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)

SCH-32615 is a new enkephalinase inhibitor whose analgesic effects were examined following its stereotactic microinjection into the periaqueductal gray (PAG) and the ventromedial medulla (VMM) regions of the brainstem of the rat. SCH-32615 produced a strong, dose-dependent, naloxone-reversible analgesia to thermal noxious stimuli as measured by the hot plate test (HP; supraspinal analgesia) and the tail flick test (TF; spinal analgesia). The peak analgesic effect was seen within 10 min and remained for 45-60 min. ED50 were for PAG, HP = 10.7 micrograms and TF = 17.3 micrograms, and for VMM, HP = 5.7 micrograms and TF = 7.2 micrograms. Using the irreversible mu receptor antagonist, beta-funaltrexamine, it was found that the endogenous enkephalins in the PAG produce their analgesic effects by acting at only one receptor subtype (the mu receptor) while in the VMM both mu and delta opioid receptors are involved (not through the delta alone as previously believed).
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PMID:Comparison of the neurochemistry of the endogenous opioid systems in two brainstem pain-processing centers. 129 34

Experiments were performed on 79 lightly pentobarbital-anesthetized rats. Rats displayed a dose-dependent increase in tail-flick latencies following the injection of dopamine (DA) into the lumbar subarachnoid space through an intrathecal tube. Sulpiride, a D2-subtype receptor antagonist, antagonized the DA-induced analgesia (antinociceptive) effect; while SCH-23390, a D1-subtype receptor antagonist, had no effect even in a higher dose. To further investigate whether the well-known spinal serotonergic, noradrenergic and opioidergic receptor systems were involved in DA-induced antinociception, their antagonists, methysergide, phentolamine, and naloxone were tested respectively. The results showed that phentolamine, but not methysergide or naloxone, could block the DA-induced antinociception. The present data provide evidence that DA exerts antinociceptive effects through D2-subtype dopamine receptor(s) at the spinal level, and that spinal alpha-adrenergic receptors may mediate this effect.
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PMID:D2 dopamine receptor involvement in spinal dopamine-produced antinociception. 143 58

Previous studies have shown that some of CNS actions of an endogenous peptide Tyr-MIF-1, are mediated by dopamine (DA) receptors. To study the effect of DA receptor blockade on the antiopiate properties of Tyr-MIF-1, the opiate form of footshock-induced analgesia was elicited in the rat. The nociceptive responses were determined using the hot-plate test (52.5 degrees C). Intraperitoneal pre-treatment with haloperidol (500 micrograms/kg), SCH 23390 (150 micrograms/kg), or spiroperidol (150 micrograms/kg) potentiated the antinociceptive effect of the footshock and blocked the antagonistic action of Tyr-MIF-1 (200 micrograms/kg and 2.0 mg/kg). A dose of haloperidol too small to potentiate the antinociceptive effect of the footshock (100 micrograms/kg) was still able to block the action of Tyr-MIF-1 (200 micrograms/kg). The results suggest that activation of DA receptors mediates the antagonizing effect of Tyr-MIF-1 on the opiate form of footshock-induced analgesia in the rat.
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PMID:Dopamine receptor antagonists block the effect of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) on the opiate form of footshock-induced analgesia. 168 56

The role played by dopamine D1 and D2 receptors in formalin test analgesia was explored by challenging D-amphetamine- and morphine-induced analgesia with mixed and selective D1 and D2 antagonists, and by examining the relative analgesic activity of mixed and selective D1 and D2 agonists. The mixed D1/D2 dopamine antagonist cis-flupenthixol (0.5 mg/kg), the D2 antagonist pimozide (0.5 mg/kg), and the D1 antagonist SCH 23390 (0.1 mg/kg) attenuated both D-amphetamine and morphine analgesia. The mixed D1/D2 agonist apomorphine and the selective D2 agonist quinpirole produced dose-dependent analgesia while the selective D1 agonist SKF 38393 was without effect. These data suggest that D1 receptors play an "enabling" role in D2 receptor-mediated analgesia in the formalin test.
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PMID:Dopamine receptor subtypes and formalin test analgesia. 168 67

In the hot plate test, the dopamine D2 receptor agonist RU 24926 as well as the mixed dopamine D1/D2 receptor agonist apomorphine dose dependently increased the nociceptive threshold of mice, as expressed by the jump latency. The dopamine D1 receptor agonist SKF 38393 was ineffective on this parameter. The effect of RU 24926 was antagonized by the dopamine D2 specific receptor antagonist sulpiride but not by the dopamine D1 specific receptor antagonist SCH 23390. It was not increased by SKF 38393. However, the effect of apomorphine was partially but significantly reduced by SCH 23390. Inhibitors of enkephalin-degrading peptidases (thiorphan and bestatin injected i.c.v. or acetorphan injected i.v.) did not potentiate the effect of apomorphine whereas the delta opioid antagonist IC 154, 129 did not reverse the apomorphine-induced analgesia. Finally, the effect of apomorphine was significantly decreased in mice rendered tolerant to morphine. It is concluded that, in mice, the antinociceptive effect induced by apomorphine results mainly from stimulation of D2 receptors. This stimulation probably involves an endogenous opioid, different from enkephalins, which acts at mu opioid receptors.
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PMID:Stimulation of dopamine D2 receptors induces an analgesia involving an opioidergic but non enkephalinergic link. 217 83

Cocaine (25 mg/kg i.p.) produces analgesia in the rat within 5 min and for a duration of 90 min as determined by the formalin test or for 30 min as determined by the hot plate test. Cocaine analgesia is unaffected by doses of naloxone that are sufficient to attenuate morphine analgesia in both tests. Chlorpromazine (3 mg/kg i.p.), SCH 23390 (100 micrograms/kg i.p.; a D1 dopamine receptor antagonist), and eticlopride (75 micrograms/kg i.p.; a D2 dopamine receptor antagonist) each attenuate cocaine analgesia in both tests at doses that alone do not affect performance in either test. Measurements of blood pressure and heart rate indicate that cocaine analgesia is not due to the activation of baroreceptor reflex afferents. We conclude that cocaine is a supraspinally acting, dopamine-mediated, non-opiate analgesic in the rat.
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PMID:Cocaine: evidence for supraspinal, dopamine-mediated, non-opiate analgesia. 264 10

To examine the role of dopamine receptor subtypes mediating analgesic and motor responses to opioids, rats were pretreated with either saline or a selective D-1 or D-2 dopamine receptor antagonist 10 min prior to morphine (12 mg/kg IP). Analgesic response latency was determined using the hot plate test (52.5 degrees C and 55 degrees C), and catalepsy was assessed using the abnormal posture test. Morphine increased analgesic response latency to 44.5 +/- 7.9% of the maximum possible response, but had no cataleptic effect in the abnormal posture test. Pretreatment with either the D-1 antagonist, SCH 23390 (50-100 micrograms/kg), or the D-2 antagonist, eticlopride (20-150 micrograms/kg), potently enhanced morphine analgesia as measured on the 52.5 degrees C hot plate. Peak analgesic responses to morphine increased to 100 +/- 0% and 91.9 +/- 7.5% of maximum with the highest doses of SCH 23390 and eticlopride, respectively. These treatments also produced catalepsy. Increasing the hot plate temperature to 55 degrees C reduced response latency in groups treated with either dopamine receptor antagonist plus morphine. This indicates that the animals were capable of responding at a shorter latency and demonstrates that motor impairment cannot account for potentiation of morphine analgesia by D-1 and D-2 antagonists at 52.5 degrees C. These results show that the relationship between dopamine and opioids with respect to analgesic and motor systems involves both dopamine receptor subtypes.
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PMID:Dopamine D-1 and D-2 receptor antagonists potentiate analgesic and motor effects of morphine. 266 24

SCH 30497 (2-[3-(1,2,3,6-tetrahydro-4-2(methylphenyl)-pyridin-1-yl) -propyl]-1,2,4-triazolo[4,3-a] pyridin-3-(2H)-one) was tested for analgesic effects in the rat, mouse and squirrel monkey. SCH 30497 showed dose-related analgesic effects in the rat yeast-paw test; at peak times the ED7sec (95% confidence limits) in mg/kg via the oral, subcutaneous, intramuscular and intravenous routes of administration were as follows, respectively: 4.7 (2.1-9.8), 5.7 (3.4-9.6), 6.4 (4.1-9.8) and 1.4 (0.6-3.2). SCH 30497 was also analgesic in the acetic acid-induced writhing test in mice (ED50 = 1.9 mg/kg p.o.) and the squirrel monkey shock titration test (ED50 = 14.5 mg/kg p.o.). It was inactive in the mouse (100 mg/kg p.o.) and rat (40 mg/kg p.o.) tail-flick tests. Thus, SCH 30497 was efficacious versus chemical, mechanical and electrical nociceptive stimuli. Naloxone antagonism of the analgesic effects of SCH 30497 was species specific with significant inhibition observed only in the rat and not in the mouse or monkey. SCH 30497 did not produce Straub tail or hyperactivity in mice. Twice daily dosing at 30 mg/kg p.o. to rats for 5 days failed to produce tolerance; in separate experiments, daily injections for 10 days at 20 or 100 mg/kg p.o. failed to induce signs of dependence following naloxone challenge. SCH 30497-induced analgesia was not attenuated in rats previously made tolerant to narcotics by implantation of a morphine pellet. SCH 30497 showed a weak ability to displace 3H-Met5-enkephalin from its binding sites on rat brain membranes (IC50 = 48 microM). SCH 30497 (100 microM) did not affect prostaglandin synthesis in vitro. In vivo, the drug did not have anti-inflammatory or ulcerogenic effects up to 80 mg/kg p.o. Acute behavioral, neurological and autonomic side effects were primarily depressant in rodents and occurred at doses greater than 15 times those that were analgesically relevant. Moderate doses in the monkey (2.5 times the ED50) and high doses in mice produced convulsions. It is hypothesized that SCH 30497-like drugs represent a new class of analgesics based on this unique pharmacological spectrum of activity.
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PMID:Pharmacological effects of SCH 30497--a novel analgesic substance. 300 16

SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine] was synthesized as a p.o. active prodrug enkephalinase inhibitor. In vivo, it is de-esterified to SCH 32615 (N-[L-(-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine), the active constituent. In vitro, the Ki for SCH 32615 to block the degradation of Met5-enkephalin by isolated enkephalinase is 19.5 +/- 0.9 nM. In contrast, SCH 32615 did not inhibit aminopeptidase or diaminopeptidase III degradation of Met5-enkephalin up to 10 microM and did not affect angiotensin converting enzyme up to 10 microM. In vivo, p.o. administered SCH 34826 potentiated the analgesic effects of D-Ala2-Met5-enkephalinamide in mice (ED50 = 5.3 mg/kg p.o.) and rats [minimal effective dose (MED) = 1 mg/kg p.o.]; SCH 32615 had no effect up to 30 mg/kg p.o., but was active parenterally (ED50 in mice = 1.4 ng/kg sc). Direct, naloxone-reversible analgesic effects of SCH 34826 were demonstrated in the mouse low temperature hot-plate test (MED = 30 mg/kg p.o.), the mouse acetic acid-induced writhing test (MED = 30 mg/kg p.o.), the rat stress-induced analgesia test (MED = 10 mg/kg p.o.) and the modified rat yeast-paw test (MED = 100 mg/kg p.o.). Using the rat D-Ala2-Met5-enkephalinamide potentiation test the duration of action of SCH 34826 was at least 4 hs. No respiratory or gastrointestinal side effects of any consequence were noted at doses up to 100 times those active in the D-Ala2-Met-5-enkephalinamide potentiation test.
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PMID:Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. 316 88

Increased tolerance to noxious stimuli during pregnancy has been demonstrated. The purpose of this study was to examine the effect of SCH 32615, an inhibitor of one of the enzymes (enkephalinase) responsible for the degradation of endogenous enkephalins, on pregnancy-induced analgesia in mice. Analgesia was tested using the hot-plate and tail-flick tests. For the hot-plate test, animals were tested in late pregnancy (Day 17 or Day 18 of pregnancy; mice deliver on Day 19) and in the postpartum period (Days 2 and 8 after delivery) in the following groups: i) no treatment (n = 15); ii) vehicle only (n = 15); iii) SCH 32615 250 mg/kg (n = 20), 150 mg/kg (n = 15), 50 mg/kg (n = 14); iv) naloxone 5 mg/kg (n = 15); v) naloxone 5 mg/kg+SCH 32615 150 mg/kg (n = 10); vi) nonpregnant control given SCH 32615 150 mg/kg (n = 14). All drugs were given subcutaneously. Hot-plate latency (HPL) was significantly higher in pregnant mice (mean hot-plate latency 17.5 s) than postpartum mice (mean hot-plate latency 11 s on Day 2 and 8.5 s on Day 8). SCH 32615 250 mg/kg and 150 mg/kg significantly enhanced this analgesia in pregnant mice (mean percent of maximum possible effect 24.2 and 29.9, respectively) but not SCH 32615 50 mg/kg or the vehicle alone (mean percent of maximum possible effect 12.4 and 0.5, respectively). Naloxone significantly lowered HPL in pregnant mice (19.8 s-16.2 s) and antagonized the effect of SCH 32615.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SCH 32615, an enkephalinase inhibitor, enhances pregnancy-induced analgesia in mice. 772 37


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