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)

Two experiments, using centrally administered [D-Ala2-MePhe4-Gly(ol)5]enkephalin (DAMGO), a selective mu-opioid agonist, assessed the thermoregulatory consequences of cold acclimation. Experiment 1 assessed whether cold acclimation influenced DAMGO hyperthermia at room temperature. Sialo-adenectomized rats were implanted with ICV cannulae and IP Mini-Mitters. After 3 weeks of exposure to 5 degrees C (cold acclimation) or 22 degrees C (non-cold acclimation) rats were pretreated with IP naltrexone HCl (2 mg/kg b.wt.) or vehicle (0.15 M saline) and later administered a 5-microliters ICV injection of 0.15 M saline, 0.1, or 1.0 microgram DAMGO. Cold acclimation exerted little effect on core temperature but potentiated DAMGO hyperthermia in a dose-dependent, naltrexone-reversible, activity-independent manner. Experiment 2 assessed the effect these same manipulations exerted on operant escape from a convective source of mild heat (37 degrees C). Duration of heat escape increased with cold acclimation in a naltrexone-resistant manner, yet was not influenced by DAMGO in either non-cold-acclimated or cold-acclimated rats. These findings suggest that two central adaptations occur with cold acclimation: A non-mu-opioid process that increases heat sensitivity and a mu-opioid process that potentiates hyperthermia but fails to alter heat escape due to mu-opioid-mediated analgesia.
 ...
PMID:Effects of cold acclimation and central opioid processes on thermoregulation in rats. 874 90

1. Rat caudal periaqueductal grey (PAG) output neurones containing rhodamine microspheres, retrogradely transported from an injection site in the rostral ventromedial medulla (RVM), were visualized in brain slices and recorded from using whole-cell patch clamp techniques. 2. The specific GABAB receptor agonist baclofen (10 microM) produced an outward current or hyperpolarization in fifty out of fifty-six caudal PAG output neurones. In 44% of these baclofen-sensitive neurones, the opioid agonist methionine enkephalin (30 microM) also produced an outward current or hyperpolarization. The opioid current reversed polarity at -104 mV and could also be produced by DAMGO, an agonist selective for the mu-subtype of opioid receptor. 3. Opioid-responding output neurones were not distributed uniformly in the caudal PAG. In horizontal slices containing lateral PAG, 56% of output neurones were inhibited by opioids, as compared with only 14% of the output neurones in slices containing ventrolateral PAG. 4. These observations are consistent with opioid disinhibition of ventrolateral PAG neurones projecting to the RVM as the predominant mechanism underlying opioid-induced analgesia in the PAG. The role of opioid receptors found on a major proportion of the output neurones in the lateral PAG remains to be established, but is assumed not be related to modulation of nociceptive function.
 ...
PMID:Opioid inhibition of rat periaqueductal grey neurones with identified projections to rostral ventromedial medulla in vitro. 882 Nov 37

Spinal administration of morphine or [D-Ala2,MePhe4,Gly(ol)5)]enkephalin (DAMGO) produces potent, naloxone-reversible analgesia that is modulated by alpha 2-adrenoceptors. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring, amidated tetrapeptide that is structurally related to the melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) family of endogenous peptides. Tyr-W-MIF-1 displays high selectivity for the mu-opioid receptor. We investigated the effect of spinal administration of Tyr-W-MIF-1 on analgesia using the mouse tail-flick assay. Intrathecal (i.t.) administration of Tyr-W-MIF-1 produced a dose-dependent analgesic response, with an ED50 of 0.41 microgram, that was reversed by naloxone. Pretreatment with the mu-opioid receptor-selective antagonist beta-funaltrexamine blocked the effect of i.t. Tyr-W-MIF-1. However, pretreatment with the mu1-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal mu2-opioid receptors. Pretreatment with desipramine, an inhibitor of norepinephrine reuptake, potentiated the analgesic effect of i.t. Tyr-W-MIF-1, producing a 3.1-fold leftward shift in the dose-response curve. Spinal administration of yohimbine, an alpha 2-adrenoceptor-selective antagonist, significantly attenuated the analgesic effect of Tyr-W-MIF-1. Thus, the potent analgesic effect of i.t. Tyr-W-MIF-1 is mediated through spinal mu2-receptors, and is modulated by norepinephrine and alpha 2-adrenoceptors.
 ...
PMID:Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by alpha 2-adrenoceptors. 884 21

We analyzed the pharmacological characteristics of (-)-3-acetyl-6 beta-acetylthio-N-cyclopropylmethyl-normorphine (KT-90) using Chinese hamster ovary (CHO) cells expressing cloned rat mu-, delta- and kappa-opioid receptors. KT-90 displaced the specific binding of the following radiolabeled ligands selective to the mu-, delta- and kappa-opioid receptors, [3H][D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO), [3H][D-Pen2,D-Pen5]enkephalin (DPDPE), [3H] (+)-(5 alpha, 7 alpha, 8 beta)-N-methyl-N-[7-(1-pyrrolidinyl) l-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593), with Ki values of 3.3 +/- 0.7, 22.8 +/- 1.5 and 1.9 +/- 0.3 nM, respectively In CHO cells expressing the mu-, delta- and kappa-opioid receptors, KT-90 inhibited forskolin (10 microM)-induced cyclic AMP accumulation in a concentration-dependent manner with IC50 values of 2337 +/- 750, 17.3 +/- 4.6 and 2.0 +/- 0.1 nM, respectively. The maximal inhibitory effects of KT-90 in the cells expressing mu-, delta- and kappa-opioid receptors were significantly lower than those of the type-selective agonists DAMGO, DPDPE and U69,593, respectively. These results indicated that KT-90 acts as a partial agonist on mu-, delta- and kappa-opioid receptors. KT-90 (10 and 100 nM), when added with morphine, produced a rightward shift of the concentration-response curve of morphine to inhibit the cyclic AMP accumulation in CHO cells expressing mu-, but not delta- or kappa-, opioid receptors. This finding is consistent with the findings that lower doses of KT-90 antagonize morphine analgesia in vivo.
 ...
PMID:Pharmacological characterization of KT-90 using cloned mu-, delta- and kappa-opioid receptors. 889 18

Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring neuropeptide that displays high selectivity for mu-opioid receptors. Recently, intrathecal (i.t.) Tyr-W-MIF-1 was shown to induce potent analgesia mediated through spinal mu2-opioid receptors in mice. In the current study, we investigated the supraspinal analgesic effects of Tyr-W-MIF-1 using intracerebroventricular (i.c.v.) administration in mice. I.c.v. Tyr-W-MIF-1 induced a dose-dependent analgesic response with an ED50 of 31.4 micrograms that was antagonized by i.c.v. naloxone (ED50 = 4.46 nmol) and the mu-opioid receptor antagonist beta-funaltrexamine but not by the mu1-opioid receptor-selective antagonist naloxonazine. I.t. naloxone (ED50 = 0.12 nmol), however, was nearly 40-fold more potent than i.c.v. naloxone at antagonizing i.c.v. Tyr-W-MIF-1-induced analgesia. Tyr-W-MIF-1 also possesses antagonist activity at mu1-opioid receptors in brain. Coadministration of i.c.v. Tyr-W-MIF-1 with i.c.v. morphine or i.c.v. [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAMGO) significantly decreased the analgesic response to either drug administered alone. Thus, Tyr-W-MIF-1 functions as a mixed mu2-opioid receptor agonist/mu1-opioid receptor antagonist after i.c.v. administration in mice.
 ...
PMID:Analgesic effects of Tyr-W-MIF-1: a mixed mu2-opioid receptor agonist/mu1-opioid receptor antagonist. 898 47

Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.
 ...
PMID:Differential opioid agonist regulation of the mouse mu opioid receptor. 899 64

1. The actions of opioids on synaptic transmission in rat periaqueductal grey (PAG) neurones were examined using whole-cell patch-clamp recordings in brain slices. 2. Methionine enkephalin (ME; 10 microM) inhibited evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 57%, non-NMDA excitatory postsynaptic currents (EPSCs) by 60%, and NMDA EPSCs by 43% in PAG neurones. This inhibition was associated with an increase in paired-pulse facilitation, was mimicked by the mu-agonist DAMGO (1-3 microM) and abolished by naloxone (1 microM). Neither the kappa-agonist U69593 (1-3 microM), nor the delta-agonist DPDPE (3-10 microM) had any specific actions on evoked PSCs. 3. ME decreased the frequency of spontaneous miniature, action potential-independent postsynaptic currents (mIPSCs by 65%, mEPSCs by 54%) in all PAG neurones, but had no effect on their amplitude distributions. The reduction in mIPSC frequency persisted in nominally Ca(2+)-free, high-Mg2+ (10 mM) solutions, which also contained Cd2+ (100 microM), or Ba2+ (10 mM). Opioid inhibition of mIPSC frequency is unlikely to be mediated by presynaptic Ca2+ or K+ conductances which are sensitive to extracellular Cd2+ or Ba2+. 4. In a subpopulation of PAG neurones, ME increased a Ba(2+)-sensitive K+ conductance at potentials below -97 mV. Opioids inhibited both GABAergic and glutamatergic synaptic transmission in all PAG neurones, independent of any postsynaptic opioid sensitivity. 5. These observations are consistent with, but only partially support, the opioid disinhibition model of PAG-induced analgesia. mu-Opioids also have the potential to modulate the behavioural and autonomic functions of the PAG via modulation of both inhibitory and excitatory presynaptic mechanisms, as well as postsynaptic mechanisms.
 ...
PMID:Presynaptic inhibitory action of opioids on synaptic transmission in the rat periaqueductal grey in vitro. 903 93

The effect of a mu-opioid receptor irreversible antagonist on the development of tolerance to fentanyl was determined in mice. Mice were injected with saline or clocinnamox (3.2 mg/kg, i.p.) and 4 h later mice implanted s.c. with a placebo pellet or an osmotic minipump that infused fentanyl (0.165 mg/kg per day) for 3 days. Fentanyl pumps and placebo pellets were removed on the third day following implantation and 4 h later mu-opioid receptor saturation binding studies in whole brain ([3H][D-Ala2,MePhe4,Gly-ol5]enkephalin: DAMGO) or fentanyl analgesic dose-response studies (tailflick assay) were conducted. Fentanyl infusions and clocinnamox both significantly reduced the potency of fentanyl by 2.8- and 2.4-fold, respectively. When fentanyl and clocinnamox were administered together, a significant 5.0-fold reduction in fentanyl potency relative to the saline-placebo group was observed, which represents an additive effect of clocinnamox and fentanyl. The ED50 of fentanyl in clocinnamox-treated mice was shifted 2.1-fold by fentanyl infusion relative to the clocinnamox-placebo group. This is comparable to the 2.8-fold shift in the ED50 produced by fentanyl infusion in saline-treated mice. In binding studies, fentanyl produced a small (-9%) reduction in Bmax, while clocinnamox significantly reduced (-41%) mu-opioid receptor density without altering affinity (Kd). In the clocinnamox-fentanyl group, there was a 50% reduction in Bmax, which is similar to the additive effect observed in analgesia studies. These data indicate that changes in mu-opioid receptor density prior to the development of tolerance to fentanyl do not impact on the magnitude of tolerance.
 ...
PMID:Magnitude of tolerance to fentanyl is independent of mu-opioid receptor density. 904 94

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

Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the delta (enkephalins) and kappa (dynorphins) opiate receptors, but none has been found to have any preference for the mu receptor. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the mu receptor, it could be important to identify endogenous peptides specific for this site. Here we report the discovery and isolation from brain of such a peptide, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has a high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the delta and kappa receptors) for the mu receptor. This peptide is more effective than the mu-selective analogue DAMGO in vitro and it produces potent and prolonged analgesia in mice. A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which differs by one amino acid, was also isolated. The new peptides have the highest specificity and affinity for the mu receptor of any endogenous substance so far described and they may be natural ligands for this receptor.
 ...
PMID:A potent and selective endogenous agonist for the mu-opiate receptor. 908 97


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