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)

The mu opioid receptor (MOR) is thought to mediate a variety of morphine's effects, including analgesia and addiction. The expression of opioid receptors can be up and down regulated, but little is known about molecular processes that regulate expression of the MOR gene. To study the regulatory elements that control expression of the human MOR (hMOR) gene, 2325 bp of the 5'-regulatory sequence of the hMOR gene were cloned and sequenced. A transcription initiation site (TIS) was mapped 252 (-252) nucleotides upstream from the translation start site (+1) by primer extension experiments using human thalamus poly(A)+ mRNA. In addition, several putative distal TISs were also identified; the most distal site was mapped 663 bp upstream of the translation start site. A series of 5'-deleted hMOR promoter-luciferase constructs were made and transiently transfected into a MOR expressing neuroblastoma cell line, SK-N-SH, and a non-expressing cell line, HeLa. These transient transfection studies indicated that the region from -563 to -292 contained a strong enhancer element(s), while the region from -776 to -564 possessed a repressor element(s). A similar transfection pattern was observed with SK-N-SH and HeLa cells, suggesting that there is not a tissue-specific element in the region from -2325 to -252.
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PMID:Functional characterization of the promoter region of the human mu opioid receptor (hMOR) gene: identification of activating and inhibitory regions. 1193 71

Although our knowledge of pain and its management in the perinatal period has increased, little is known about the first hours and days of life when major physiologic transition events occur. Prematurity and critical illnesses further complicate analgesic use during this time. Increased morbidity and mortality have been shown in infants receiving placebo infusions after surgery compared with infants with analgesia, highlighting the negative consequences of pain in infants. Opioids can help promote hemodynamic stability, promote respirator synchrony, and decrease the incidence of grade III & IV intraventricular hemorrhage in ventilated preterm neonates. Long-term follow-up studies suggest improved behavioral and cognitive outcomes in children given morphine infusions during NICU confinement. The necessity of fetal analgesia is dictated by the ability of the fetus to feel pain and by the adverse effects of noxious stimuli on future sensory development. Effects of drugs given to the pregnant woman on the (preterm) newborn might be influenced by decreased or absent transplacental transport, compression of the umbilical cord during delivery, or diminished blood flow in the placenta in pre-eclamptic women, resulting in higher serum concentrations. Pharmacokinetics and drug metabolism change in the last trimester, and pain sensitivity may be altered after 32 weeks of gestation. Consequently, dose and dose interval may vary considerably between neonates and within an individual during the first days of life. This subpopulation is not homogenous, and drug doses in a term neonate with a postnatal age of 2 weeks may be quite different from those at birth and are certainly different from those in a premature neonate. Size must be disentangled from age-related factors when examining developmental pharmacokinetic parameters. There are no longitudinal studies published investigating the pharmacokinetic properties of any analgesic more than once per infant. Polymorphisms of the genes encoding for the enzymes involved in the metabolism of analgesics or in genes involved in receptor expression may contribute to the large interindividual pharmacokinetic parameter variability. Polymorphism of the human mu opioid receptor has not yet satisfactorily explained pharmacodynamic variability.
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PMID:The effects of analgesia in the vulnerable infant during the perinatal period. 1238 Apr 72

The present study characterizes the relationship between the endogenous mu opioid peptides endomorphin-1 (EM-1) and endomorphin-2 (EM-2) and several splice variants of the cloned mu opioid receptor (MOR-1) encoded by the mu opioid receptor gene (Oprm). Confocal laser microscopy revealed that fibers containing EM-2-like immunoreactivity (-LI) were distributed in close apposition to fibers showing MOR-1-LI (exon 4-LI) and to MOR-1C-LI (exons 7/8/9-LI) in the superficial laminae of the lumbar spinal cord. We also observed colocalization of EM-2-LI and MOR-1-LI in a few fibers of lamina II, and colocalization of EM-2-LI and MOR-1C-LI in laminae I-II, and V-VI. To assess the functional relevance of the MOR-1 variants in endomorphin analgesia, we examined the effects of antisense treatments that targeted individual exons within the Oprm1 gene on EM-1 and EM-2 analgesia in the tail flick test. This antisense mapping study implied mu opioid receptor mechanisms for the endomorphins are distinct from those of morphine or morphine-6beta-glucuronide (M6G).
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PMID:Anatomical and functional correlation of the endomorphins with mu opioid receptor splice variants. 1238 36

In contrast to other opioids, fentanyl and buprenorphine share a number of physicochemical properties that render both agents potentially suitable for transdermal delivery. However, there are significant differences between them in terms of their pharmacological profiles, as fentanyl is a full mu opioid receptor agonist capable of exerting a maximal response in certain tissues, while buprenorphine is a partial agonist unable to exert this maximum effect even at high doses. This review examines the hypothesis that partial opioid agonists would confer a number of benefits over full agonists, namely effective analgesia with a better tolerability and a lower propensity for addiction, with respect to fentanyl and buprenorphine. An attempt is also made to correlate clinical differences between these drugs with their respective agonist profiles and other differential pharmacokinetic/pharmacodynamic properties. Despite a dearth of directly comparative trials, the pharmacology of fentanyl and buprenorphine is well documented. Considerable data concerning buprenorphine suggest that the advantages initially espoused for partial opioid agonists are not borne out in clinical practice. Indeed, it may be postulated that full mu opioid agonists, particularly those with high selectivity and potency such as fentanyl, have a superior clinical profile and fulfill the above criteria more closely. Relative receptor binding, selectivity, potency and intrinsic efficacy of the opioids appear to be key determinants of their individual pharmacological profiles, contributing significantly to the heterogeneity of this class of analgesics.
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PMID:Partial versus full agonists for opioid-mediated analgesia--focus on fentanyl and buprenorphine. 1246 29

The analgesia produced by inhibitory G protein-coupled receptor agonists involves coordinated postsynaptic inhibition via G protein-coupled inwardly rectifying potassium channels (GIRKs) and presynaptic inhibition of neurotransmitter release through regulation of voltage-gated Ca(2+) channels. Here, we used mice lacking the GIRK2 channel subunit to assess the relative contribution of these two effector systems to nociceptive processing in male and female mice. Compared with female WT mice, male WT mice exhibited higher pain thresholds and enhanced opioid (morphine) and alpha(2)-adrenergic (clonidine) receptor-induced antinociception in a spinal reflex test. The GIRK2-null mutation reduced the "pain" threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold. In addition, deletion of GIRK2 channels in mutant mice largely eliminated clonidine antinociception and significantly decreased morphine antinociception. Furthermore, the more pronounced morphine and clonidine-induced antinociception in male mice disappeared in the GIRK2 mutants. Based on the almost complete loss of clonidine-induced antinociception in the mutant mice, we conclude that it is primarily mediated by postsynaptic alpha(2)-adrenergic receptors. In contrast, the significant residual morphine effect in the mutant mice points to the presynaptic mu opioid receptor as a major contributor to its analgesic action. Finally, our results suggest that the reduced pain responsiveness of male compared with female mice results in part from GIRK2-coupled postsynaptic receptors that are activated by endogenous antinociceptive systems.
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PMID:Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. 1249 46

Our previous studies revealed that interleukin-2 (IL-2) exerted peripheral antinociception that was partially mediated by mu opioid receptors. No ionic explanations of this effect have yet been reported. The present study was designed to investigate effects of IL-2 on the physiological properties of capsaicin-sensitive small dorsal root ganglion (DRG) neurons, which are predominantly responsible for nociceptive transmission from the periphery to the spinal cord. Intracellualr recordings of DRG neurons were made in DRG/peripheral nerve preparation in vitro. IL-2 (10(3) U/ml) produced membrane hyperpolarization of -9.4 +/- 3.0 mV and this effect was blocked by beta-FNA (5 microM), a mu opioid receptor antagonist. Under whole-cell patch clamp recordings, transient high-threshold Ca(2+) currents were inhibited by -56.6 +/- 11.3% by IL-2. Simultaneous calcium imaging showed that this cytokine also inhibited depolarization-evoked increase in intracellular calcium concentration. All the effects of IL-2 were blocked by naloxone (1 microM). Consistent with previous studies, DAMGO, a selective mu opioid agonist, exerted similar inhibitory effects on membrane potentials and Ca(2+) currents. The present results indicated that mu opioid receptors were involved in the regulatory effects of IL-2 on membrane potentials and calcium channels in DRG neurons, which may contribute to IL-2-induced peripheral analgesia.
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PMID:Interleukin-2 regulates membrane potentials and calcium channels via mu opioid receptors in rat dorsal root ganglion neurons. 1252 82

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

Opioid ligands may exert antinociception through receptors expressed on peripheral afferent axons. Whether local opioid receptors might attenuate neuropathic pain is uncertain. In this work, we examined the function and expression of local mu opioid receptors (MORs) associated with the chronic constriction injury (CCI) model of sciatic neuropathic pain in rats. Low-dose morphine or its carrier were percutaneously superfused over the CCI site with the injector blinded to the identity of the injectate. Morphine, but not its carrier, and not equimolar systemic doses of morphine reversed thermal hyperalgesia in a dose-related, naloxone-sensitive fashion. Moreover, analgesia was conferred at both 48 hours and 14 days after CCI, times associated with very different stages of nerve repair. Equimolar local DAGO ([D-Ala2, N-Me-Phe4, Gly5-(ol)] enkephalin), a selective MOR ligand, provided similar analgesia. Local morphine also attenuated mechanical allodynia. MOR protein was expressed in axonal endbulbs of Cajal just proximal to the injury site, in aberrantly regenerating small axons in the epineurial sheath around the CCI site and in residual small axons distal to the CCI lesion. Sensory neurons ipsilateral to CCI had an increase in the proportion of neurons expressing MOR. We suggest that local MOR expressed in axons may be exploited to modulate some forms of neuropathic pain.
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PMID:Mu opioid receptors and analgesia at the site of a peripheral nerve injury. 1260 4

Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, delta opioid receptor ligands have been useful in enhancing morphine's potency. The underlying molecular basis for these observations is not understood. We propose the modulation of receptor function by physical association between mu and delta opioid receptors as a potential mechanism. In support of this hypothesis, we show that mu-delta interacting complexes exist in live cells and native membranes and that the occupancy of delta receptors (by antagonists) is sufficient to enhance mu opioid receptor binding and signaling activity. Furthermore, delta receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric associations between mu-delta opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.
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PMID:A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. 1504 95

Methadone is a widely used synthetic opioid which is administered as a racemic mixture of (R)-(--)- and (S)-(+)-enantiomers, with only (R)-(--)-methadone possessing mu opioid receptor agonist activity. Methadone inhibits numerous immune functions in vitro at concentrations above 10 microM in a nonstereoselective and naloxone-insensitive fashion, suggesting the presence of nonclassical opioid receptors on immune cells. No in vivo data on the effects of methadone's enantiomers on immune function are available. Therefore, the stereoselectivity of methadone's analgesia (hot plate latency) in vivo and immune suppression ex vivo (splenocyte proliferation) was investigated in groups of Balb/c mice. Significant analgesia was observed in animals that received racemic methadone (P=0.0012, 52% MPE) and (R)-(--)-methadone (P=0.0002, 70% MPE) when compared to saline-treated controls, while (S)-(+)-methadone was devoid of any such effect (-4% MPE). In vivo (R)-(--)- and racemic methadone caused significant inhibition (P<0.001, greater than -70%) of basal proliferation compared to saline control. In stark contrast to analgesia, in vivo (S)-(+)-methadone caused significantly greater inhibition of basal proliferation (P<0.001, -130%) than (R)-(--)- and racemic methadone. The immune suppression caused by methadone is not purely a classical opioid response but involves nonclassical opioid receptors located at the central level, which have yet to be characterised. Moreover, the dose at which immune suppression occurred could be achieved clinically.
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PMID:(S)-(+)-methadone is more immunosuppressive than the potent analgesic (R)-(--)-methadone. 1535 21


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