morphine efficacy through a mu-delta receptor interaction.
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PMID:Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats. 853 Nov 1

Antinociceptive effects of systemically or locally administered opioid mu, kappa and delta agonists were evaluated in a rat model of visceral pain. Resiniferatoxin (RTX, 3 nmol), a capsaicin-like mutant, produced abdominally directed grooming behavior after direct administration into the urinary bladder (intravesical, Lves.) by indwelling cannula. Systemic (s.c. or i.p.) pretreatment with the mu agonists morphine or [D-Ala2, NMePhe4, Gly-ol]enkephalin (Damgo), the kappa agonists trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (U50,488) or [5R-(5,7,8-beta)]-N-methyl-N-[7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec - 8-yl]-4-benzofuranacetamide (CI-977), or the nonpeptidic delta agonist (+/-)-4-((alpha-R*)-alpha-((2S*,5R(*)-4-Allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N, N-diethylbenzamide (BW373U86) dose-dependently decreased RTX-induced abdominal licking; such antinociception was selectively blocked by the appropriate receptor-selective antagonists beta-funaltrexamine (mu), nor-binaltorphimine (kappa) and naltrindole (delta). Local (i.ves.) BW373U86, [D-Ala2,Glu4]deltorphin (DELT II) and Cl-977 also significantly decreased RTX-induced licking. Intracerabroventricular quaternary naloxone partially blocked the effects of systemic morphine, but not that of CI-977 or BW373U86. Intraperitoneal quaternary naloxone blocked the effect of local and systemic BW373U86 but not that of local or systemic CI-977; systemic morphine was partially blocked. Thus, systemic mu, kappa and delta agonists all produced antinociception against a novel visceral chemical stimulus in the rat. Local CI-977 also produced antinociception, but the only compound clearly acting at peripheral opioid receptors was BW373U86, a delta agonist. This study suggests that opioid delta receptors may be present on bladder nociceptive afferents and may be activated for production of peripheral analgesia.
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PMID:Opioid antinociception in a rat model of visceral pain: systemic versus local drug administration. 853 Nov 26

The analgesic effects of 12 opioid agonists in amphibians were measured using the acetic acid test. Spinal administration of dermorphin, [D-Ala2,NMePhe4,Gly-ol]-enkephalin, fentanyl and morphine (mu opioids); [D-Ser2,Leu5-Thr6]-enkephalin, [D-Ala2,D-Leu5]-enkephalin, [D-Pen2,D-Pen5]-enkephalin and deltorphin (delta opioids); and Cl977 [(5R)-(544 alpha,744 alpha,845 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4,5]dec-8yl]-4-benzofuranacetamide monohydrochloride, bremazocine), U50488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide methanesulfonate) and nalorphine (kappa opioids) produced a dose-dependent and long-lasting analgesia in the Northern grass frog, Rana pipiens. With all opioids, time course experiments showed that this analgesic effect lasted for at least 4 hr, with no untoward effects observed within each dosage range used. The analgesic effects of the 12 opioids were blocked by systemic naltrexone pretreatment. Comparison of dose-response curves demonstrated that the rank order of potency was such that, in general, mu opioids > delta opioids > kappa opioids. Dose-response curves obtained in the presence of a fixed dose of naltrexone showed the greatest shift for [D-Ser2,Leu5-Thr6]-enkephalin, less so for [D-Ala2,NMePhe4,Gly-ol]-enkephalin and the least shift for bremazocine. ED50 values for mu and delta opioids in the amphibian acetic acid test were significantly correlated to ED50 values of the same opioids reported in the literature for the rodent TF test. These results show that a spinal site of opioid analgesia is present in amphibians and supports the utility of this alternative, nonmammalian model for studies of opioid analgesia and pain research.
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PMID:Relative analgesic potency of mu, delta and kappa opioids after spinal administration in amphibians. 863 8


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