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

The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited the binding of 0.25 nM [3H][D-Ala2, (Me)-Phe4,Gly(ol)5]enkephalin (DAMGO) with IC 50 values of less than 2 nM. Preincubation of membranes with MET-CI-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opioid binding sites without a change in affinity. In the mouse 55 degrees C warm-water tail-flick assay, neither MET-Cl-CAMO nor N-CPM-MET-Cl-CAMO at doses up to 100 nmol produced antinociception after intracerebroventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. The antagonism produced by 1 nmol of either MET-Cl-CAMO or N-CPM-MET-Cl-CAMO reached a maximal effect after 24 h, and lasted up to 48 h. Analgesia mediated by delta- or kappa-opioids was not altered by either compound. In summary, the data suggest that MET-Cl-CAMO and N-CPM-MET-Cl-CAMO are long-term, mu-opioid receptor antagonists, devoid of agonist properties in the mouse tail-flick assay, and that N-CPM-MET-Cl-CAMO may produce its antagonistic effects by binding irreversibly to the mu-opioid receptor.
 ...
PMID:14 beta-Chlorocinnamoylamino derivatives of metopon: long-term mu-opioid receptor antagonists. 905 44

The tridecapeptide, neurotensin elicits naloxone-insensitive analgesia after its intracebroventricular administration in mice. We used this central pharmacological effect to assess the putative contribution of the endopeptidase 3.4.24.15 to central inactivation of the peptide. By means of combinatorial chemistry, we previously designed the first potent endopeptidase 3.4.24.15 inhibitor. This agent, Z-(L,D)Phe psi(PO2CH2)(L,D)Ala-Lys-Met (phosphodiepryl 21), is shown here to behave as a fully specific endopeptidase 3.4.24.15 inhibitor, as demonstrated by the absence of effect on a series of other exo- and endopeptidases belonging to various classes of proteolytic activities present in murine brain membranes. Furthermore, central administration of phosphodiepryl 21 drastically prolongs the forepaw licking latency of mice tested on the hot plate and injected with sub-maximally active doses of neurotensin. Altogether, our results demonstrated that, in addition to endopeptidase 3.4.24.16, endopeptidase 3.4.24.15 likely contributes to the physiological termination of the neurotensinergic message in murine brain.
 ...
PMID:Contribution of endopeptidase 3.4.24.15 to central neurotensin inactivation. 934 27

To delineate fully opioid peptide function in cutaneous inflammatory and nociceptive responses, it is necessary to know first which opioid peptides are present in the skin and which cellular elements in the skin store and secrete them. Merkel cells are cutaneous neuroendocrine cells, which may derive from the neural crest or from undifferentiated keratinocytes with stem cell character. The neuroendocrine character of Merkel cells is supported by their immunoreactivity for chromogranin A (CGA) and a variety of neuropeptides, among them the opioid peptide [Met]enkephalin as shown in guinea-pig and mouse. This study investigates in the rat whether the preprodynorphin derived opioid peptide dynorphin A is expressed in cutaneous Merkel cells and possibly related to an aminergic phenotype. Light microscopic immunohistochemistry revealed dynorphin A immunoreactivity in Merkel cells to be codistributed with immunoreactivity for calcitonin gene-related peptide (CGRP) and CGA, two well-established merker peptides of mammalian Merkel cells. Vibrissal Merkel cells stained for the neuroendocrine vesicular monoamine transporter isoform 1 (VMAT1) but not for the predominantly neuronal isoform 2 (VMAT2). Merkel cell staining for dynorphin A, VMAT1, CGA, and CGRP was unaffected by experimental denervation. Dynorphin A and a still unidentified monoamine, possibly serotonin, may cofunction as autocrine or paracrine mediators in the mechanosensory Merkel cell--axon complex and are potentially involved in peripheral analgesia.
 ...
PMID:Cutaneous Merkel cells of the rat contain both dynorphin A and vesicular monoamine transporter type 1 (VMAT1) immunoreactivity. 967 97

Neuropeptide Y (NPY) and endogenous opioids (EOPs) such as methionine-enkephalin (Met-enk) regulate similar physiological responses, but it is not known whether nociceptive and immune responses also show analogy after intracerebroventricular (i.c.v.) application. Dose-response studies show that Met-enk stimulates the blood granulocyte and splenic natural killer (NK) cell function of Lewis rats at a low dose (10(2) ng/kg, i.c.v.), whereas a high dose (10(5) ng/kg) causes suppression of innate immune functions associated with analgesia in the hot-plate test. At 15 min, 1 h and 24 h after i.c.v. application, both Met-enk (10(2) ng/kg) and NPY (1 ng/kg) produced similar effects: An initial suppression of innate immune function was followed by a long lasting stimulatory action on cell functions and serum interleukin-6 (sIL-6) levels. Thus, central NPY application resembles Met-enk-induced immunostimulation at doses not affecting nociception, suggesting an involvement of both peptides in shaping stress-induced immunomodulation of the non-analgetic form, possibly via activation of a common immunomodulatory effector mechanism.
 ...
PMID:Centrally applied NPY mimics immunoactivation induced by non-analgesic doses of met-enkephalin. 987 22

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.
 ...
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

Peptide E is a 25-amino acid peptide derived from proenkephalin A that was originally isolated from the bovine adrenal medulla. Bovine peptide E (BPE), which possesses a Met- and a Leu-enkephalin sequence at its N- and C-terminus, respectively, has been described as a highly potent and selective mu-opioid receptor agonist. Paradoxically, the frog counterpart of peptide E (FPE), which exhibits only two amino acid substitutions (Met15-->Gln and Leu25-->Met) compared with BPE, was found to be totally devoid of antinociceptive activity. To decipher this apparent discrepancy, we have decided to compare the structural and pharmacological characteristics of FPE, BPE, and the chimeric peptide [Gln15]BPE (Q15BPE). In methanol, all three peptides exhibited virtually the same conformation, the central region of each peptide (residues 10-20) being involved in a regular helix. Intracerebroventricular administration of FPE, BPE, or Q15BPE, at doses up to 1000 ng per mouse, did not induce any analgesic effects, as evaluated by the hot plate and writhing tests, whereas, in the same tests, beta-endorphin at a dose of 100 ng provoked profound analgesia. Concomitant administration of FPE, BPE, or Q15BPE (100 ng) with the aminopeptidase-N inhibitor bestatin (50 microg) or the endopeptidase 24-11 inhibitor thiorphan (10 microg) did not produce analgesic responses. Antinociceptive effects were only observed when very high doses of FPE, BPE, and Q15BPE (10000 ng per mouse) were administered. These data clearly demonstrate that, contrary to what has been previously reported, peptide E is virtually devoid of opioid activity.
 ...
PMID:The proenkephalin A-processing product peptide E, which encompasses two enkephalin sequences, has a much lower opioid activity than beta-endorphin. 1047 88

Gender-related differences in response to drugs of abuse, such as cocaine and morphine, have been reported both in humans and in experimental animals. Besides causing analgesia, morphine has recently been shown to exert strong immunosuppressive activity. However, no data on the influence of gender on the immunomodulatory effects of morphine or opioid peptides have been reported yet. The aim of this study was to test the influence of gender on the immunomodulatory ability of the endogenous opioid peptide [Met(5)]enkephalin (MENK) in mice. This was done by comparing the proliferative ability of splenic T- and B-lymphocytes 14 h after systemic (intraperitoneal; i.p.) administration of [Met(5)]enkephalin (2.5, 5 or 10 mg/kg body weight). The proliferative ability of T- and B-lymphocytes was assessed by testing their in vitro response to graded concentrations of the T- and B-cell mitogens, concanavalin-A (Con-A) and lipopolysaccharide (LPS), respectively. The results obtained showed that [Met(5)]enkephalin, at a dose of 2.5 mg/kg, enhanced the proliferative ability of T-lymphocytes in male mice, but not in female mice. Similarly, [Met(5)]enkephalin, at doses of 2.5 and 5 mg/kg, enhanced the proliferative ability of splenic B-lymphocytes in male mice, whereas in female mice a decrease was observed ([Met(5)]enkephalin 2.5 mg/kg, LPS 10 microg/ml). [Met(5)]enkephalin, at a dose of 10 mg/kg, did not affect the proliferative ability of either lymphocyte population, regardless of gender. The [Met(5)]enkephalin-induced stimulatory effect on both T- and B-lymphocyte proliferation was reversed by naloxone (10 mg/kg body weight), injected prior to [Met(5)]enkephalin, suggesting an involvement of opioid receptors. Thus, the data presented provide evidence for the gender-related response of murine splenic lymphocytes to immunomodulation by [Met(5)]enkephalin, administered in vivo. This finding may be relevant to the potential use of [Met(5)]enkephalin in adjuvant therapy for immunocompromised states, such as acquired immunodeficiency syndrome (AIDS) or malignancies.
 ...
PMID:Gender-related differences in murine T- and B-lymphocyte proliferative ability in response to in vivo [Met(5)]enkephalin administration. 1074 78

Methionine-enkephalin (Met-Enk) induces notable alterations in immune and central nervous system functions. The present study was conducted in order to compare peripheral and central effects of Met-Enk on nonspecific immunity, open field behavior and pain perception in the rat. The results showed that 0.2 mg/kg of Met-Enk given intraperitoneally (i.p.) increased concanavalin A (Con-A)-induced paw edema and enhanced basal and phorbol myristate acetate (PMA)-stimulated H(2)O(2) production of peritoneal macrophages. Met-Enk-induced immunopotentiation was antagonized by anti-Met-Enk antibodies (anti-Met-Enk-Ig) and quaternary naltrexone (qNtx). Met-Enk injected i.p. produced an increase of horizontal and vertical locomotor activity in the open field that was reversed by i. p. administration of anti-Met-Enk-Ig and qNtx. The dose of 0.2 mg/kg of Met-Enk applied i.p. did not affect the number of writhes in the test of analgesia. Intracerebroventricular (i.c.v.) injection of Met-Enk, given in a dose that was previously shown to be immunostimulatory, enhanced only basal H(2)O(2) production of peritoneal macrophages, and anti-Met-Enk-Ig antagonized this effect. Besides, i.c.v. treatment with anti-Met-Enk-Ig increased and decreased H(2)O(2) production of peritoneal macrophages under basal and stimulated conditions, respectively. Met-Enk and anti-Met-Enk-Ig injected i.c.v. did not influence activity in the open field and pain sensitivity. Thus, the i.c.v. dose of Met-Enk that was sufficient to modulate immune functions did not influence behavior. It may be concluded that Met-Enk modulated nonspecific immune responses and open field behavior by peripheral mechanisms.
 ...
PMID:Peripheral effects of methionine-enkephalin on inflammatory reactions and behavior in the rat. 1096 31

We have previously shown that beta-endorphin (END) is contained and released from memory-type T-cells within inflamed tissue and that it is capable to control pain (J Clin Invest 100(1) (1997) 142). Methionine-enkephalin (MET) and Dynorphin-A (DYN) are endogenous opioids with preference for delta- and kappa-opioid receptors, respectively. Both MET and DYN are produced and contained within immune cells. The goal of this study was to determine the release characteristics of MET and DYN in a rat model of localized hindpaw inflammation and to examine the antinociceptive role of MET and DYN in a Freund's adjuvant induced model of inflammatory pain. We found that corticotropin-releasing factor (CRF) can stimulate the release of both MET and DYN from lymphocytes. This release is dose-dependent and reversible by the selective CRF antagonist alpha-helical-CRF. Furthermore, CRF (1.5 ng) produces analgesia when injected into the inflamed paw, which is reversible by direct co-administration of antibodies to MET. Lymphocyte content of MET was 7.0+/-1.4 ng/million cells, whilst DYN content was ~30-fold lower. Both END and DYN, but not MET, were released by IL-1. Consistently, IL-1 produced peripheral analgesic effects which were not reversed by antibodies to MET. These results indicate that both MET and DYN play a role in peripheral analgesia but have different characteristics of release. These studies further support a role of the immune system in the control of inflammatory pain. This may be particularly important in patients suffering from compromised immune systems as with cancer and AIDS.
 ...
PMID:Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. 1151 79

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.
 ...
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


<< Previous 1 2 3 4 5 6 7 8 9 10