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)

Central morphine analgesia is significantly greater in male than in female rats. Since mu and delta opioid receptor subtypes have been implicated in supraspinal analgesia, the present study evaluated whether gender or adult gonadectomy altered (a) analgesia on the tail-flick and jump tests following central administration of the mu-selective agonist, [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAMGO) and the delta-selective agonist, [D-Ser2,Leu5] enkephalin-Thr6 (DSLET) and (b) mu1, mu2 and delta opioid receptor binding. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia than sham-operated females on the tail-flick test following DAMGO, but not DSLET. Gender differences were not observed for DAMGO and DSLET analgesia on the jump test. Gonadectomy failed to consistently affect either DAMGO or DSLET analgesia. Regression analyses failed to reflect significant shifts in the dose-response functions for either agonist on either measure. Gender differences were not observed for mu1, mu2, or delta binding in hypothalamus or cortex. These data are compared with analgesic responses sensitive to gender differences.
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PMID:Gender effects and central opioid analgesia. 167 51

Several phenylhydrazone derivatives of oxymorphone [phenylhydrazone and p-nitrophenylhydrazone (OxyPNPH)] as well as oxymorphonazine produce a wash-resistant inhibition of radiolabeled opioid binding, suggesting nonequilibrium binding to opiate receptors. All are agonists and, in an effort to correlate their prolonged inhibition of binding with their pharmacology, we examined their analgesic actions in vivo. Dose-response curves at 1 hr revealed similar potencies of oxymorphone and the derivatives, with the exception of OxyPNPH which was significantly less potent. After 10 hr, oxymorphone at doses up to 50 mg/kg did not demonstrate any effect. In contrast, OxyPNPH at 25 mg/kg elevated tail-flick latencies from 2 to over 8 sec after 10 hr. The 50-mg/kg dose elevated latencies to approximately 5 sec after 24 hr. Oxymorphonazine and oxymorphone phenylhydrazone also produced a prolonged analgesia, although not as effectively as OxyPNPH. The prolonged analgesic actions of OxyPNPH were highly dependent upon a critical period of 2 to 3 h immediately after injection. Blockade of receptors during this period with naloxone prevented analgesia at all time points examined. If the long duration of action of OxyPNPH resulted simply from a long half-life and persistent-free compound within the brain, analgesia should have returned by 8 hr, at which time naloxone has been eliminated. The absence of analgesia 8 hr after both OxyPNPH and naloxone argues against simple pharmacokinetic mechanisms for the prolonged analgesia and is consistent with persistent receptor occupation. OxyPNPH (25 mg/kg) administered in vivo lowered radiolabeled opioid binding effectively in brain membranes despite extensive washing. OxyPNPH lowered mu1 binding by approximately 60% and mu2 binding by 35% whereas delta binding was not lowered significantly.
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PMID:Irreversible opiate agonists and antagonists. IV. Analgesic actions of 14-hydroxydihydromorphinone hydrazones. 245 49

To determine whether the differences in development of acute tolerance to several morphine actions correlate with the mu receptor subtype mediating them, we have examined the appearance of acute tolerance to analgesia, respiratory depression, gastrointestinal transit, and hormone release in an intravenous morphine infusion model. Analgesia, a naloxonazine-sensitive mu1 action, peaked at 2 hr after initiation of the infusions. The log dose-response relationship of the infusion rate to peak tailflick latency was linear from 10 to 50 micrograms/kg/min. By 8 hr, the tailflick latencies declined nearly to baseline levels, implying the rapid development of tolerance. Tolerance to morphine-induced prolactin release, another mu1 action, also developed rapidly over 8 hr. In contrast two mu2 actions, respiratory depression measured with arterial blood gas, determinations and gastrointestinal transit, showed no significant tolerance over a similar 8 hr infusion. We also observed no tolerance to morphine-induced growth hormone release, a non-mu1 action, over the same period. Thus, these results demonstrate that mu1 actions develop tolerance in an infusion model far more rapidly than a number of naloxonazine-insensitive (non-mu1) ones and may help explain differences in the rate of tolerance development to morphine actions.
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PMID:Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. 255 41

Morphine-6 beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To define more fully the importance of this compound in morphine action, we have compared the analgesic actions of morphine and its 6 beta-glucuronide metabolite after both peripheral and central administration. Given s.c., morphine-6 beta-glucuronide elicited analgesia with an effect approximately twice that of morphine due, in part, to its long duration of action and also inhibited gastrointestinal motility. Both actions were easily reversed by naloxone (s.c.). However, when injected either i.c.v. or intrathecally, morphine-6 beta-glucuronide was approximately 90- and 650-fold more potent an analgesic than morphine, respectively. Whereas morphine in these studies was equipotent at both levels of the neuraxis as an analgesic, the 6 beta-glucuronide was approximately 5-fold more effective at the level of the spinal cord than supraspinally. The mu 1-selective antagonist naloxonazine blocked the analgesic effect of systemic and i.c.v. morphine-6 beta-glucuronide much as it blocked morphine, implying a role for mu1 receptors in these actions. Like morphine, morphine-6 beta-glucuronide analgesia after intrathecal injection was not sensitive to naloxonazine, suggesting a mu2 mechanism within the spinal cord. Together, these results imply that morphine-6 beta-glucuronide elicited its analgesic actions through the same receptor mechanisms as morphine. Mice highly tolerant to morphine after implantation of morphine pellets showed cross-tolerance to morphine-6 beta-glucuronide (s.c.). The high potency of morphine-6 beta-glucuronide strongly suggests that this metabolite plays an important role in morphine's actions.
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PMID:Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. 281 Jan 9

We have developed a quantitative computerized subtraction technique to demonstrate in rat brain the regional distribution of mu1 sites, a common very-high-affinity binding site for both morphine and the enkephalins. Low concentrations of [D-Ala2, D-Leu5]enkephalin selectively inhibit the mu1 binding of [3H]dihydromorphine, leaving mu2 sites, while low morphine concentrations eliminate the mu1 binding of [3H][D-Ala2, D-Leu5]enkephalin, leaving delta sites. Thus, quantitative differences between images of sections incubated in the presence and absence of these low concentrations of unlabeled opioid represent mu1 binding sites. The regional distributions of mu1 sites labeled with [3H]dihydromorphine were quite similar to those determined by using [3H][D-Ala2, D-Leu5]enkephalin. High levels of mu1 binding were observed in the periaqueductal gray, medial thalamus, and median raphe, consistent with the previously described role of mu1 sites in analgesia. Other regions with high levels of mu1 binding include the nucleus accumbens, the clusters and subcallosal streak of the striatum, hypothalamus, medial habenula, and the medial septum/diagonal band region. The proportion of total specific binding corresponding to mu1 sites varied among the regions, ranging from 14% to 75% for [3H][D-Ala2, D-Leu5]enkephalin and 20% to 52% for [3H]dihydromorphine.
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PMID:Visualization of mu1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique. 299 78

Several types of opioid binding sites have been differentiated using biochemical and pharmacological criteria. We have used quantitative in vitro autoradiography to compare the levels of mu1 and mu2 opioid binding in the mouse central nervous system. Mu1 sites have a high affinity for all labeled opioids studied to date and have been associated with their analgesic effects, whereas mu2 sites have a high affinity only for opiate alkaloids and have been associated with their respiratory depressant effects. We used [3H]dihydromorphine (DHM) to visualize total mu sites (mu1 and mu2) and [3H]DHM plus a low concentration of [D-Ala2-D-Leu5]enkephalin (DADL) to visualize mu2 sites. Levels of mu1 binding were determined by subtracting mu2 binding from total mu binding. This mu1 distribution was confirmed in selected regions by an alternate method using [3H]DADL. High ratios of mu1 to mu2 binding were noted in frontal cortex, nucleus accumbens, rostral striatum, ventral pallidum, ventral periaqueductal gray matter, and laminae I and II of the spinal cord. The observation of high densities of mu1 binding in certain pain processing areas correlates with behavioral and pharmacological studies suggesting that analgesia from opiates and opioids is mediated primarily by mu1 sites. In other areas, such as the limbic system, dorsal nucleus of the vagus nerve, and nucleus of the solitary tract, either a low ratio of mu1 to mu2 binding or no mu1 binding was observed. This differential regional localization of mu1 and mu2 binding provides further evidence for the distinctness of these sites.
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PMID:Autoradiographic distribution of mu1 and mu2 opioid binding in the mouse central nervous system. 300 May 29

Binding and pharmacological studies suggest a common opiate and enkephalin binding site in addition to their previously reported selective sites. This common high affinity site has tentatively been named mu1, distinguishing it from the morphine-selective site (mu2) and enkephalin-selective site (delta). The existence of this additional common high affinity site and its association with opiate and opioid peptide analgesia may help explain some pharmacological observations, such as the cross tolerance between morphine and enkephalin analgesia and the lack of cross tolerance between them in the guinea pig ileum and mouse vas deferens bioassays.
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PMID:High and low affinity opioid binding sites: relationship to mu and delta sites. 629 18

Although MOR-1 encodes a mu opioid receptor, its relationship to the pharmacologically defined mu receptor subtypes has been unclear. Antisense mapping now suggests that these subtypes result from alternative splicing of MOR-1. Three oligodeoxynucleotide probes targeting exon 1 and another oligodeoxynucleotide directed against the coding region of exon 4 block supraspinal morphine analgesia, a mu1 action, while five of six oligodeoxynucleotides directed against exons 2 and 3 are inactive. Inhibition of gastrointestinal transit and spinal morphine analgesia, two mu2 actions, are blocked only by the probe against exon 4 and not by those directed against exon 1. In contrast, the analgesic actions of the extraordinarily potent mu drug morphine-6 beta-glucuronide are blocked by six different antisense oligodeoxynucleotides targeting exons 2 and 3, but not by those acting on exons 1 or 4. These results suggest that the mu1 and mu2 receptor subtypes originally defined in binding and pharmacological studies result from alternative splicing of MOR-1 while morphine-6 beta-glucuronide acts through a novel, previously unidentified receptor which is yet another MOR-1 splice variant.
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PMID:Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6 beta-glucuronide receptor. 764 56

Morphine coadministered at the level of the brainstem and the spinal cord in rodents elicits a profound synergism with a combined analgesic potency almost 10-fold greater than that seen with morphine in either region alone. In the present study, we demonstrate that supraspinal mu2 receptors mediate this synergy, whereas morphine given only within the brainstem elicits analgesia through mu1 receptors. In the mu1-deficient CXBK strain of mice, morphine given intracerebroventricularly (i.c.v.) alone at doses up to 10 micrograms fails to produce greater than 20% analgesia in marked contrast to CD-1 mice (ED50 0.51 micrograms i.c.v.). At the spinal level, both the CXBK and CD-1 strains are equally sensitive to morphine (ED50 0.91 and 0.94 micrograms intrathecally, respectively), a mu2 action. Morphine administered i.c.v. potentiates a fixed low dose of intrathecal morphine as effectively in the CXBK mice as the CD-1 mice. Additional studies using selective mu antagonists differentiated these two analgesic responses pharmacologically. The mu1-selective drug naloxonazine (35 mg/kg s.c.) antagonizes the analgesic actions of morphine given only supraspinally without diminishing the potency of i.c.v. morphine in the synergy model. beta-Funaltrexamine, which blocks both mu1 and mu2 receptors, given i.c.v. antagonizes the analgesia after supraspinal morphine alone (ID50 2.5 micrograms i.c.v.) or its potentiation of intrathecal morphine (ID50 2.4 micrograms i.c.v.) equally well, confirming the involvement of mu receptors in both actions. In contrast, naloxonazine reverses the analgesia after supraspinal morphine alone (ID50 2.8 micrograms i.c.v.) almost 6-fold more potently than the synergy between i.c.v. and intrathecal morphine (ID50 18.3 micrograms i.c.v.). Together our results indicate the presence of two genetically and pharmacologically distinct populations of supraspinal mu receptors capable of mediating analgesia.
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PMID:Independent expression of two pharmacologically distinct supraspinal mu analgesic systems in genetically different mouse strains. 838 34

A possible correlation of behavioral, antinociceptive and cataleptic responses with central delta- and mu-opioid receptor stimulation was tested for in the rat by i.c.v. injections of some synthetic deltorphin analogs. At doses ranging from 0.1 to 3.0 nmol/rat, the selective delta-opioid receptor agonist, [D-Ala2,Glu4]deltorphin (Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2), induced a dose-dependent stereotyped pattern of locomotor activity, reaching the maximum in the first 30 min; doses higher than 30 nmol induced early and fleeting antinociception. The replacement of Glu4 by Gly, Ala, Val, His or Asn yielded peptides with a lower delta-selectivity because of a gain in mu-affinity. [D-Ala2,Ala4]deltorphin (0.14-4.0 nmol) induced negligible behavioral stimulation but a rapidly appearing and long-lasting analgesia and catalepsy. The other four synthetic peptides induced biphasic effects: low dosages stimulated locomotion whereas higher doses initially suppressed, then increased locomotor activity. At doses ranging from 1 to 70 nmol all the peptides induced analgesia and catalepsy. In experiments examining the locomotor and antinociceptive effects induced by 14 nmol of [D-Ala2,Gly4]deltorphin in rats pretreated with mu and delta antagonists, the non-selective mu-opioid receptor antagonist, naloxone (1 mg/kg i.p.), reduced analgesia and abolished the initial hypolocomotion. The delta-selective antagonist, naltrindole (10 mg/kg i.p.), abolished locomotor activity without affecting analgesia. The mu1 -selective antagonist, naloxonazine (10 mg/kg i.v.), seemed to prolong analgesia and immobility. Hence this peptide appears to activate, in addition to delta-receptors, mainly the opioid receptor mu2-subtype, which mediates catalepsy in the rat. We suggest that the mu2- and delta-opioid receptors of the rat brain modulate locomotor behavior by activating functionally opposed responses. [D-Ala2,Ala4]deltorphin had an antinociceptive and cataleptic potency higher than would have been expected from its mu-affinity. A possible explanation might be a mu/delta-opioid receptor interaction.
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PMID:Antinociceptive and behavioral effects of synthetic deltorphin analogs. 872 Apr 71


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