Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Opioid receptor agonists produce analgesia through multiple systems activated by stimulation of mu(1), mu(2), delta(1), delta(2) and kappa(1) opioid receptors. Morphine analgesia is modulated by stimulation of alpha(2) adrenoceptors. To understand how multiple opioid analgesic systems interact with alpha(2)-adrenoceptor systems, analgesic cross-tolerance between the alpha(2) adrenoceptor agonist xylazine and opioid receptor agonists was studied using the mouse tail-flick assay. Mice received either xylazine (20 mg/kg, s.c.) or saline (1 ml/kg) for five days. On day six, mice received a dose of s.c. xylazine, i.c.v. [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin (DAMGO), i.t. Tyr-Pro-Trp-Gly-NH(2) (Tyr-W-MIF-1), i.c.v. or i.t. [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), i.t. [D-Ala(2)]deltorphin II (deltorphin II), or s.c. trans-(+/-)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl-cyclohexyl] benzeneacetamide (U50,488). Xylazine tolerant mice required 4. 57-fold more xylazine to elicit the same response as saline treated animals and showed a 2.55-fold shift in i.c.v. DAMGO and a 3.37-fold shift in i.c.v. DPDPE antinociception. No cross-tolerance was seen with i.c.v. deltorphin II, i.t.Tyr-W-MIF-1, i.t. DPDPE, i.t. Tyr-W-MIF-1 or s.c. U50,488. These results implicate alpha(2) adrenoceptor systems in the modulation of supraspinal mu(1), and delta(1) opioid analgesic circuitry and raise the possibility that mu(2), delta(2) or kappa(1) opioid receptor agonists may be alternated with alpha(2) adrenoceptor agonists to minimize tolerance or treat opioid-tolerant patients.
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PMID:Cross-tolerance between analgesia produced by xylazine and selective opioid receptor subtype treatments. 1068 82

We studied the acute tolerance liability of peripheral opioid analgesia in mice. The analgesia was assessed by the inhibition of bradykinin (BK)-induced nociceptive action by using a newly developed flexor reflex paradigm. Morphine [intraplantarly (i.pl.)] given ipsilaterally to BK showed a dose-dependent reduction of the BK (2 pmol) responses, whereas the administration of 10 nmol of morphine into the contralateral side failed to show any significant analgesic effects. Furthermore, DAMGO ([D-Ala(2),MePhe(4), Gly-ol(5)]-enkephalin), a mu-opioid receptor (MOR) agonist, and U-69593, a kappa-opioid receptor (KOR) agonist, but not DSLET ([D-Ser(2)]Leu-enkephalin-Thr(6)), a delta-opioid receptor agonist, showed similar analgesia on the BK responses. The morphine- or U-69593 [(5alpha,7alpha, 8beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec -8yl] benzeneacetamide]-induced analgesia was markedly attenuated by the intrathecal injection of each antisense oligodeoxynucleotide for the MOR or KOR, respectively, suggesting that these peripheral analgesia are mediated through MORs and KORs located on nociceptor endings, respectively. As BK response was completely recovered to the control level 4 h after morphine (3 nmol i.pl.) or U-69593 (10 nmol i.pl.) administration, these compounds were challenged again to see the inhibition of BK responses. Although morphine analgesia by the second challenge was markedly attenuated, U-69593 analgesia was not. The attenuated morphine analgesia was completely reversed by the pretreatment of calphostin C, Go6976, or HBDDE, a protein kinase C inhibitor, but not by KT-5720, a protein kinase A inhibitor. These results suggest that selective acute tolerance of peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs located on polymodal nociceptors, respectively, in the bradykinin-nociception test in mice was mediated through protein kinase C activation.
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PMID:Protein kinase C-mediated acute tolerance to peripheral mu-opioid analgesia in the bradykinin-nociception test in mice. 1077 42

We have previously demonstrated that electrical stimulation of the ventral periaqueductal gray matter (PAG) produced analgesia in neuropathic pain in rats. Opioids were also shown to be involved in analgesic effects. This study sought to determine whether opiates microinjected into the ventral PAG produce analgesia. Male Sprague-Dawley rats were chronically implanted with a guide cannula in the PAG under pentobarbital anesthesia and both the tibial and sural nerves were completely cut. Pain sensitivity was postoperatively measured with a von Frey filament and acetone applied to the sensitive area for 1 week. Opioids such as [D-Ala2,N-MePhe4,Gly(ol)5]-enkephalin (DAMGO) and [D-Pen ,D-Pen5]-enkephalin (DPDPE) were injected into the PAG. DAMGO, a mu-opioid agonist, and DPDPE, a delta-opioid agonist, were highly effective in reducing neuropathic pain. These effects were reversed by naloxone. These results suggest that the neurons in the ventral PAG are activated by opioids to produce analgesia and that specific opioid receptors are involved in the descending pain inhibition system from the PAG.
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PMID:Microinjection of opiates into the periaqueductal gray matter attenuates neuropathic pain symptoms in rats. 1084 48

Previously, it was determined that microinjection of morphine into the caudal portion of subnucleus caudalis mimicked the facilitatory effects of intravenous morphine on cornea-responsive neurons recorded at the subnucleus interpolaris/caudalis (Vi/Vc) transition region. The aim of the present study was to determine the opioid receptor subtype(s) that mediate modulation of corneal units and to determine whether opioid drugs affected unique classes of units. Pulses of CO(2) gas applied to the cornea were used to excite neurons at the Vi/Vc ("rostral" neurons) and the caudalis/upper cervical spinal cord transition region (Vc/C1, "caudal" neurons) in barbiturate-anesthetized male rats. Microinjection of morphine sulfate (2.9-4.8 nmol) or the selective mu receptor agonist D-Ala, N-Me-Phe, Gly-ol-enkephalin (DAMGO; 1.8-15.0 pmol) into the caudal transition region enhanced the response in 7 of 27 (26%) rostral units to CO(2) pulses and depressed that of 10 units (37%). Microinjection of a selective delta ([D-Pen(2,5)] (DPDPE); 24-30 pmol) or kappa receptor agonist (U50488; 1.8-30.0 pmol) into the caudal transition region did not affect the CO(2)-evoked responses of rostral units. Caudal units were inhibited by local DAMGO or DPDPE but were not affected by U50,488H. The effects of DAMGO and DPDPE were reversed by naloxone (0.2 mg/kg iv). Intravenous morphine altered the CO(2)-evoked activity in a direction opposite to that of local DAMGO in 3 of 15 units, in the same direction as local DAMGO but with greater magnitude in 4 units, and in the same direction with equal magnitude as local DAMGO in 8 units. CO(2)-responsive rostral and caudal units projected to either the thalamic posterior nucleus/zona incerta region (PO/ZI) or the superior salivatory/facial nucleus region (SSN/VII). However, rostral units not responsive to CO(2) pulses projected only to SSN/VII and caudal units not responsive to CO(2) projected only to PO/ZI. It was concluded that the circuitry for opioid analgesia in corneal pain involves multiple sites of action: inhibition of neurons at the caudal transition region, by intersubnuclear connections to modulate rostral units, and by supraspinal sites. Local administration of opioid agonists modulated all classes of corneal units. Corneal stimulus modality was predictive of efferent projection status for rostral and caudal units to sensory thalamus and reflex areas of the brain stem.
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PMID:Cornea-responsive medullary dorsal horn neurons: modulation by local opioids and projections to thalamus and brain stem. 1093 27

The novel endogenous mu-opioid receptor (MOR) agonists endomorphin 1 (EM1) and 2 (EM2) were tested for their cardiorespiratory effects in conscious, freely behaving rats. After systemic (intravenous) administration of EM1, EM2, or the selective MOR agonist DAMGO, analgesia, minute ventilation (V E), heart rate (HR) and mean arterial blood pressure (BP) were measured. The threshold dose for analgesia was similar for all 3 peptides ( approximately 900 nmol/kg). All 3 compounds elicited biphasic V E responses, with marked, short-lived V E depressions (4-6 s) followed by more sustained V E increases (10-12 min). However, compared with responses elicited by EM2 or DAMGO, EM1 decreased V E only at higher doses, and produced greater V E stimulation. Morphine produced a V E decrease, but no subsequent V E increase. EM2 and DAMGO decreased HR and BP, while EM1 decreased HR, but did not decrease BP in conscious rats at doses up to 9,600 nmol/kg. In anesthetized rats, all 3 peptides decreased HR and BP. The decreases in V E, HR, and BP were blocked by the MOR antagonist, naloxone HCI (NIx). Only the HR and BP responses, however, were blocked by naloxone-methiodide (MeNIx), indicating central mediation of V E responses and peripheral mediation of cardiovascular responses. We conclude that MOR-selective compounds vary in their cardiorespiratory response characteristics which could be linked to differential cellular actions. The results support the concept that the analgesic, respiratory, and cardiovascular effects of MOR agonists can be dissociated and that EM1-like compounds could provide the basis for novel, safer analgesics.
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PMID:Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine. 1098 19

The endogenous opioid neurotransmitter beta-endorphin (beta-END), a product of the proopiomelanocortin (POMC) gene, is strongly implicated in the control of the female reproductive cycle, stress responses, and antinociception. Using selective gene targeting, we have generated a strain of mice that do not express any beta-END. These mice exhibit both normal reproduction and normal basal and stress-induced hypothalamic-pituitary-axis activity, but exhibit a significantly attenuated opioid-mediated stress-induced analgesia. To further understand the cellular bases of these responses, we have studied mediobasal hypothalamic (MBH) neurons, including POMC neurons, using whole-cell patch recording in an in vitro slice preparation. Twenty-seven MBH cells were recorded in wild-type and 25 MBH cells were recorded in beta-END knockout mice. Neurons from both genotypes showed a significant positive correlation between DAMGO concentration (from 30 nM to 10 microM) and the induced outward K(+) current. The genotypes did not differ, however, in either the DAMGO-induced maximum outward current response or EC(50), or for the maximal response to the GABA(B) agonist baclofen. Furthermore, quantitative receptor autoradiography utilizing (3)H-DAMGO did not reveal any differences in total mu-opioid receptor binding between genotypes. Therefore, we conclude that the complete absence of beta-END throughout development did not alter either the expression of mu-opioid receptors or their coupling to K(+) channels in MBH neurons.
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PMID:Effect of the mu-opioid agonist DAMGO on medial basal hypothalamic neurons in beta-endorphin knockout mice. 1107 Apr 24

Local anaesthetics potentiate epidural or intrathecal opioid analgesia via a poorly defined mechanism. In this study, we have examined the interaction of local anaesthetics (lidocaine, bupivacaine and its optical isomers, tetracaine, procaine and prilocaine) with recombinant mu-, kappa-, and delta-opioid receptors expressed in Chinese hamster ovary cells (CHO-mu, kappa, and delta, respectively). Lidocaine produced a concentration-dependent displacement of radiolabelled opioid antagonist [3H]diprenorphine ([3H]DPN) binding with the following rank order of inhibitor constant (Ki): kappa (210 microM) > mu (552 microM) > delta (1810 microM). Procaine, prilocaine, tetracaine and bupivacaine also displaced [3H]DPN binding in CHO-mu with Ki values of 244, 204, 43 and 161 microM respectively. Lidocaine produced a concentration-dependent and naloxone-insensitive inhibition of cAMP formation in all cell lines including untransfected cells. Concentration producing 50% inhibition of maximum was mu, 1.32 mM; kappa, 2.41 mM; delta, 1.27 mM; untransfected, 2.78 mM. When lidocaine (300 microM) was co-incubated with spiradoline (kappa-selective) and [D-Ala2, MePhe4, Gly(ol)5] enkephalin (DAMGO mu-selective) in CHO-kappa and mu cells we did not observe an additive interaction for cAMP formation. In contrast, there was an apparent inhibitory action of the combination at the kappa receptor. This study suggests that clinical concentrations of local anaesthetics interact with mu and kappa but not delta opioid receptors. As there was no synergism between local anaesthetics and opioids we suggest that the interaction of these agents in the clinical setting does not occur at the cellular level.
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PMID:Interaction of local anaesthetics with recombinant mu, kappa, and delta-opioid receptors expressed in Chinese hamster ovary cells. 1109 91

Although both pre- and postsynaptic mechanisms have been implicated in the analgesia produced by mu-opioids at the spinal cord, it is not known under what conditions these different controls come into play. Because the mu-opioid receptor (MOR) can be visualized in individual lamina II excitatory interneurons and internalizes into endosomes on ligand binding, we tested whether MOR internalization could be monitored and used to measure postsynaptic MOR signaling. To test whether endogenous opioids modulate these lamina II interneurons during noxious stimulation, we next assessed the magnitude of postsynaptic MOR internalization under a variety of nociceptive conditions. As observed in other systems, we show that MOR internalization in dorsal horn interneurons is demonstrated readily in response to opioid ligands. The MOR internalization is dose-dependent, with a similar dose-response to that observed for opioid-induced increases in potassium conductance. We demonstrate that MOR internalization in lamina II neurons correlates precisely with the extent of analgesia produced by intrathecal DAMGO. These results suggest that MOR internalization provides a good marker of MOR signaling in the spinal cord and that postsynaptic MORs on lamina II interneurons likely participate in the analgesia that is produced by exogenous opioids. We found, however, that noxious stimuli, under normal or inflammatory conditions, did not induce MOR internalization. Thus, endogenous enkephalins and endomorphins, thought to be released during noxious peripheral stimuli, do not modulate nociceptive messages via postsynaptic MORs on lamina II interneurons. We suggest that any endogenous opioids that are released by noxious stimuli target presynaptic MORs or delta-opioid receptors.
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PMID:Postsynaptic signaling via the [mu]-opioid receptor: responses of dorsal horn neurons to exogenous opioids and noxious stimulation. 1110 61

This review summarizes our studies using pharmacological, neurochemical and molecular biological methods on the nociception in the CNS and opioid receptors (OPRs). We designed an in vitro fluorometric on-line monitoring system including an immobilized glutamate dehydrogenase column, and for the first time actually demonstrated that capsaicin induced the release of glutamate from rat dorsal horn slices containing the terminal area of primary afferents, in concentration-dependent, extracellular Ca(2+)-dependent and tetrodotoxin-resistant manners. Further, such a release was shown to be inhibited through mu- and delta-opioid receptors and alpha 2-adrenoceptors. On the other hand, we found that intracerebroventricular injections of interleukin (IL)-1 beta in rats produced biphasic effects on the mechanical nociception in rats (hyperalgesia in lower concentrations but analgesia in higher ones) and that similar injections of cytokine-induced neutrophil chemoattractant-1 (CINC-1) facilitated mechanical nociception in rats. The above described facts suggest that glutamate and some sorts of cytokines (IL-1 beta and CINC-1) contribute to nociception at least from the primary afferents to the spinal dorsal horn neurons and in higher brain, respectively. We have cloned rat kappa- and mu-opioid receptors. Using cloned cDNA for OPRs, we demonstrated (1) the distribution of mRNAs for OPRs in the rat central nervous system, (2) coexistence of each type of mRNA for mu-, delta- and kappa-OPRs and pre-protachykinin A mRNA in the dorsal root ganglion neurons, (3) an increased expression of mu- and kappa-OPR mRNAs in the I-II layers of rat lumbar dorsal horn with an adjuvant arthritis in the hind limb, (4) the inhibitions of N- and Q-types of Ca2+ channels by mu- and kappa-OPR agonists and (5) cross-desensitization of the inhibition through a common intracellular phosphorylation-independent mechanism, (6) pharmacological characterization of "antagonist analgesics" as partial agonists at every type of OPRs, and (7) the key-structure(s) of OPRs for discriminative binding of DAMGO to mu-OPR.
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PMID:[Molecular neuropharmacology of nociceptive transmission and opioid receptors]. 1119 80

mu- and delta-Opioid agonists interact in a synergistic manner to produce analgesia in several animal models. Additionally, receptor binding studies using membranes derived from brain tissue indicate that interactions between mu- and delta-opioid receptors might be responsible for the observation of multiple opioid receptor subtypes. To examine potential interactions between mu- and delta-opioid receptors, we examined receptor binding and functional characteristics of mu-, delta-, or both mu- and delta-opioid receptors stably transfected in rat pituitary GH(3) cells (GH(3)MOR, GH(3)DOR, and GH(3)MORDOR, respectively). Saturation and competition binding experiments revealed that coexpression of mu- and delta-opioid receptors resulted in the appearance of multiple affinity states for mu- but not delta-opioid receptors. Additionally, coadministration of selective mu- and delta-opioid agonists in GH(3)MORDOR cells resulted in a synergistic competition with [(3)H][D-Pen(2,5)]enkephalin (DPDPE) for delta-opioid receptors. Finally, when equally effective concentrations of [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) and two different delta-opioid agonists (DPDPE or 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydroquinolino-[2,3,3-g]-isoquinoline; TAN67) were coadministered in GH(3)MORDOR cells, a synergistic inhibition of adenylyl cyclase activity was observed. These results strongly suggest that cotransfection of mu- and delta-opioid receptors alters the binding and functional characteristics of the receptors. Therefore, we propose that the simultaneous exposure of GH(3)MORDOR cells to selective mu- and delta-opioid agonists produces an interaction between receptors resulting in enhanced receptor binding. This effect is translated into an augmented ability of these agonists to inhibit adenylyl cyclase activity. Similar interactions occurring in neurons that express both mu- and delta-opioid receptors could explain observations of multiple opioid receptor subtypes in receptor binding studies and the synergistic interaction of mu- and delta-opioids in analgesic assays.
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PMID:Interaction of co-expressed mu- and delta-opioid receptors in transfected rat pituitary GH(3) cells. 1125 22


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