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

Acetorphan, an enkephalinase inhibitor, or morphine was injected in mice which had received saline or morphine (32 mg/kg s.c. twice a day on 8 consecutive days) chronically. In the hot-plate test, the analgesia (increase in jump latency) induced by morphine (2 mg/kg i.p.) or by the mu selective opioid agonist, [D-Ala2,N-Me-Phe4, Gly5-ol]enkephalin (DAGO) (1.5, 3 or 6 ng/mouse i.c.v.), was significant in the saline group but was strongly decreased in morphine-pretreated mice. In contrast the analgesic effect of acetorphan (5 mg/kg i.v.) or of the delta selective opioid agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) (0.75, 1.5 or 3 micrograms/mouse i.c.v.) was similar in both groups. These results suggest that the enkephalins protected by acetorphan act on the delta receptor site to produce antinociception.
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PMID:Desensitization of mu-opioid receptors does not modify the analgesia induced by an enkephalinase inhibitor. 166 49

Characterization of the distribution of the peptide-degrading enzyme neutral endopeptidase-24.11 (E.C. 3.4.24.11; NEP; enkephalinase) in the rat brainstem was examined by means of a unique fluorescent histochemical method. Enzyme staining was completely blocked by three potent NEP inhibitors (thiorphan, phosphoramidon, and JHF-26) at a concentration of 50 nM, supporting the specificity of this method to visualize sites of NEP activity selectively. At all levels of the brainstem, NEP was localized to cell bodies, cell processes or terminal-like fields and was localized to more than 90 distinct nuclei or subnuclei. In the mesencephalon these included the central gray, cuneiform n., dorsal and lateral tegmental n., inferior colliculus, interpeduncular n., lateral and medial geniculate n., central linear raphe n., mesencephalic n. of the trigeminal nerve, mammillary nuclei, occulomotor n., red n., superior colliculus, ventral n. of the lateral lemniscus, substantia nigra-ventral tegmental area, and the zona incerta. In the pons, NEP staining was restricted to fewer regions or nuclei, including the dorsal and ventral cochlear n., facial n., motor trigeminal n., principal sensory trigeminal n., parabrachial nuclei, pontine n., the oral and caudal pontine reticular n., pontine olivary nuclei, several pontine tegmental nuclei, pontine raphe nuclei, and the trapezoid n. In the cerebellum, staining was localized largely to the granule cell layer of the cerebellar cortex. Scattered staining was observed in the molecular cell layer. The medulla contained extensive NEP staining localized to nuclei that included the ambiguous n., dorsal motor n. of the vagus, hypoglossal n., inferior olivary n., prepositus hypoglossus n., solitary tract n., nuclei of the spinal tract of the trigeminal n., and the lateral, medial, and superior vestibular nuclei. Nuclei of the medullary reticular formation that were also richly stained for NEP included the raphe magnus n., raphe obscurus n., raphe pallidus n., dorsal, lateral, and ventral reticular nuclei of the medulla, and the gigantocellular, lateral paragigantocellular, linear, paramedian and parvicellular reticular nuclei. The widespread distribution of NEP in the brainstem suggests the existence of a number of functional systems, including the pathways involved in the mechanisms of pain and analgesia, which are potential targets of NEP inhibitors. In most regions, the distribution of NEP closely overlapped with that reported for the enkephalins, and showed a more restricted overlap with the reported distribution of substance P.
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PMID:Fluorescent histochemical localization of neutral endopeptidase-24.11 (enkephalinase) in the rat brainstem. 169 88

Transcutaneous cranial electrical stimulation with Limoge's currents has been shown to facilitate anesthesia/analgesia in surgical patients. However, the neurobiologic substrate of this effect remains unknown. The present study was designed to analyze the influence of transcranial electrical stimulation (TCES) on halothane requirements in rats and the contribution of the central endogenous opioid, alpha 2-adrenergic and 5-hydroxytryptamine (5-HT1 and 5-HT2) serotonergic systems to this effect. The influence of TCES on the MAC of halothane (MACH) and its reversibility by a subcutaneous 2 mg/kg naloxone injection were first determined in 20 rats using a randomized blinded protocol. MACH was decreased markedly in stimulated animals (TCES, n = 10) in comparison with sham-operated nonstimulated rats (controls, n = 10): MACH = 0.60 +/- 0.15, mean +/- SD, versus 1.07 +/- 0.05 vol%, P less than 0.001. In TCES animals, naloxone administration restored MACH values to the levels of controls but failed to affect MACH in controls. The influence of the duration of TCES applied prior to MACH determination was further investigated in 30 animals. The magnitude of MACH reduction was significantly increased with the cumulative duration of stimulation. For each duration of stimulation tested, administration of a 5-micrograms intracerebroventricular (icv) dose of the enkephalinase inhibitor thiorphan significantly enhanced TCES effects (P less than 0.05). Finally, the icv administration of a 15-micrograms naloxone dose appeared to reverse completely the MACH reduction elicited by TCES (n = 8, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcranial electrical stimulation with Limoge's currents decreases halothane requirements in rats. Evidence for the involvement of endogenous opioids. 173 2

In unanaesthetized acupuncture-sensitive rabbit d-phenylalanine injection didn't change the EP in response to tooth pulp electrostimulation, but prolonged the analgetic effect of auriculo-acupuncture stimulation 15 Hz expressed by decreasing of the amplitude of N1P2 component EP. In acupuncture-resistant rabbit d-phenylalanine injection induced analgetic effect which was enhanced and prolonged by auriculo-acupuncture stimulation. It's suggested that the recovery of pain sensibility after acupuncture analgesia is determined by enkephalinase's mechanism activation which is activated permanently in acupuncture-resistant rabbits.
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PMID:[Action of an enkephalinase blocker on the effect of acupuncture in acupuncture sensitive and resistant rabbits]. 177 10

The enkephalinase inhibitor thiorphan was infused intracerebroventricularly in rats during 14 days (25 micrograms/5 microliters/hr), inducing an average inhibition of cerebral enkephalinase of about 65%. Animals were tested during the infusion for their response to acetorphan, a parenterally active derivative of thiorphan. When administered intravenously on day 8 of the infusion, acetorphan (5 mg/kg) significantly increased locomotion in chronic saline-infused rats but not in animals receiving thiorphan. Furthermore, when injected at the same dose on day 10, acetorphan did not modify the latency to jump, in the hot plate test, in thiorphan-treated rats, whereas it elicited a significant analgesia in chronic saline-treated controls. These data show that the effects induced by the administration of an enkephalinase inhibitor were diminished after a period of chronic inhibition of the enzyme, suggesting the development of tolerance.
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PMID:Chronic inhibition of enkephalinase induces changes in the antinociceptive and locomotor effects of the enkephalinase inhibitor acetorphan in rats. 178 43

The aim of the present study was to investigate if a physical dependence could be induced by chronic activation of the endogenous enkephalinergic system. We have therefore evaluated naloxone-induced withdrawal syndrome in rats after central infusion during 7 days of comparable antinociceptive doses of RB 38 A ((R,S)HONH-CO-CH2-CH(CH2C6H5)-CONH-CH(CH2C6H5)-COOH), a mixed enkephalin catabolism blocker and of the selective mu, DAGO (Tyr-D-Ala-Gly-(Me)Phe-Gly-ol) and delta, DSTBULET (Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr), opioid agonists. The responses were compared to those induced by RB 38 B ((S,S)HONH-CO-CH2-CH(CH2C6H5)-CONH-CH(CH2C6H5)-COOH), a selective inhibitor of the 24.11 neutral endopeptidase (NEP) 'enkephalinase'. DAGO induced a severe withdrawal syndrome evidenced by a large weight loss, hypothermia, jumping, mastication, teeth chattering, diarrhoea, lacrimation and salivation. In contrast, DSTBULET and RB 38 A produced only a moderate physical dependence. Only two signs were statistically different in these two groups: wet dog shakes and temperature. Chronic i.c.v. administration of DAGO, DSTBULET and RB 38 A produced a time-dependent reduction in analgesia, but 120 h after continuous infusion only RB 38 A was able to still induce a significative antinociceptive effect. The present data suggest that even in the drastic conditions used here long-term complete inhibition of enkephalin catabolism induces a weak tolerance and a moderate physical dependence, similar to that produced by delta opioid agonists. This effect was not observed after chronic selective inhibition of NEP by RB 38 B.
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PMID:Differences in physical dependence induced by selective mu or delta opioid agonists and by endogenous enkephalins protected by peptidase inhibitors. 216 53

Transplants of adrenal medullary tissue or isolated chromaffin cells into the spinal cord subarachnoid space has been shown to reduce pain sensitivity in rats. This analgesia probably results from the release of neuroactive substances, particularly opioid peptides, from the transplanted cells since it is induced by nicotinic stimulation of chromaffin cell receptors, and can be blocked by naloxone. However, this analgesia is short-lived, most likely due to the rapid hydrolysis of opioid peptides. The purpose of this study was to determine whether protection of opioid peptide hydrolysis by the potent enkephalinase inhibitor kelatorphan could prolong this analgesia. Results indicated that the intrathecal injection of kelatorphan in animals with either adrenal medullary or chromaffin cell implants significantly prolonged nicotine-stimulated analgesia. Pretreatment with naloxone completely eliminated this analgesia. These results suggest that it may be possible to induce long-term reductions in pain sensitivity using enkephalinase inhibitors following the transplantation of opioid peptide-producing cells into the CNS.
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PMID:Prolonged analgesia by enkephalinase inhibition in rats with spinal cord adrenal medullary transplants. 236 94

Application of tail-pinch stress to the terrestrial slug, Arion ater, produced a significant increase in the response time when tested on the hot-plate for foot-lifting response. The analgesia was completely reversed by injections of the opiate antagonists, naltrexone and ICI 174864, in a dose-dependent manner. Analgesia could also be elicited by the injection into the foot of beta-endorphin and the enkephalin analogues, DAGO and DADLE. No effect was seen with dynorphin A (1-8) or dynorphin A (1-17). The stress-induced analgesia disappeared after 30 minutes but could be maintained for 100 min following the injection of a mixture of bestatin and the enkephalinase inhibitor, N-carboxymethyl-L-phenylalanyl-L-leucine. This work suggests that in the slug, a physical stressor produces an analgesia which may be due to the release of endogenous opiates.
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PMID:The involvement of opioid peptides in stress-induced analgesia in the slug Arion ater. 256 26

The analgesic effects of very low current transcranial electrostimulation are naloxone-reversible and thus presumably mediated by endogenous opioid activity. The present experiments indicate that blocking enkephalinase activity by i.c.v. thiorphan or i.p. acetorphan results in an increased analgesic effect of electrostimulation as measured by the 50 degrees C wet tail flick test. In the case of each drug, rats receiving both drug and electrostimulation displayed significantly more analgesia than rats receiving electrostimulation and injection vehicle alone, rats receiving drug and sham stimulation or rats receiving vehicle and sham stimulation.
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PMID:Augmented analgesic effects of enkephalinase inhibitors combined with transcranial electrostimulation. 271 74


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