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Volumn 325, Issue 2-3, 1997, Pages 155-164

In mononeuropathic rats, the enhancement of morphine antinociception by L-365,260, a selective CCK(B) receptor antagonist, depends on the dose of systemic morphine and stimulus characteristics

Author keywords

260; Antinociception; CCK(B); L 365; Mononeuropathic rat; Morphine; Naloxone; Receptor antagonist; Struggle latency; Vocalization threshold

Indexed keywords

1 (2,3 DIHYDRO 1 METHYL 2 OXO 5 PHENYL 1H 1,4 BENZODIAZEPIN 3 YL) 3 (3 METHYLPHENYL)UREA; CHOLECYSTOKININ RECEPTOR; CHOLECYSTOKININ RECEPTOR BLOCKING AGENT; MORPHINE; NALOXONE;

EID: 19244368994     PISSN: 00142999     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0014-2999(97)00123-4     Document Type: Article
Times cited : (28)

References (46)
  • 1
    • 0026549204 scopus 로고
    • Antinociceptive effects of acute and chronic injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats
    • Ardid, D. and G. Guilbaud, 1992, Antinociceptive effects of acute and chronic injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats, Pain 49, 279.
    • (1992) Pain , vol.49 , pp. 279
    • Ardid, D.1    Guilbaud, G.2
  • 2
    • 0025370633 scopus 로고
    • Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy
    • Attal, N., F. Jazat, V. Kayser and G. Guilbaud, 1990, Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy, Pain 41, 235.
    • (1990) Pain , vol.41 , pp. 235
    • Attal, N.1    Jazat, F.2    Kayser, V.3    Guilbaud, G.4
  • 3
    • 0026010636 scopus 로고
    • Behavioral evidence that systemic morphine may modulate a phasic pain-related behavior in a rat model of peripheral mononeuropathy
    • Attal, N., Y.L. Chen, V. Kayser and G. Guilbaud, 1991, Behavioral evidence that systemic morphine may modulate a phasic pain-related behavior in a rat model of peripheral mononeuropathy, Pain 47, 65.
    • (1991) Pain , vol.47 , pp. 65
    • Attal, N.1    Chen, Y.L.2    Kayser, V.3    Guilbaud, G.4
  • 4
    • 0020033595 scopus 로고
    • Distribution of cholecystokinin (CCK) in the rat lower brain stem nuclei
    • Beinfeld, M.C. and M. Palkovits, 1982, Distribution of cholecystokinin (CCK) in the rat lower brain stem nuclei, Brain Res. 238, 260.
    • (1982) Brain Res. , vol.238 , pp. 260
    • Beinfeld, M.C.1    Palkovits, M.2
  • 5
    • 0019497036 scopus 로고
    • The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay
    • Beinfeld, M.C., D.K. Meyuer, R.L. Eskay, R.T. Jensen and M.J. Brownstein, 1981, The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay, Brain Res. 212, 51.
    • (1981) Brain Res. , vol.212 , pp. 51
    • Beinfeld, M.C.1    Meyuer, D.K.2    Eskay, R.L.3    Jensen, R.T.4    Brownstein, M.J.5
  • 6
    • 0023895875 scopus 로고
    • A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
    • Bennett, G.J. and Y.K. Xie, 1988, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 33, 87.
    • (1988) Pain , vol.33 , pp. 87
    • Bennett, G.J.1    Xie, Y.K.2
  • 7
    • 0028016036 scopus 로고
    • Mu and delta opioid receptors mediate opposite modulation by morphine of the spinal release of cholecystokinin-like material
    • Benoliel, J.J., E. Collin, A. Mauborgne, S. Bourgoin, J.C. Legrand, M. Hamon and F. Cesselin, 1994, Mu and delta opioid receptors mediate opposite modulation by morphine of the spinal release of cholecystokinin-like material, Brain Res. 653, 81.
    • (1994) Brain Res. , vol.653 , pp. 81
    • Benoliel, J.J.1    Collin, E.2    Mauborgne, A.3    Bourgoin, S.4    Legrand, J.C.5    Hamon, M.6    Cesselin, F.7
  • 8
    • 0030583714 scopus 로고    scopus 로고
    • Further evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in mononeuropathic rats: Involvement of kappa, but not delta, opioid receptors
    • Catheline, G., V. Kayser and G. Guilbaud, 1996, Further evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in mononeuropathic rats: involvement of kappa, but not delta, opioid receptors, Eur. J. Pharmacol. 315, 135.
    • (1996) Eur. J. Pharmacol. , vol.315 , pp. 135
    • Catheline, G.1    Kayser, V.2    Guilbaud, G.3
  • 9
    • 0020525719 scopus 로고
    • Ethical standards for investigations of experimental pain in animals
    • Committee for Research and Ethical Issues of the IASP, 1983, Ethical standards for investigations of experimental pain in animals, Pain 16, 109.
    • (1983) Pain , vol.16 , pp. 109
  • 10
    • 0027272042 scopus 로고
    • Selective opioid receptor agonists modulate mechanical allodynia in an animal model of neuropathic pain
    • Desmeules, J., V. Kayser and G. Guilbaud, 1993, Selective opioid receptor agonists modulate mechanical allodynia in an animal model of neuropathic pain, Pain 53, 277.
    • (1993) Pain , vol.53 , pp. 277
    • Desmeules, J.1    Kayser, V.2    Guilbaud, G.3
  • 11
    • 0029035350 scopus 로고
    • Influence of the sympathetic nervous system in the development of abnormal pain-related behaviours in a rat model of neuropathic pain
    • Desmeules, J.A., V. Kayser, J. Weil-Fuggaza, A. Bertrand and G. Guilbaud, 1995, Influence of the sympathetic nervous system in the development of abnormal pain-related behaviours in a rat model of neuropathic pain, Neuroscience 67, 941.
    • (1995) Neuroscience , vol.67 , pp. 941
    • Desmeules, J.A.1    Kayser, V.2    Weil-Fuggaza, J.3    Bertrand, A.4    Guilbaud, G.5
  • 12
    • 0023836208 scopus 로고
    • Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718
    • Dourish, C.T., D. Hawley and S.D. Iversen, 1988, Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718, Eur. J. Pharmacol. 147, 469.
    • (1988) Eur. J. Pharmacol. , vol.147 , pp. 469
    • Dourish, C.T.1    Hawley, D.2    Iversen, S.D.3
  • 13
    • 0025093603 scopus 로고
    • The selective CCK-B antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat: Evidence for mediation of CCK/opioid interactions by CCK-B receptor
    • Dourish, C.T., M.F. O'Neill, J. Coughlan, S.J. Kitchener, D. Hawley and S.D. Iversen, 1990, The selective CCK-B antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat: evidence for mediation of CCK/opioid interactions by CCK-B receptor, Eur. J. Pharmacol. 176, 35.
    • (1990) Eur. J. Pharmacol. , vol.176 , pp. 35
    • Dourish, C.T.1    O'Neill, M.F.2    Coughlan, J.3    Kitchener, S.J.4    Hawley, D.5    Iversen, S.D.6
  • 14
    • 0020681585 scopus 로고
    • Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia
    • Faris, P.L., B.R. Komisaruk, L.R. Watkins and D.J. Mayer, 1983, Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia, Science 219, 310.
    • (1983) Science , vol.219 , pp. 310
    • Faris, P.L.1    Komisaruk, B.R.2    Watkins, L.R.3    Mayer, D.J.4
  • 15
    • 0002471733 scopus 로고
    • Does hyperalgesia to cooling stimuli characterize patients with sympathetically-maintained pain (reflex sympathetic dystrophy)?
    • eds. R. Dubner, G.F. Gebhardt and M.R. Bond (Elsevier, Amsterdam)
    • Frost, S.A., S.N. Raja, J.N. Campbell and R.A. Khan, 1988, Does hyperalgesia to cooling stimuli characterize patients with sympathetically-maintained pain (reflex sympathetic dystrophy)?, in: Proceedings of the Vth World Congress of Pain, eds. R. Dubner, G.F. Gebhardt and M.R. Bond (Elsevier, Amsterdam) p. 151.
    • (1988) Proceedings of the Vth World Congress of Pain , pp. 151
    • Frost, S.A.1    Raja, S.N.2    Campbell, J.N.3    Khan, R.A.4
  • 16
    • 0025242773 scopus 로고
    • Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy
    • Guilbaud, G., J.-M. Benoist, F. Jazat and M. Gautron, 1990, Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy, J. Neurophysiol. 64, 1537.
    • (1990) J. Neurophysiol. , vol.64 , pp. 1537
    • Guilbaud, G.1    Benoist, J.-M.2    Jazat, F.3    Gautron, M.4
  • 17
    • 0019984785 scopus 로고
    • Caerulein and cholecystokinin suppress β-endorphin-induced analgesia in the rat
    • Itoh, S., G. Katsuura and Y. Maeda, 1982, Caerulein and cholecystokinin suppress β-endorphin-induced analgesia in the rat, Eur. J. Pharmacol. 80, 421.
    • (1982) Eur. J. Pharmacol. , vol.80 , pp. 421
    • Itoh, S.1    Katsuura, G.2    Maeda, Y.3
  • 18
    • 0026099124 scopus 로고
    • The 'tonic' pain-related behaviour seen in mononeuropathic rats is modulated by morphine and naloxone
    • Jazat, F. and G. Guilbaud, 1991, The 'tonic' pain-related behaviour seen in mononeuropathic rats is modulated by morphine and naloxone, Pain 44, 97.
    • (1991) Pain , vol.44 , pp. 97
    • Jazat, F.1    Guilbaud, G.2
  • 19
    • 0020621399 scopus 로고
    • The analgesic effects of morphine, but not those of the enkephalinase inhibitor thiorphan, are enhanced in arthritic rats
    • Kayser, V. and G. Guilbaud, 1983, The analgesic effects of morphine, but not those of the enkephalinase inhibitor thiorphan, are enhanced in arthritic rats, Brain Res. 267, 131.
    • (1983) Brain Res. , vol.267 , pp. 131
    • Kayser, V.1    Guilbaud, G.2
  • 20
    • 0028945541 scopus 로고
    • Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy
    • Kayser, V., J. Desmeules and G. Guilbaud, 1995a, Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy, Pain 60, 275.
    • (1995) Pain , vol.60 , pp. 275
    • Kayser, V.1    Desmeules, J.2    Guilbaud, G.3
  • 21
    • 0028887593 scopus 로고
    • Evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in rats with peripheral mononeuropathy
    • Kayser, V., S.H. Lee and G. Guilbaud, 1995b, Evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in rats with peripheral mononeuropathy, Neuroscience 64, 537.
    • (1995) Neuroscience , vol.64 , pp. 537
    • Kayser, V.1    Lee, S.H.2    Guilbaud, G.3
  • 24
    • 0028365663 scopus 로고
    • Differential action of morphine and various opioid agonists on thermal allodynia and hyperalgesia in mononeuropathic rats
    • Lee, S.H., V. Kayser, J. Desmeules and G. Guilbaud, 1994, Differential action of morphine and various opioid agonists on thermal allodynia and hyperalgesia in mononeuropathic rats, Pain 57, 233.
    • (1994) Pain , vol.57 , pp. 233
    • Lee, S.H.1    Kayser, V.2    Desmeules, J.3    Guilbaud, G.4
  • 25
    • 0000199819 scopus 로고
    • Classification of chronic pain. Descriptions of chronic pain syndromes and definition for terms. Prepared by IASP Sub-Committee on Taxonomy
    • Merskey, H., 1986, Classification of chronic pain. Descriptions of chronic pain syndromes and definition for terms. Prepared by IASP Sub-Committee on Taxonomy, Pain (Suppl. 3), S1.
    • (1986) Pain , Issue.3 SUPPL.
    • Merskey, H.1
  • 26
    • 0022657202 scopus 로고
    • Two brain cholecystokinin receptors: Implications for behavioral actions
    • Moran, T.H., P.M. Robinson, M.S. Goldrich and P.R. McHugh, 1986, Two brain cholecystokinin receptors: implications for behavioral actions, Brain Res. 362, 175.
    • (1986) Brain Res. , vol.362 , pp. 175
    • Moran, T.H.1    Robinson, P.M.2    Goldrich, M.S.3    McHugh, P.R.4
  • 27
    • 0025353776 scopus 로고
    • Repeated low doses of morphine do not induce tolerance but increase the opioid antinociceptive effect in rats with a peripheral neuropathy
    • Neil, A., V. Kayser, G. Chen, G. Guilbaud, 1990, Repeated low doses of morphine do not induce tolerance but increase the opioid antinociceptive effect in rats with a peripheral neuropathy. Brain Res. 522, 140.
    • (1990) Brain Res. , vol.522 , pp. 140
    • Neil, A.1    Kayser, V.2    Chen, G.3    Guilbaud, G.4
  • 28
    • 0025987264 scopus 로고
    • Effects of guanethidine on sensitization to natural stimuli and self-mutilating behaviour in rats with a peripheral neuropathy
    • Neil, A., N. Attal and G. Guilbaud, 1991, Effects of guanethidine on sensitization to natural stimuli and self-mutilating behaviour in rats with a peripheral neuropathy, Brain Res. 565, 237.
    • (1991) Brain Res. , vol.565 , pp. 237
    • Neil, A.1    Attal, N.2    Guilbaud, G.3
  • 29
    • 0029554222 scopus 로고
    • Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats
    • Nichols, M.L., D. Bian, M.H. Ossipov, J. Lai and F. Porreca, 1995, Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats, J. Pharmacol. Exp. Ther. 275, 1339.
    • (1995) J. Pharmacol. Exp. Ther. , vol.275 , pp. 1339
    • Nichols, M.L.1    Bian, D.2    Ossipov, M.H.3    Lai, J.4    Porreca, F.5
  • 30
    • 0026754744 scopus 로고
    • Traitement pharmacologique de la douleur neuropathique
    • Ollat, H., 1992, Traitement pharmacologique de la douleur neuropathique, Rev. Neurol. (Paris) 148, 521.
    • (1992) Rev. Neurol. (Paris) , vol.148 , pp. 521
    • Ollat, H.1
  • 31
    • 0024507977 scopus 로고
    • Morphine-induced analgesia in the rat paw pressure test is blocked by CCK and enhanced by the CCK antagonist MK-329
    • O'Neill, M.F., C.T. Dourish and S.D. Iversen, 1989, Morphine-induced analgesia in the rat paw pressure test is blocked by CCK and enhanced by the CCK antagonist MK-329, Neuropharmacology 28, 243.
    • (1989) Neuropharmacology , vol.28 , pp. 243
    • O'Neill, M.F.1    Dourish, C.T.2    Iversen, S.D.3
  • 32
    • 0027944479 scopus 로고
    • Naltrindole, an opioid 8 antagonist, blocks the enhancement of morphine-antinociception induced by a CCK-B antagonist in the rat
    • Ossipov, M., C.J. Kovelowski, T. Vanderah and F. Porreca, 1994, Naltrindole, an opioid 8 antagonist, blocks the enhancement of morphine-antinociception induced by a CCK-B antagonist in the rat, Neurosci. Lett. 181, 9.
    • (1994) Neurosci. Lett. , vol.181 , pp. 9
    • Ossipov, M.1    Kovelowski, C.J.2    Vanderah, T.3    Porreca, F.4
  • 33
    • 0023001748 scopus 로고
    • Neuropathic pain syndromes, with special reference to causalgia and reflex sympathetic dystrophy
    • Payne, R., 1986, Neuropathic pain syndromes, with special reference to causalgia and reflex sympathetic dystrophy, Clin. J. Pain 2, 59.
    • (1986) Clin. J. Pain , vol.2 , pp. 59
    • Payne, R.1
  • 34
    • 0027390069 scopus 로고
    • Are mechanical and cold allodynia in mononeuropathic and arthritic rats relieved by systemic treatment with calcitonin or guanethidine?
    • Perrot, S., N. Attal, D. Ardid and G. Guilbaud, 1993, Are mechanical and cold allodynia in mononeuropathic and arthritic rats relieved by systemic treatment with calcitonin or guanethidine?, Pain 52, 41.
    • (1993) Pain , vol.52 , pp. 41
    • Perrot, S.1    Attal, N.2    Ardid, D.3    Guilbaud, G.4
  • 35
    • 0023720087 scopus 로고
    • The novel CCK antagonist L364,718 abolishes caerulein- But potentiates morphine-induced antinociception
    • Rattray, M., C.C. Jordan and J. De Belleroche, 1988, The novel CCK antagonist L364,718 abolishes caerulein- but potentiates morphine-induced antinociception, Eur. J. Pharmacol. 152, 163.
    • (1988) Eur. J. Pharmacol. , vol.152 , pp. 163
    • Rattray, M.1    Jordan, C.C.2    De Belleroche, J.3
  • 36
    • 0030056472 scopus 로고    scopus 로고
    • Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine
    • Singh, L., R.J. Oles, M.J. Field, P. Atwal, G.N. Woodruff and J.C. Hunter, 1996, Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine, Br. J. Pharmacol. 118, 1317.
    • (1996) Br. J. Pharmacol. , vol.118 , pp. 1317
    • Singh, L.1    Oles, R.J.2    Field, M.J.3    Atwal, P.4    Woodruff, G.N.5    Hunter, J.C.6
  • 38
    • 0019817258 scopus 로고
    • Localization and opiate receptor binding of enkephalin, CCK and ACTH/β-endorphin in the rat central nervous system
    • Stengaard-Pedersen, K. and L.-I. Larsson, 1981, Localization and opiate receptor binding of enkephalin, CCK and ACTH/β-endorphin in the rat central nervous system, Peptides 2 (Suppl. 1), 3.
    • (1981) Peptides , vol.2 , Issue.1 SUPPL. , pp. 3
    • Stengaard-Pedersen, K.1    Larsson, L.-I.2
  • 39
    • 0016737525 scopus 로고
    • New peptide in the vertebrate central nervous system reacting with gastrin antibodies
    • Vanderhaeghen, J.-J., J.C. Signeau and W. Gepts, 1975, New peptide in the vertebrate central nervous system reacting with gastrin antibodies, Nature 257, 604.
    • (1975) Nature , vol.257 , pp. 604
    • Vanderhaeghen, J.-J.1    Signeau, J.C.2    Gepts, W.3
  • 40
    • 0026559686 scopus 로고
    • Purification, molecular cloning and functional expression of the cholecystokinin receptor from rat pancreas
    • Wank, S.A., R. Harkins, R.T. Jensen, H. Shapira, A. Weerth and T. Slattery, 1992, Purification, molecular cloning and functional expression of the cholecystokinin receptor from rat pancreas, Proc. Natl. Acad. Sci. USA 89, 3125.
    • (1992) Proc. Natl. Acad. Sci. USA , vol.89 , pp. 3125
    • Wank, S.A.1    Harkins, R.2    Jensen, R.T.3    Shapira, H.4    Weerth, A.5    Slattery, T.6
  • 41
    • 0025076926 scopus 로고
    • PD 134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes
    • Wiesenfeld-Hallin, Z., X.-J. Xu, J. Hughes, D.C. Horwell and T. Hökfelt, 1990, PD 134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes, Proc. Natl. Acad. Sci. USA 87, 7105.
    • (1990) Proc. Natl. Acad. Sci. USA , vol.87 , pp. 7105
    • Wiesenfeld-Hallin, Z.1    Xu, X.-J.2    Hughes, J.3    Horwell, D.C.4    Hökfelt, T.5
  • 42
    • 0027175963 scopus 로고
    • Up-regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat
    • Xu, X.-J., M.J.C. Puke, V.M.K. Verge, Z. Wiesenfeld-Hallin, J. Hughes and T. Hökfelt, 1993, Up-regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat, Neurosci. Lett. 152, 129.
    • (1993) Neurosci. Lett. , vol.152 , pp. 129
    • Xu, X.-J.1    Puke, M.J.C.2    Verge, V.M.K.3    Wiesenfeld-Hallin, Z.4    Hughes, J.5    Hökfelt, T.6
  • 43
    • 0028278671 scopus 로고
    • Chronic pain-related behaviors in spinally injured rats: Evidence for functional alterations of the endogenous cholecystokinin and opioid systems
    • Xu, X.-J., J.-X. Hao, A. Seiger, J. Hughes, T. Hökfelt and Z. Wiesenfeld-Hallin, 1994, Chronic pain-related behaviors in spinally injured rats: evidence for functional alterations of the endogenous cholecystokinin and opioid systems, Pain 56, 271.
    • (1994) Pain , vol.56 , pp. 271
    • Xu, X.-J.1    Hao, J.-X.2    Seiger, A.3    Hughes, J.4    Hökfelt, T.5    Wiesenfeld-Hallin, Z.6
  • 44
    • 0029611202 scopus 로고
    • Role of cholecystokinin-B receptor in the maintenance of thermal hyperalgesia induced by unilateral constriction injury to the sciatic nerve in the rat
    • Yamamoto, T. and N. Nozaki-Tguchi, 1995, Role of cholecystokinin-B receptor in the maintenance of thermal hyperalgesia induced by unilateral constriction injury to the sciatic nerve in the rat, Neurosci. Lett. 202, 89.
    • (1995) Neurosci. Lett. , vol.202 , pp. 89
    • Yamamoto, T.1    Nozaki-Tguchi, N.2
  • 46
    • 0007724016 scopus 로고
    • Peripheral and central nervous mechanisms of nociception, pain and pain therapy: Facts and hypotheses
    • eds. J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Raven Press, New York, NY)
    • Zimmermann, M., 1979, Peripheral and central nervous mechanisms of nociception, pain and pain therapy: facts and hypotheses, in: Proceedings of the 2nd World Congress of Pain, eds. J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Raven Press, New York, NY) p. 3.
    • (1979) Proceedings of the 2nd World Congress of Pain , pp. 3
    • Zimmermann, M.1


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